Rare Diseases Report
FY 2001

National Heart, Lung, and Blood Institute


Overview of NLHBI Rare Diseases Research Activities

NHLBI provides leadership for a national program in the causes, diagnosis, treatment, and prevention of diseases of the heart, blood vessels, lungs, and blood, and sleep disorders, and in the uses of blood and the management of blood resources. It conducts and supports, through research in its own laboratories and through extramural research grants and contracts, an integrated and coordinated program that includes basic investigations, clinical trials, epidemiological studies, and demonstration and education projects.

Although the major part of the research supported by NHLBI addresses common conditions such as hypertension, coronary heart disease, and chronic obstructive pulmonary disease, a significant amount of research is devoted to rare diseases in children and adults. NHLBI activities related to rare disease research in fiscal year (FY) 2001 are described below.

Recent Scientific Advances in Research on Rare Disease

Heart and Vascular Diseases Program


Abetalipoproteinemia is a recessive disorder characterized by the absence of apoprotein B-containing lipoproteins from plasma. Fat malabsorption is severe and triglyceride accumulation occurs. Acanthocytosis, a rare condition in which the majority of red blood cells have multiple spiny cytoplasmic projections, is common. Additional symptoms appear to be secondary to defects in the transport of vitamin E in blood. Projects using genetic, biochemical, and metabolic approaches to study various aspects of the disease were underway in four grants in FY 2001. The disorder appears to be related to abnormal processing of apolipoprotein B (apoB) due to an absence of the microsomal triglyceride transfer protein (MTP). In FY 2001, studies indicated that MTP is implicated in both apoB lipoprotein and triglyceride secretion. Cells lacking the ability to make MTP are unable to assemble and secrete apoB-containing lipoproteins. However, when MTP production is rectified (through appropriate transfection), apoB-containing lipoproteins are once more assembled and secreted.

Antiphospholipid Syndrome (APS)

APS is characterized by the presence of circulating autoantibodies to certain phospholipids (lipids containing phosphorus). It is clinically manifested by recurrent blood clotting disorders, a history of fetal deaths, and autoimmune diseases such as thrombocytopenia. One NHLBI-supported grant is engaged in efforts to develop more standardized imunoassays that will reliably detect individual antiphospholipid antibodies and is also investigating the role of the syndrome in atherogenesis. Circulating antibodies to oxidized phospholipids, particularly cardiolipin, were found in FY 2001 to correlate with the presence of isoprostanes, strong biomarkers for atherogenesis and a means of indicating the extent of atherosclerosis. Genes of autoantibodies that were cloned on the basis of their ability to bind to oxidized phospholipids have been discovered to play an important role in atherogenesis and to confer protection against certain bacterial infections.

Arrhythmogenic Right Ventricular Dysplasia (ARVD)

ARVD is a family of rare cardiomyopathies that results in sudden cardiac death and heart rhythm disturbances including fibrillation. Most forms are believed to be due to the inheritance of autosomal dominant mutations in genes whose identities remain largely unknown but that clearly affect myocardial integrity. ARVD is characterized by marked, selective, right ventricular dilatation, myocardial cell death, and cell replacement with fat cells and fibrous tissue. Expression in gene carriers is variable, but in those who display symptoms the outcome is frequently lethal. NHLBI supports work on ARVD at one of its Specialized Centers of Research (SCOR) in Sudden Cardiac Death and sponsors a network of three separate groups to investigate causes of familial forms of ARVD and genotpye-phenotype relationships. In FY 2001 the SCOR investigators identified a candidate gene product for a Neuroblastoma apoptosis-related RNA-binding protein that may correspond to a chromosomal mutation identified earlier as being common to patients with the congenital form of ARVD.

Bartter's Syndrome

Bartter's syndrome, a rare autosomal recessive disease, typically manifests itself through salt imbalance and low blood pressure. Research on Bartter’s syndrome is currently being pursued as a part of the NHLBI SCOR program in the Molecular Genetics of Hypertension. The discovery that a mutation in an ATP-sensitive K channel can lead to Bartter’s syndrome establishes the genetic heterogeneity of the disease and demonstrates that this K channel may be an important regulator of blood pressure, ion balance, and fluid balance.


Beta-sitosterolemia is a rare inborn error of metabolism characterized by increased absorption of dietary cholesterol and plant and shellfish sterols. Patients with beta-sitosterolemia have a markedly increased risk of premature cardiovascular disease. Effective treatment is not available at present, although a number of drugs are under development. NHLBI supports research into beta-sitosterolemia through its intramural Molecular Diseases Branch and its extramural grant programs. One NHLBI-supported investigator at the Medical University of South Carolina, who is investigating the molecular mechanisms of cholesterol absorption and excretion in families with beta-sitosterolemia, has identified two separate defective genes. Additional research is identifying specific ABCG sterol transporter protein mutations in affected families.

Brugada's Syndrome

Brugada’s syndrome is a rare inherited disorder characterized by cardiac electrophysiological abnormalities – specifically, right bundle branch block and ST elevation in the precordial leads – and is associated with a high occurrence of sudden cardiac death. The condition is currently believed to be similar in cause and potential treatment to some forms of the long QT syndrome. Both appear to be caused by mutations at different locations in the SCN5A cardiac muscle sodium ion channel gene and by resulting aberrations in depolarization and repolarization of these cells. One NHLBI-supported study demonstrated in FY 2001 that distinct mutations within a single residue of SCN5A can give rise to either Brugada syndrome (tyrosine to histidine mutation) or to long QT syndrome (tyrosine to cysteine mutation) adding evidence for a close relationship between these disorders.

Congenital Heart Disease

Congenital heart disease affects about 8 in 1,000 live-born infants (32,000 per year in the US), making it the most common birth defect. Abnormal formation of the embryonic heart results in both structural and functional heart defects. It is an important cause of infant mortality, pediatric and adult morbidity, and shortened adult life expectancy. About one-third of affected infants and children require open heart surgery or interventional cardiac catheterization to repair or ameliorate their defects. Approximately the same proportion have associated extracardiac anomalies such as chromosomal abnormalities and syndromes involving other organ systems.

NHLBI has supported research in pediatric cardiovascular medicine since it first funded heart research grants in 1949. Researchers supported by NHLBI have been instrumental in developing diagnostic imaging techniques, including fetal imaging; surgical techniques, including various operations and refinements in cardiopulmonary bypass; and medical therapies now used to ensure healthy survival for most affected children. They have also made significant contributions to the epidemiology of congenital heart disease and to understanding the molecular and genetic basis of normal and abnormal heart development.

A key finding from NHLBI-funded researchers this year was the identification of a new gene, Bop, that is the primary controller in a cascade of genetic events that lead to the development of heart ventricles in mouse embryos. This finding may eventually lead to understanding ventricular malformations in humans.

DiGeorge Syndrome

DiGeorge syndrome occurs with an estimated frequency of 1 in 4,000 live births. It is characterized by many abnormalities, including cardiac outflow tract anomalies, hypoplasia of the thymus and parathyroid glands, cleft palate, facial dysmorphogenesis, learning difficulties, and other neurodevelopmental deficits. It is usually sporadic, but may be inherited, and is caused by deletion of a segment of chromosome 22. The specific gene that is abnormal has not been identified. NHLBI supports both human and animal studies of DiGeorge syndrome through several grants, including two SCORs in Pediatric Cardiovascular Disease. The finding by NHLBI-funded researchers that mice with chromosomal deletions similar to those found in humans with DiGeorge syndrome have deficits in learning and memory could lead to improved treatments for psycho-developmental abnormalities in affected individuals. Such results support the need for a comprehensive therapeutic approach to children with DiGeorge syndrome, such as the team approach developed by a SCOR at the Children’s Hospital of Philadelphia.

Doxorubicin Cardiomyopathy

The generic drug, doxorubicin (brand name, Adriamycin) is a potent, broad-spectrum antitumor agent effective in treating a variety of cancers including solid tumors and leukemia. Unfortunately, its clinical use is limited by dose-dependent cardiac side effects that lead to degenerative cardiomyopathy, congestive heart failure, and death. In addition, some adult patients treated with the drug when they were children are now developing dilated cardiomyopathy. Endocardial biopsies from patients undergoing doxorubicin therapy reveal a disruption of myofibrils, impairment of microtubule assembly, and a swelling of the endoplasmic reticulum. Doxorubicin cardiotoxicity is also characterized by a dose-dependent decline in mitochondrial oxidative phosphorylation and a decrease in high-energy phosphate pools.

Several NHLBI-supported investigators have reported research advances in the past year. One has demonstrated that cardiac tissue from doxorubicin-treated rats expresses an increased tolerance for withstanding short periods of oxygen deprivation. This observation is providing novel insights into the molecular regulation of compensatory responses that may underlie the “adaptation phenomenon” that has been widely described for other types of cardiac challenge. The same investigator has observed a potential cardioprotective effect against doxorubicin-induced mitochondrial cardiomyopathy by carvedilol, a non-selective beta-blocker with alpha-1 blocking (vasodilating) and anti-oxidant properties. This promising result provides exciting opportunities for supporting clinical trials of carvedilol as protection against the debilitating side-effects of doxorubicin. This is particularly relevant in that the class of drugs known as beta-adrenergic receptor antagonists, of which carvedilol is one, are currently widely prescribed as safe and effective prophylactic measures for treating many other cardiovascular disorders, including congestive heart failure. Adding doxorubicin-induced cardiomyopathy to the list of indications for carvedilol may prove to be a highly effective means of reducing the incidence and/or severity for cardiac failure that limits the clinical success currently achievable with doxorubicin.

Another investigator is examining explicit pathways through which reactive oxygen species are involved in doxorubicin-induced cardiomyopathy. She has discovered a marked inhibition of activity of the myocardial membrane-associated enzyme phospholipase A2 by clinically relevant concentrations of doxorubicin. This novel observation suggests new means of doxorubicin action and has significant implications for elucidating the mechanisms underlying doxorubicin cardiotoxicity and pharmacological interventions to prevent it.


Dysbetalipoproteinemia is a rare disorder with a strong heritable component characterized by the presence of beta-migrating very low-density lipoprotein (VLDL). The disorder leads to the formation of characteristic yellow skin plaque (xanthomas) and predisposes to early ischemic heart disease and peripheral vascular disease. Research into the genetics and biochemical events underlying the etiology and pathophysiology of the disease is underway in two NHLBI-supported grants. A mutant form of apoprotein E (apo-E2) has been identified as the primary molecular defect in dysbetalipoproteinemia. Animal models synthesizing apo-E variants are being created to facilitate basic research. In FY 2001, animals expressing human apo-E2 were found to have significant increases in the apo-E2 content of VLDL and intermediate-density lipoproteins (IDL). High levels of apo-E2 are accompanied by higher levels of total cholesterol and plasma triglycerides.

Familial Hypercholesterolemia (FH)

FH is an inherited autosomal dominant trait characterized by elevated concentrations of low-density lipoproteins (LDL). Cholesterol derived from LDL is deposited in arteries and causes heart attacks and xanthoma lesions on tendons and skin. The defect in FH is a mutation in the gene specifying the receptor for plasma LDL. The receptors facilitate removal of LDL and, when deficient or absent, the rate of LDL removal is low, resulting in an elevated LDL level. The homozygous form of FH is rare (one in a million), but people who have it are highly prone to premature coronary heart disease. Several NHLBI grants support studies on the biochemistry, genetics, and potential treatment of the disease. A major program project supports research on various aspects of regulating LDL receptors and cholesterol levels in the blood. Genetically-manipulated animal models have been created specifically to study FH. Regulation of LDL receptor activity and other lipoprotein receptors involved in disease progression is being elucidated. Development of apheresis methods for removing excess LDL from plasma is progressing, and testing of a combination of pharmacological agents is being planned.

Familial Hypertrophic Cardiomyopathy (FHCM)

FHCM is associated with myofibrillar disarray in the heart muscle that in turn leads to fibrosis and hypertrophy (enlargement of the heart). Although patients may remain asymptomatic for some time, eventually shortness of breath, palpitations, and heart failure emerge, and sudden death ensues. Some die during childhood whereas others survive to their sixth or seventh decade. FHCM is associated with mutations in more than one protein, suggesting a heterogeneous group of disorders. During the past decade, scientists made significant progress in uncovering the genes associated with FHCM. It is known, for instance, that FHCM can be caused by many different mutations in the contractile proteins that comprise the heart wall. However, understanding of who will die suddenly or whether certain factors, such as high blood pressure or extreme stress, will trigger sudden death remains elusive. NHLBI supports research on the genetic basis and mechanisms involved through several investigator-initiated grants and in two SCORs in Heart Failure.

One SCOR program has demonstrated that simvastatin reverses cardiac hypertrophy and fibrosis in a rabbit model, and losartan reverses fibrosis in a mouse model. This is the first time that any drug has been shown effectiveness in an animal model of FHCM. Additionally, these investigators have preliminary findings that spironolactone is equally effective as a treatment, indicating that angiotensin II is involved in fibrosis and hypertrophy formation. An investigator in the second SCOR program has observed that the immunosuppressive drug, cyclosporin A, dramatically exacerbates the hypertrophic response in his mouse model of FHCM and that the calcium channel blocker, diltiazem, prevents this cyclosporin A-mediated response. He is currently assessing the effects of calcium channel blockers on the course of FHCM in mice.

Familial Hypobetalipoproteinemia (FHBL)

FHBL is an apparently autosomal dominant disorder of lipid metabolism characterized by very low levels of apoprotein B-containing lipoprotein cholesterol. One NHLBI-supported project is using genetic, biochemical, and metabolic approaches to study various aspects of the disease. In FY 2001, information gained from newly-identified families with FHBL enabled researchers to markedly narrow down the chromosome region containing the responsible genes. The most promising of the 60 genes in this narrower region are now being sequenced. Also, eight families have been identified that may have a new form of FHBL, since they have a susceptibility region near, but not in, the apoB gene on chromosome 2.

Infectious Myocarditis

Infectious myocarditis, which affects both children and adults, is an inflammation of the heart muscle that sometimes leads to progressive heart failure and the need for heart transplantation. NHLBI supports both human and animal studies of the disease. The infectious agent, Coxsackievirus B3 (CB3), is believed to be involved in many clinical cases of human myocarditis. One NHLBI-supported investigator is studying both susceptible and resistant strains of CB3 to determine the role of natural killer cells and cytokines – components of the innate immune system – in the pathology of myocarditis. The presence of certain cytokines in mice indicates that a Th1 immune response is taking place. In male mice, this response appears to be related to increased disease. Another investigator is looking at the pathogenesis of acute rheumatic fever (ARF), a consequence of group A streptococcal bacteria. Here, too, evidence supports a role for a Th1 response in the pathogenesis of the disease. Reovirus-induced myocarditis in mice provides an outstanding tool to investigate non-immune mediated myocarditis. The reovirus (reo is an acronym for respiratory enteric orphan) is a naturally occurring virus that is believed to cause mild infections of the upper respiratory and gastrointestinal tract of humans. Studies have shown that viral RNA synthesis in cardiac myocytes is a determinant of reovirus-induced myocarditis. Furthermore, genetic analysis of reoviruses that cause myocarditis has implicated several specific viral genes.

Klippel-Trenaunay-Weber Syndrome (KTWS)

KTWS is a very rare vascular deformation disease involving capillary, lymphatic, and venous channels. It usually manifests as cutaneous port-wine capillary malformations, varicose veins, and enlargement of soft tissues and bone in one limb. KTWS symptoms are usually present at birth, with 75 percent of patients having symptoms before the age of 10. A molecular approach to characterizing the genes that contribute to KTWS is being taken in an NHLBI-supported grant at the Cleveland Clinic Foundation. The investigator proposes that KTWS pathogenesis involves the disruption of key genes for vascular morphogenesis during embryonic development. He has characterized a KTS translocation involving chromosomes 5 and 11 and identified a novel vascular gene as the strong candidate gene for KTWS.

Long QT Syndrome (LQTS)

LQTS is characterized clinically by a prolonged QT segment on an electrocardiograph and is associated with syncope, ventricular arrhythmias, and sudden cardiac death. This family of related diseases is believed to be caused by alterations in the cardiac cell action potential induced by mutations in at least six cardiac ion channel genes. NHLBI currently supports research on LQTS through a SCOR on Sudden Cardiac Death and through numerous individual grants that address the various molecular, clinical, and genetic bases of the condition. One NHLBI-supported study identified in FY 2001 mutations in the genes encoding the beta adrenergic receptors that may be associated with acquired LQTS, thus indicating a possible role for non-channel proteins in contributing to the development of arrhythmias and sudden death.

Niemann-Pick Type C Disease (NPC)

NPC is an autosomal recessive, lipid-storage disorder that is usually characterized by excessive accumulation of cholesterol in the liver, spleen, and other vital organs. Patients have cardiovascular disease, enlargement of the liver and spleen (hepatosplenomegaly), and severe progressive neurological dysfunction. Biochemical analyses of NPC cells suggest an impairment in the intracellular transport of cholesterol to post-lysosomal destinations. The gene deficiency in Niemann-Pick disease types A and B has been identified as sphingomyelinase. The gene deficiency in types C and D has been identified as the NPC-1 protein, but few clues regarding its potential function(s) have been derived. Two NHLBI grants and a subproject in a SCOR program support research to study the regulation of intracellular cholesterol movement that leads to cholesterol accumulation in NPC disease.

The accumulation of cholesterol in NPC results from an imbalance in the flow of cholesterol among membrane compartments. Characterization of a putative cholesterol sensor in the plasma membrane that affects cholesterol trafficking into or out of cells is underway. The gene deficiency in NPC that encodes a cholesterol-binding protein has been identified. These new data will help fill a major gap in current understanding of cholesterol transport in the cell. Building on our knowledge of how cholesterol gets into lysosomes and what happens after lipid reaches the endoplasmic reticulum (ER), researchers now face the challenge of elucidating how cholesterol gets out of the lysosomes and into the ER.

Smith-Lemli-Opitz Syndrome (SLOS)

SLOS is an inherited autosomal recessive disorder caused by a defect in the enzyme that catalyzes the last step in cholesterol biosynthesis. As a result, endogenous cholesterol synthesis is inadequate to meet biological demands for functions such as membrane structure and bile acid synthesis, and the precursor 7-dehydrocholesterol and its derivatives accumulate. Newborns with SLOS have a distinctive facial dysmorphism; suffer from multiple congenital anomalies including cleft palate, congenital heart disease, genitourinary abnormalities, and malformed limbs; and exhibit severe developmental delays, digestive difficulties, and behavioral problems. The syndrome is thought to account for many previously unexplained cases of mental retardation. During FY 2001 NHLBI supported two investigator-initiated grants whose research foci are relevant to SLOS. One is conducting basic studies in sterol balance and lipid metabolism on 50 infants with SLOS. The study is also investigating the effectiveness of cholesterol-supplemented baby formula in ameliorating some of the behavioral and digestive symptoms of SLOS, and the effectiveness of simvastatin therapy in lowering the plasma concentrations of toxic forms of abnormal cholesterol precursor compounds. Intermediate evaluation of progress indicates that infants tolerate the treatments well. The second grant, which ended in FY 2001, focused on basic analytical chemistry aspects of SLOS in the hope of developing an improved diagnostic test. Diagnostic and screening tests for SLOS are based on the presence of abnormally high levels of certain compounds from the sterol biosynthesis pathway that build up due to a lack of needed enzymes. Improved chemistry methods developed with support from this grant have led to improved separation of these compounds and more accurate determination of their concentrations in blood and other biological fluids, such as amniotic fluid.

Tangier Disease

Tangier disease is a rare syndrome characterized by a deficiency of high-density lipoprotein (HDL), mild hypertriglyceridemia, neurologic abnormalities, and massive cholesterol ester deposits in various tissues, such as the tonsils. The disease is inherited as an autosomal co-dominant trait and appears due to hypercatabolism rather than a defect in HDL synthesis. A member of the ATP-binding cassette (ABC) transporter family, human ABCA1, located on chromosome 9 has been identified as the defective gene. ABCA1 is conceived as the gatekeeper for eliminating excess cholesterol from tissues and therefore key in determining the amount of cholesterol accumulating in the artery wall. Research on the cell biology and biochemistry of the human ABCA1 and its role in the disease is underway in two NHLBI-supported studies. In FY 2001, these studies found that unsaturated fatty acids reduce macrophage ABCA1 content by enhancing its degradation rate. Also, ABCA1 was shown to be responsible for the transport of a-tocopherol from cells.

The NHLBI intramural Molecular Disease Branch also has been actively studying Tangier disease for a number of years and announced five major findings in FY 2001:

(1) The complete genomic sequence and the regulatory elements modulating gene expression have been determined for the ABCA1 transporter,

(2) ABCA1 transgenic mice have been developed to study the mechanisms involved in the removal of excess cholesterol from cells,

(3) the ABCA1 transporter has been shown to recycle from the cell surface to a late endocytic compartment establishing a new pathway for the transport of intracellular cholesterol to the cell membrane for removal by HDL,

(4) the specific plasma apolipoproteins in HDL which act as acceptors for cholesterol removed from cells mediated by the ABCA1 transporter have been identified and the molecular structural requirements to function as cholesterol acceptors have been elucidated, and

(5) Overexpression of the ABCA1 transporter in mice results in a marked decrease in diet induced atherosclerosis indicating that the development of drugs to upregulate the expression of the ABCA1 transporter may be a new approach to the treatment of cardiovascular disease.

Lung Diseases Program

Advanced Sleep Phase Syndrome (ASPS)

ASPS is a rare, genetically-based sleep disorder characterized by an early evening onset of sleep, normal sleep duration, and spontaneous early awakening. NHLBI supports basic research to elucidate the neural pathways through which the biological clock mechanism regulates sleep; clinical research to elucidate genetic risk factors; and applied research on the role of the biological clock in disturbed sleep and alertness of shift workers, school-age children, and drowsy drivers.

Alpha-1 Antitrypsin (AAT) Deficiency

AAT deficiency is an inherited deficiency of a circulating proteinase inhibitor that is manufactured primarily in the liver. Deficiency states (circulating serum AAT levels below 0.6 mg/ml) are associated with emphysema, presumably from inadequate protection against enzymatic destruction by neutrophil elastase. Fifteen percent of the AAT-deficient population also develop liver disease. NHLBI funds a variety of clinical and basic research on AAT deficiency, including studies of the molecular mechanisms that impair secretion of AAT, methods of gene therapy delivery, and how to increase the availability of defective, but partially active, AAT. NHLBI-supported investigators are defining the abnormalities and degradation pathways of the AAT protein, characterizing the inflammation that leads to disease in various AAT deficiency states, and evaluating the possibility of treating the disease with drugs that would enhance the release of partially active mutant protein from liver cells. A genetics study of families is seeking to identify other genes that may modify the nature and severity of the disease as expressed in different individuals. In addition to research that specifically focuses on AAT, NHLBI supports related studies addressing the general causation of emphysema; the function, synthesis, secretion, and interaction of the enzymes that are inhibited by AAT; animal models of other enzyme inhibitor deficiencies; gene regulation; gene therapy; cellular signaling, injury, and repair; and protein processing.


Asbestosis, an occupational lung disease, is the interstitial pneumonitis and fibrosis caused by exposure to asbestos fibers. New research findings have improved understanding of the role of genetic susceptibility in lung injury from asbestos. Following asbestos exposure, lung fibroblasts are activated to grow and produce connective tissue. Certain inbred mice, the 129 mouse strain, do not develop asbestos-induced fibrogenesis, whereas other inbred strains do. Studies using growth factors suggest that the fiber deposition in the lungs of 129 mice is due to an intrinsic difference in the ability of the lung fibroblasts to respond to growth factors. In mice it was also demonstrated that excess levels of transforming growth factor-beta (TGF-beta) can induce fibrogenesis in the lungs of fibrogenic-resistant mice, thus providing a clue as to how individual growth factors may contribute to the development of fibroproliferative lung disease.

Bronchopulmonary Dysplasia (BPD)

BPD is a chronic lung disease characterized by disordered lung growth, specifically, changes in cell size and shape and a reduction in the number of alveolar structures available for gas exchange. It affects at least 10,000 very-low-birth-weight infants each year and is associated with neonatal intensive care costs as high as $60,000 per patient. The incidence of BPD has increased in recent years due to the increased survival of smaller premature infants. The NHLBI Collaborative Program for Research in BPD provides a well-characterized primate model for a multi-disciplinary exploration of the etiology of the disease. NHLBI also supports two clinical trials on the role of nitric oxide in preventing and treating chronic lung disease in premature infants. A safety and dosage Phase II clinical trial for intratracheal instillation of the anti-inflammatory uteroglobin, CC10, in premature infants is nearing completion. In FY 2001, reduction of ventilatory injury with Nasal Continuous Positive Airway Pressure (nCPAP) was demonstrated in the pre-term baboon model of BPD; histologic examination revealed thin saccular walls with minimal fibro-proliferation and improvements in internal alveolar surface area. In addition, the NHLBI intramural research program developed new technologies for the prevention of nosocomial pneumonia and ventilator-induced injury that may reduce patient morbidity and mortality in the intensive care unit.

Churg-Strauss Syndrome

Churg-Strauss syndrome is a rare disorder that was first reported in the 1950s. It is characterized by the formation and accumulation of an abnormally large number of certain white blood cells (eosinophils), inflammation of blood vessels (angiitis or vasculitis), and inflammatory nodular lesions (granulomatosis). Onset typically occurs between 15 to 70 years of age, and the disease affects both males and females. Patients with the syndrome are often affected by asthma. Churg-Strauss syndrome can be severely debilitating, and even fatal if untreated, but patients usually respond well to corticosteroid treatment. Over 90 cases of Churg-Strauss Syndrome have been reported in less than 2 years by physicians who had switched asthma patients from corticosteroid therapy to anti-leukotriene therapy. It is unclear whether the increased reports of Churg-Strauss are the result of an untoward effect of the anti-leukotriene therapy or a primary eosinophilic disease that had been clinically recognized and treated as asthma but was “uncovered” as Churg-Strauss once the corticosteroid therapy was withdrawn. NHLBI does not currently support research specifically investigating Churg-Strauss syndrome, however, it does support numerous investigator-initiated grants studying the basic mechanisms of asthma, including examination of the role of eosinophils. NHLBI also supports clinical studies of severe asthma and of medications used in asthma management, such as anti-leukotriene therapy. An NIH workshop report on the relationship of asthma therapy and Churg-Strauss syndrome was published in the Journal of Allergy and Clinical Immunology in FY 2001.

Congenital Central Hypoventilation Syndrome (CCHS)

CCHS, also known as “Ondine's Curse”, is a rare disorder characterized by normal breathing while awake but shallow breathing during sleep that is not effective in moving fresh air into the lungs. NHLBI supports a basic research program to elucidate the anatomical and physiological organization responsible for neural rhythm generation and translation into breathing. Research is focused on improving our understanding of how breathing is regulated and the conditions under which reflexive generation of respiratory rhythm is abolished. Identification of the neuronal pathways producing respiratory rhythm and pattern are prerequisite for a full understanding of a variety of respiratory sleep disorders such as CCHS. Recent findings obtained from overnight sleep studies indicate that CCHS is associated with a diminished sensitivity to levels of carbon dioxide in blood during non-rapid eye movement (non-REM) sleep. During REM sleep, other neural drives to breathe appear to supervene to enable adequate ventilation. Genetic and pathological studies of CCHS patients may enable identification of the genes or areas of the central nervous system involved in the syndrome and the abnormalities in ventilation.

Congenital Diaphragmatic Hernia (CDH)

CDH is a developmental disorder that occurs once in every 2,400 births. Often CDH occurs in isolated fashion, i.e., not associated with other life-threatening anomalies or chromosomal aberrations. Affected neonates usually die soon after birth because lung tissue compressed by the herniated viscera is inadequately developed, and hypoplasia of the pulmonary vascular bed leads to pulmonary hypertension or persistent fetal circulation syndrome. For infants who survive this disease, the cost of postnatal care can exceed $100,000. In June 1999, NHLBI awarded a grant for an investigator-initiated clinical trial to test the efficacy of an in utero surgical technique to correct lung hypoplasia as compared to post-natal care in a group of human fetuses at 24-28 weeks gestation in whom the most severe form of congenital diaphragmatic hernia had been identified. Because the group assigned to post-natal care had an approximate mortality of 30 percent, rather than the expected 80 percent, it was concluded that a much larger sample size would be required. The investigators were unable to arrange for the necessary multi-site collaborations, so enrollment had to be terminated in July 2001. The patients already enrolled in the trial continue to be followed.

Cystic Fibrosis (CF)

CF is a multi-system disease characterized by defective transport of chloride and sodium across the cell membrane. It is the nation’s number one genetic cause of death among children and young adults. More than 25,000 Americans have CF, with an incidence of about 1 in 3,300 among Caucasians. Ninety percent of persons with CF die from pulmonary complications. The responsible gene, the CF transmembrane conductance regulator (CFTR), was identified in 1989. More than 800 mutations and DNA sequence variations identified in the CFTR gene contribute to the highly variable presentation and course of the disease. NHLBI supports a vigorous program of basic, clinical, and behavioral research focused on the etiology, pathophysiology, and treatment of the pulmonary manifestations of CF. The NHLBI Program in Gene Therapy for Cystic Fibrosis and Other Heart, Lung, and Blood Diseases is focused on overcoming the many barriers to gene therapy for CF, such as vector entry, persistence of expression, selective targeting to appropriate organ or cell, toxicity of the vector, and host immune response. The program also evaluates potential new pharmacologic therapies. An example of a promising therapeutic strategy being investigated for CF is the screening of compounds that upregulate the “chaperone proteins” that maintain CFTR in its proper shape to function correctly.

Lack of understanding of the pathogenesis of CF airways disease reflects, in part, ignorance of the physiology of the airway surface liquids (ASL) that are vital for gas exchange and lung defense in the normal lung. A major scientific advance over the past year has provided definitive evidence for the importance of low ASL volume in the pathogenesis of CF airway epithelial disease, contributing to “thickened” mucus generated by ASL volume depletion and greater adherence of mucins to the surfaces of the CF airways. Based on these findings, studies are underway to develop therapeutic approaches to normalize ASL volume in CF. In addition, the NHLBI intramural program reported in FY 2001 that diagnostic approaches based on immunological detection of the Pseudomonas aeruginosa type III secretory apparatus and its associated cytotoxins provide evidence for early colonization and/or infection in children with CF.

Idiopathic Pulmonary Fibrosis (IPF)

IPF is a rare chronic lung disease of unknown cause affecting between 3 and 30 individuals per 100,000 population. Individuals with IPF develop abnormal, excessive scarring in the lungs that can cause progressive shortness of breath and coughing. Currently available treatments, most commonly with corticosteroids in combination with other potent drugs, and less commonly with lung transplantation, do little to prevent a relatively rapid death in most patients. NHLBI-supported research on IPF is examining the molecular and cellular events that trigger the inflammation of alveoli seen in the early stages of the disease and that influence progression to the irreversible, fibrotic end stage. Three NHLBI intramural observational clinical research protocols focusing on the natural history and pathogenesis of the disease are open for enrollment of subjects with familial and non-familial forms of IPF. The protocols have established collaborations with extramural sites and are working with the Pulmonary Fibrosis Association and other patient-support organizations to recruit patients. In FY 2001 NHLBI intramural scientists found that aberrant transcriptional control in alveolar macrophages may be a contributing factor in the pathogenesis of IPF.

Lymphangioleiomyomatosis (LAM)

LAM is a rare lung disease that affects women, usually during their reproductive years. Symptoms develop as the result of proliferation of atypical, non-malignant smooth muscle cells in the lungs. Diagnosis is usually made by lung biopsy. Common symptoms include shortness of breath, cough, and sometimes coughing up blood. Patients often develop spontaneous pneumothorax or chylous pleural effusion (collapse of the lung or collection of milky looking fluid around the lung). The clinical course of LAM is quite variable, but is usually slowly progressive, eventually resulting in death from respiratory failure. Although no treatment has been proven effective in halting or reversing LAM, lung transplantation is a valuable treatment for patients with end-stage lung disease. Some patients with tuberous sclerosis complex (TSC), a genetically transmitted disease, develop lung lesions identical to those seen in LAM. In some cases, the clinical distinction between TSC and LAM may be difficult.

NHLBI supports research on LAM in both its intramural and extramural programs. As part of the intramural program, the Institute has established a research laboratory at the NIH Clinical Center to learn more about the cause and progression of LAM at the clinical, cellular, and molecular levels. Researchers are determining the characteristics of the unusual smooth muscle cells that damage the lungs of LAM patients. An important aspect of the research is learning how growth is regulated in these cells.

The NHLBI extramural program supports a national LAM Patient Registry that is coordinated by the Cleveland Clinic Foundation. The Office of Research on Women’s Health co-funds the registry with NHLBI. The LAM Registry began enrolling patients in the summer of 1998. Enrollment closed in September 2001 with 253 LAM patients recruited. The Registry is helping to manage the collection and distribution of LAM tissue for current LAM projects, as well as serving as a repository of LAM tissue for future research.

During FY 2001 additional progress was made in understanding the genetic mechanisms leading to smooth muscle proliferation in LAM and the relationship between LAM and TSC. Previously it was reported that mutations in the TSC2 gene can cause pulmonary LAM. More recently it was shown that in an individual patient the same types of mutations occur in cells taken from LAM lesions in the lungs and in cells taken from kidney tumors, known as angiomyolipomas. This suggests that the cells in the lung and the kidney have a common genetic origin. This discovery may lead to new diagnostic and therapeutic strategies for women with LAM. Also in FY 2001, the NHLBI intramural program reported that data from its ongoing study of the natural history of LAM have established clinical, pathological, physiological, and genetic criteria that define disease severity and progression.


Narcolepsy is a disabling sleep disorder affecting over 100,000 people in the US. It is characterized by excessive daytime sleepiness and rapid onset of deep (REM) sleep. Other symptoms involve abnormalities of dreaming sleep, such as dream-like hallucinations and transient periods of physical weakness or paralysis (cataplexy). Through programs such as the SCOR in Neurobiology of Sleep and Sleep Apnea, NHLBI supports research on the regulation of sleep and wakefulness, the regulation of muscle tone during sleep, and the genetic basis of narcolepsy in humans and animals. One new study finds that low cerebrospinal fluid levels of hypocretin, a neurochemical messenger linking sleep with the regulation of muscle tone, are highly specific to narcolepsy and could potentially have utility as a diagnostic procedure. Another study has determined that hypocretin is an excitatory chemical in brain regions regulating sleep.

Persistent Pulmonary Hypertension of the Newborn (PPHN)

PPHN affects approximately 1 in 1,250 live born term infants. Due to inappropriate muscularization of fetal pulmonary vessels, the lung arteries of affected newborns fail to dilate after birth to allow for normal blood flow through the lung. Such infants are poorly oxygenated and require costly and prolonged medical care including: intubation of the airway, inhalation of 100 percent oxygen, mechanical ventilation, and, often, heart/lung bypass (extracorporeal membrane oxygenation). One NHLBI SCOR on the Pathobiology of Lung Development is focused on the unique vascular response of the neonate to injurious stimuli with a view toward identifying the basic molecular mechanisms involved in the development of the vasculature. Such research may provide information for the treatment of hypertensive pulmonary disorders such as PPHN. Enrollment began in late1999 for a clinical study that will address maternal risk factors such as cigarette smoking and antenatal exposure to the non-steroidal anti-inflammatory drugs, aspirin and ibuprofen. Experimental evidence consistently suggests that maternal exposure to these agents plays a role in the etiology of the disorder. Buccal cell specimens are being collected and stored for future genetic analyses should a relationship be demonstrated.

Inhaled nitric oxide (NO) is an experimental therapy that offers promise for less invasive treatment of PPHN. Recent studies point to a critical role for endogenous NO as a modulator of levels of vasoactive mediators whose levels determine pulmonary vascular tone and reactivity. There are three known isoforms of NO synthase (NOS) in mammals and all are developmentally regulated in the fetal lung. Recent work with a premature baboon model of BPD has demonstrated a decline in two NO isoforms, nNOS and eNOS, during the genesis of chronic lung disease. Other investigators report a bi-phasic release of NO in response to shear stress during development. These findings suggest that NO plays an important role during lung development.

Primary Ciliary Dyskinesia (PCD)

PCD, also known as Kartegener’s syndrome or immobile ciliary syndrome, is an inherited disease characterized by defects in the cilia lining the respiratory tract. The result is impaired ciliary function, reduced or absent mucous clearance, and susceptibility to chronic, recurrent respiratory infections, including sinusitis, bronchitis, pneumonia, and otitis media. The disease typically affects children ages 0 to 18, but the defect associated with it has a variable clinical impact on disease progression in adults as well. Many patients experience hearing loss, male infertility is common, and situs inversus (having organs on the opposite side from usual) occurs in approximately 50 percent of PCD patients. Clinical progression of the disease is variable with lung transplantation required in severe cases. For most patients, aggressive measures to enhance clearance of mucus, prevent respiratory infections, and treat bacterial superinfections are recommended. Although the true incidence of the disease is unknown, it is estimated to be 1 in 32,000 or higher. Recent results of NHLBI-supported studies are providing new insight into the identification of the genetic basis of PCD. As part of an overall effort to gather sufficient numbers of patients for phenotypic and genetic studies, an international database containing detailed pedigrees, natural history information, and clinical and physiologic data of well-characterized PCD patients and family members is being assembled. A selected cohort of patients with defects in the outer dynein arm (ODA) of cilia, the most common form of PCD, were chosen for initial genetic studies. Identification of six to ten genes for the vast majority of common PCD patients who have ODA defects could lead to genetic diagnostic testing, enabling more definitive identification and earlier diagnosis of PCD patients.

Primary Pulmonary Hypertension (PPH)

PPH is a rare, progressive lung disorder characterized by a sustained elevation of pulmonary artery pressure. It is associated with structural changes in the small pulmonary arteries and arterioles resulting in resistance to blood flow. The process eventually leads to an enlarged, overworked right ventricle that is unable to pump enough blood to the lungs resulting in heart failure and death, usually within 3-5 years of initial diagnosis. Estimates of the incidence of PPH range from 1 to 2 per million, with women being predominantly affected. Approximately 6-10 percent of cases are familial PPH, a form inherited as an autosomal dominant trait. NHLBI supports basic research on the cellular and molecular events underlying the pathogenesis of PPH. The dominant themes of this research are: (a) isolation and characterization of a familial PPH gene, (b) better understanding of the structural aspects of the disease that cause proliferative and obliterative changes in the vasculature, (c) identification of genetic factors that affect functional and structural changes in the vasculature, (d) development of preclinical markers, and (e) identification and evaluation of more effective treatments.

In November 2001, the FDA approved a new drug, Bosentan (Tracleer) for the treatment of PPH. Bosentan is the first oral treatment approved for PPH, and is also the first in a new class of drugs, known as endothelin receptor anatagonists, to be available commercially. Endothelin, a potent vasoconstrictor that also stimulates growth of vascular cells, is present in high concentrations in the bloodstream of patients with PPH. Results of a small (32 patient) double-blind, placebo-controlled study suggest that Bosentan, which acts by blocking endothelin receptors, increases exercise capacity and improves heart function in patients with pulmonary hypertension. Future trials should help clinicians better define the place of this new class of agents in the therapy of pulmonary hypertension. Larger studies will be needed to address important issues such as improvement in survival and their potential use in severely ill patients who are receiving prostacyclin therapy. Other recent work suggests that levels of circulating endothelin may serve as prognostic markers for patients with PPH and as a tool for the selection of patients who may benefit from treatment with endothelin receptor antagonists.

Multiple agents represent another approach beginning to be applied to the treatment of PPH. Investigators are exploring, for example, the use of an oral phosphodiesterase inhibitor (sildenafil) as a therapeutic adjunct to inhaled iloprost. In very preliminary studies, sildenafil caused a long-lasting reduction in pulmonary artery pressure and pulmonary vascular resistance, with a further additional improvement after iloprost inhalation. Similarly, a small pilot study of iloprost inhalation combined with epoprostenol treatment in patients who had adverse effects during treatment with epoprostenol showed that the combination therapy significantly reduced pulmonary artery pressure and improved cardiac index and other indicators of cardiopulmonary function. These findings suggest that combined therapies may be useful in improving treatment of PPH.

The discovery last year of a genetic cause of PPH has opened up a host of opportunities for research into the etiology and pathogenesis of PPH. New findings this year suggest that there is considerable heterogeneity in mutations of a gene (BMPR2) that is associated with PPH. Additional factors, either genetic and/or environmental, may be required for development of the clinical phenotype. Other PPH genes remain to be identified since approximately half of the PPH families have BMPR2 mutations. Data suggest that many cases of apparently sporadic PPH may in fact be familial, as failure to detect familial PPH is complicated by incomplete expression within families, skipped generations, and insufficient family pedigrees.

Recent findings on the pathogenesis of PPH indicate that endothelial cells within plexiform lesions of patients with PPH have genetic alterations associated with genetic (microsatellite) instability and abnormal growth and gene expression similar to that seen in neoplasia. Other studies suggest that the disorganized growth of endothelial cells in plexiform lesions from PPH patients involves disordered angiogenesis thus allowing for the expansion of endothelial cells. Pulmonary smooth muscle cells from patients with PPH have recently been reported to show abnormal responses to cell growth signaling pathways, and a recently published study from researchers in France is providing evidence for a link between abnormal expression of a serotonin transport protein and abnormal proliferation of vascular smooth muscle in PPH patients.


Sarcoidosis is a disease involving organ systems throughout the body, in which normal tissue is invaded by pockets of inflammatory cells called granuloma. Most sarcoidosis patients have granuloma in their lungs. The disease can exist in a mild form that spontaneously disappears or in a severe form that results in a life-long condition. Estimates of the number of Americans afflicted range from 13,000 to 134,000, and between 2,600 and 27,000 new cases appear each year. As many as 5 percent of individuals with pulmonary sarcoidosis die of causes directly related to the disease. The morbidity associated with the disease can be severe and result in significant loss of function and decrease in quality of life. The causes of sarcoidosis are presently unknown, but disease development is thought to involve the victim's immune system. NHLBI supports laboratory-based research to investigate granuloma formation and to obtain a better understanding of initiating events, the disease process, and the contribution of susceptibility genes.

A multi-center NHLBI study conducted from 1996 to 1999 found that sarcoidosis patients were almost five times more likely than controls to report a sibling or parent with a history of sarcoidosis. White sarcoidosis cases were much more likely to have an affected relative than were African-American cases. However, the investigators found that even for family members (siblings and parents) the risk of sarcoidosis is small, about one percent, and therefore concluded that increased surveillance is probably not warranted. They also found that sarcoidosis appears to increase the risk of depression.

Blood Diseases and Resources Programs

Aplastic Anemia (AA) and Paroxysmal Nocturnal Hemoglobinuria (PNH)

AA is a form of bone marrow failure in which hematopoietic cells are replaced by fat, resulting in low blood counts. In PNH, a clone derived from a single hematopoietic stem cell expands, leading to marrow failure, red blood cell destruction, and venous thrombosis. The NHLBI intramural Hematology Branch has a large clinical and laboratory program devoted to bone marrow failure syndromes, including AA and PNH. Bench studies include immunology, cell biology, virology, and molecular biology approaches to the failure to produce blood cells. Clinical studies include therapeutic interventions to reduce autoimmunity in patients with AA. In FY 2001 the branch established an animal model of immune-mediated AA, showing the pivotal role of type 1 cytokines in causing severe marrow cell destruction. In addition, it completed analysis of its large trial of immunosuppression in severe AA and found that early robust improvement in blood counts is highly predictive of long-term survival without malignant evolution.

Cooley's Anemia

Cooley’s anemia (also called beta-thalassemia, thalassemia major, or Mediterranean anemia) is a genetic blood disease that results in an inadequate production of hemoglobin. Individuals affected with Cooley's anemia require frequent and lifelong blood transfusions. Because the body has no natural means to eliminate iron, the iron contained in transfused red blood cells builds up over many years and eventually becomes toxic to tissues and organ systems. In addition, many affected children acquire other diseases such as hepatitis through years of transfusion exposure.

NHLBI’s extramural research efforts related to Cooley’s anemia include (a) identification of mutations in the globin gene cluster that lead to the disorder, (b) elucidation of the mechanisms and therapeutic approaches associated with naturally occurring mutations that result in elevated levels of fetal hemoglobin (Hb F) in adult red blood cells, (c) iron chelation, (d) clinically-useful therapies and drugs, including gene therapy, (e) efficient identification and targeting of hematopoietic stem cells, (f) how ex vivo manipulation of stem cells alters their biologic properties, and (g) improved vectors for use in gene transfer efforts. The Institute’s strategic approach also includes a clinical research network to test new therapies and a program of sibling donor cord blood banking and transplantation for hemoglobinopathy families.

FY 2001 witnessed a number of important scientific advances for Cooley’s anemia. New methods of transfusion therapy are being developed to improve adherence with deferoxamine regimens for patients receiving chronic transfusions. Less toxic methods of stem cell transplantation are being developed that may be useful for patients with thalassemia. For example, the NHLBI intramural program is working on a vaccine to prevent cytomegalovirus reactivation after stem cell transplantation using a CMV pp65 protein canarypox construct. Finally, several compounds that increase Hb F values have been described. They are hydroxyurea, which is a compound in routine use in sickle cell disease, a number of butyrate-based compounds, and 5-azacytidine.

Creutzfeldt-Jakob Disease (CJD)

CJD is a slowly degenerative, invariably fatal, rare disease of the central nervous system, characterized by motor dysfunction, progressive dementia, and vacuolar degeneration of the brain. The disease has been associated with a transmissible agent. A protease-resistant protein or prion is the hallmark of the transmissible spongiform encephalophaties (TSE) family of diseases to which CJD belongs. Classical CJD occurs worldwide at a rate of 1-2 cases per million per year. The lack of a rapid, sensitive, and specific test for TSE infectivity has slowed progress in the study and control of CJD and other prion diseases. The development of assay systems to detect prion diseases is a high priority in public heath. It could form the basis of a blood/tissue donor screening test, and provide a diagnostic test for neurologists; there is currently no way of detecting the disease in its pre-clinical stage. These assays could also be useful in testing for TSE in animals, especially domestic animals used for human consumption. In FY 2001, NHLBI-supported investigators reported that mouse skeletal muscle can propagate prions and accumulate substantial titers of them. Because significant dietary exposure to prions might occur through the consumption of meat, even if it is largely free of neural and lymphatic tissue, a comprehensive effort to map the distribution of prions in the muscle of infected livestock is needed. Furthermore, muscle may provide a readily biopsied tissue that can be used to diagnose prion disease in asymptomatic animals and even humans.

Fanconi Anemia (FA)

FA is an autosomal recessive bone marrow failure syndrome characterized by a decrease in blood cells and platelets (pancytopenia), developmental defects, and cancer susceptibility. Many FA patients can be identified at birth because of congenital anomalies, although approximately 25 percent do not have birth defects. FA is a clinically heterogeneous disorder; it can currently be divided into at least eight different complementation groups designated A through G. Delineation of the interrelationship of the FA proteins and their functions through localization and functional studies is a high priority research area for NHLBI. In addition, NHLBI supports research that focuses on identifying and cloning the remaining FA genes, developing protocols for efficient identification and targeting of hematopoietic stem cells, obtaining information on how ex vivo manipulation of stem cells alters their biologic properties, producing improved vectors, and exploring the utility of cord blood banking. Two FA genes, FAC and FAA, that account for an estimated 75 percent of all FA patients world wide, have been cloned. The cellular localization of the functional complex and the role of the complex in DNA repair and prevention of mutagenesis have been exciting developments over the past year. Recent transplantation protocols using Fludarabine have provided new hope that stem cell transplantation may be a therapeutic option for patients with FA.

Graft versus Host Disease (GvHD)

Acute GvHD is a condition that typically occurs within 3 months after allogeneic hematopoietic stem cell transplantation. Donor T cells react against “foreign” tissue antigens in the recipient. GvHD is characterized by skin rash, liver dysfunction, vomiting, and diarrhea. Acute GvHD often precedes development of chronic GvHD, which may require years of treatment with immunosuppressive drugs. NHLBI supports basic and clinical research grants focused on understanding the pathophysiology of GvHD, especially in unrelated transplants. The NHLBI program emphasizes understanding of the roles of both major and minor histocompatibility antigens in disease pathogenesis, development of tolerance, function of donor T cells in allogeneic hosts, and mechanisms of GvHD prevention including depletion of donor T cells from the graft. Current studies attack the problem of GvHD from several directions: the variables that affect its induction and severity; the effector mechanisms; and whether GvHD can be suppressed while other necessary immune responses are maintained. The program supports two multi-center clinical studies: the Unrelated-Donor Marrow Transplant Trial of T-cell Depletion and the Cord Blood Banking and Transplantation Study. The Blood and Marrow Clinical Transplant Network was funded in FY 2001 to conduct Phase III trials including studies of GvHD. To date, older or sicker patients have been excluded from allogeneic hematopoietic cell transplantation (HCT) because of toxicities from the treatment regimen. Recently, investigators have developed a less toxic regimen, based on the use of postgrafting immunosuppression to control graft rejection and GvHD, that has dramatically reduced the acute toxicities of allografting. Now HCT with the induction of potent graft-versus-tumor effects can be performed in previously ineligible patients, largely in an outpatient setting. Finally, the NHLBI intramural research program in FY 2001 described how the alloimmune environment reshapes the immune response of the donor after stem cell transplantation by identifying innate T cell responses to known and putative tumor specific antigens.


Hemophilia is a hereditary bleeding disorder that results from a deficiency in either blood coagulation factor VIII or factor IX. There are about 20,000 hemophiliacs in the US, all of whom are dependent on lifelong treatment to control periodic bleeding episodes. NHLBI supports a broad spectrum of activities on blood coagulation and its disorders. Research on hemophilia includes viral and non-viral approaches for gene therapy, mechanisms of antibody inhibitor formation, modification of factors for improved therapeutics, safety of plasma derived products, and blood product associated infections. In addition, basic genetic, molecular biology, and protein biochemistry studies of factors VIII and IX are supported to improve understanding of the mechanisms of action and regulation of these critical coagulation proteins. One program project studies multiple approaches to developing gene-based therapies for hemophilia A and B, and another studies new therapies that can be used in the presence of inhibitory antibodies.

Gene therapy studies by NHLBI-supported scientists have shown sustained expression of factor IX in mice and hemophilic dogs after administration of adeno-associated viral (AAV) vector expressing factor IX. Based on pre-clinical safety and efficacy data, a clinical study for intrahepatic delivery of AAV vector expressing factor IX was initiated in August 2001. Studies by NHLBI-supported investigators have improved understanding of the immune response to factor VIII that leads to the formation of inhibitory antibodies. Studies in a hemophilia mouse model demonstrated in FY 2001 that long-term immune tolerance to factor VIII could be induced after early blockade of the interaction between the antibodies CD40 and CD40L. In addition, the structure of a region of factor VIII bound to an inhibitory antibody was determined that could be useful in efforts to develop less antigenic factor VIII products.

Immune Thrombocytopenic Purpura (ITP)

ITP is an autoimmune disease manifested by production of antibodies that react with specific proteins on the surface of platelets. The reaction results in rapid clearance or destruction of platelets (thrombocytopenia) and clinically-significant bleeding. The underlying cause is unknown, but the disease is associated with other autoimmune disorders. Although ITP may occur at any age, acute (temporary) thrombocytopenic purpura is most commonly seen in young children. About 85 percent of affected children recover within 1 year and experience no recurrence. Thrombocytopenic purpura is considered chronic when it lasts more than 6 months. Its onset may occur at any age. Adults more often have the chronic disorder and females are affected two to three times more often than males. Most adult patients respond at least transiently to standard therapies including steroids and splenectomy, but a majority eventually relapse and some develop very severe chronic refractory ITP.

Part of the NHLBI research program on thrombosis and hemostasis is directed toward understanding the biology of platelet production from megakaryocytes, the function of the growth factor thrombopoietin (TPO), and the structure and function of platelet surface glycoprotein antigens. Studies on TPO have not borne out the initial promise of this therapeutic strategy. While mice with the TPO gene “knocked out” maintained a basal level of circulating platelets and did not bleed, a number of human subjects with thrombocytopenia who received TPO developed antibodies to the protein and their clinical conditions worsened. The investigators concluded that TPO is an amplification factor, but it may not be essential for megakaryocytopoiesis and platelet production. On the other hand, migration of the bone marrow megakaryocytes to a more permissible environment for platelet production could be a critical factor. In another development, a monoclonal antibody, rituximab, directed to B-lymphocytes for the treatment of cancer, was found in initial studies to be beneficial for patients with ITP.


Lymphedema is an accumulation of lymphatic fluid in interstitial tissue that causes swelling, most often in the arm(s) and/or leg(s), and occasionally in other parts of the body. Lymphedema can develop when lymphatic vessels are missing or impaired (primary or congenital), or when lymph vessels are damaged or lymph nodes removed (secondary). When the impairment becomes so great that the lymphatic fluid exceeds the lymphatic transport capacity, an abnormal amount of protein-rich fluid collects in the tissues of affected areas. Left untreated, this stagnant, protein-rich fluid not only causes tissue channels to increase in size and number, but also reduces oxygen availability in the transport system, interferes with wound healing, and provides a culture medium for bacteria that can result in a lymphangitis infection. The incidence of primary lymphedema has been estimated to be between 1 in 6,000 and 1 in 300 live births, so it may be a rare disease, or it may be a more common disease which predisposes to the secondary type and is under recognized. NHLBI investigator-initiated projects are seeking to identify the developmental, molecular, and cellular defects that contribute to lymphedema and are seeking to design effective therapeutic interventions to treat both primary and secondary lymphedemas. In December 2000, NHLBI issued a Program Announcement (PA) inviting applications to study the pathogenesis and treatment of lymphedema.

Sickle Cell Disease (SCD)

SCD is an inherited blood disorder that is most common among people whose ancestors come from Africa, the Middle East, the Mediterranean basin, or India. SCD is the most common genetic blood disorder in the U.S., affecting approximately 1 in 500 African-American newborns and 1 in 1,000 Hispanic newborns. It occurs when an infant inherits the gene for the sickle hemoglobin from both parents or the gene for sickle hemoglobin from one parent and the gene for another abnormal hemoglobin from the other parent. In patients with the disease, the hemoglobin molecules in the red blood cells (RBCs) which carry oxygen throughout the body tend to damage the RBC walls, causing them to stick to blood vessel walls. This leads to the painful sickle cell episodes that are the hallmark of the disease. Chronic end-organ damage occurs to the brain, lungs, kidneys, spleen, and liver, and leads to premature death, with the median age at death for severely affected individuals occurring between 42 and 48 years.

NHLBI’s current sickle cell disease portfolio includes research on the following topics: (a) development of methods for gene transfer and gene replacement in the hematopoietic stem cell; (b) characterization of interactions between sickle cells and the vascular endothelium; (c) improved understanding of hemoglobin gene switching to allow increased production of fetal hemoglobin; (d) a Phase III clinical trial of hydroxyurea in children with sickle cell anemia to determine if hydroxyurea can prevent the onset of chronic end organ damage; (e) an epidemiologic study of the incidence of parvovirus B19 seroconversion in children with sickle cell disease; (f) an epidemiologic study of the adult patients who participated in the Multicenter Study of Hydroxyurea Trial; (g) a study of non-myeloablative preparative regimens for bone marrow transplantation leading to mixed chimerism as curative therapy for severely affected SCD patients; and (h) a study of sibling cord blood banking and transplantation of cord blood derived stem cells to cure severely affected sickle cell disease patients. In addition, the NHLBI Intramural program continued an ongoing seroconversion study of B19 parvovirus in sickle cell anemia patients in preparation for a recombinant vaccine trial of baculovirus-engineered empty capsids.

Progress in SCD research in FY 2001 was highlighted by a report of a gene therapy cure of the transgenic mouse model of sickle cell disease. Investigators at the Massachusetts Institute of Technology and the Albert Einstein College of Medicine announced the insertion of a beta hemoglobin A gene variant into hematopoietic stem cells in two transgenic SCD mouse models (Berkeley and SAD). The animals were able to produce the corrected hemoglobin cells for up to 10 months with associated correction of hematologic parameters, splenomegaly, and prevention of urine concentrating defect. This experiment paves the way for additional animal studies and ultimately human clinical trials to find a safe way to neutralize the abnormal blood producing gene before the introduction of gene-therapy-treated blood producing cells.

Systemic Lupus Erythematosus (SLE)

SLE or “lupus” is an autoimmune disorder in which the body produces antibodies that harm its own cells and tissues. Typical symptoms of SLE are fatigue, arthritis, fever, skin rashes, and kidney problems. Lupus affects more women than men. Patients with SLE have a higher incidence of thrombosis and spontaneous loss of pregnancy. Its cause is unknown and there is no known cure, but the symptoms can be controlled with appropriate treatment and most patients can lead an active life. As part of its broad program of research in hemostasis and thrombosis, NHLBI is supporting studies on the development of diagnostic tests in pregnant women with SLE. Recent studies suggest that circulating antibodies in lupus patients compete with a protein, annexin V, that forms an anti-thrombotic shield in the placenta. The result is that procoagulant phospholipids remain exposed, cause thrombosis in the vessels of the placenta, and lead to fetal loss.

Thrombotic Thrombocytopenic Purpura (TTP)

TTP is a potentially fatal disease characterized by low blood platelet levels and widespread platelet thrombi in arterioles and capillaries. Both endothelial cell damage and intravascular platelet aggregation have been suggested in the pathogenesis of TTP. Microscopic examination of thrombi has revealed the presence of abundant von Willebrand factor (vWf), a plasma protein. An interaction between vWf and the platelet surface glycoprotein complex I (GP I) is believed to be essential for the formation of a thrombus. vWf is synthesized as large polymers and is then cleaved into smaller units by a plasma protease. NHLBI grantees have confirmed the presence of inhibitory antibodies to this enzyme in the plasma of some patients with TTP. Inhibition of the enzyme results in large multimers of vWf in plasma that can spontaneously aggregate platelets. The NHLBI grantees succeeded in isolating a new metalloprotease, the ADAMTS 13 degradative enzyme inhibitor, and established that mutations in the gene that expresses ADAMTS 13 are the genetic basis of familial TTP. Efforts are being made to produce recombinant ADAMTS 13.

Rare Disease Research Initiatives

Ongoing Initiatives

• Adult Hydroxyurea Patient Follow-up Study (aka: Multicenter Study of Hydroxyurea in Sickle Cell Anemia (MSH) Patients' Follow-up)
• Beryllium-Induced Diseases
• Cellular and Molecular Mechanisms of Primary Pulmonary Hypertension
• Chronic Fatigue Syndrome: Pathophysiology and Treatment
• Clinical Research on Cooley's Anemia
• Comprehensive Sickle Cell Centers
• Creutzfeldt-Jakob Disease Assay Methods Development
• Developmental Processes in Differential Expression of Globin Genes
• Environment/Infection/Gene Interactions in Autoimmune Disease
• Genomic Applications for Heart, Lung, and Blood Research
• Homocyst(e)inemia and Atherosclerosis
• Human Umbilical Cord Blood Stem and Progenitor Cells: Collection, Storage, and Transplantation
• Immunogenetics of Inhibitor Formation in Hemophilia
• Mitochondrial DNA Mutations in Heart, Lung, and Blood Diseases
• Molecular Biology and Genetics of Sleep and Sleep Disorders
• Programs of Excellence in Gene Therapy
• Retinoid Treatment in Emphysema: Feasibility Studies
• SCOR in Hematopoietic Stem Cell Biology
• SCOR in Neurobiology of Sleep and Sleep Apnea, Airway Biology and Pathogenesis of Cystic Fibrosis, and Acute Lung Injury
• SCOR in Pathobiology of Fibrotic Lung Disease, Pathobiology of Lung Development, and Cellular and Molecular Mechanisms of Asthma
• SCOR in Pediatric Cardiovascular Disease
• Stem Cell Transplantation to Establish Allochimerism
• Strategies to Augment Alveolization
• Thalassemia (Cooley's Anemia) Clinical Research Network
• Thrombocytopenia: Pathogenesis and Treatment
• Tuberculosis Academic Award
• Vascular and Hematopoietic Development and Disease

Initiatives Started in 2001

Blood and Marrow Transplant Clinical Research Network

A new RFA, initiated by NHLBI and cosponsored by NCI, organizes a network to accelerate research on the management of hematopoietic stem cell transplantation, standardize existing treatments, and evaluate new ones. The network of 14 interactive clinical centers and a data coordinating center provides a coordinated, flexible mechanism over a maximum period of 10 years to accept ideas and build consensus from the transplant community; develop protocols; expeditiously perform multi-center Phase II and Phase III clinical trials; provide information to physicians, scientists, and the public; and, in turn, improve stem cell transplantation therapy for diseases such as leukemia, sickle cell disease, thalassemia, and Fanconi anemia.

Genetic Aspects of Tuberculosis in the Lung

A new RFA, initiated by NHLBI and cosponsored by NIAID, stimulates research on the genetic aspects of tuberculosis in the lung, exploiting advances in molecular biology and genomics research. Special attention is paid to the interaction between host and microbial genes and to the identification of genes or families of genes that determine virulence or latency, or that determine reactivation of disease or resistance to antituberculous drugs. Of particular interest are studies using new biotechnologies such as microarrays, molecular beacon technology, or differential signature-tagged mutagenesis (DSTM), and studies involving innovative collaborations with computational biologists to identify genes that mediate the pathogenesis of tuberculosis and elucidate the responsible mechanisms. To encourage junior level quantitative biologists to work on the genetic aspects of tuberculosis, the Mentored Quantitative Research Career Development Award (K25) has been included as one of the mechanisms of support .

Genetic Modifiers of Single Gene Defect Diseases

A new RFA, initiated by NHLBI and cosponsored by NIDDK, encourages studies to identify and characterize the genes responsible for modifying the clinical progression and outcomes of heart, lung, and blood diseases due to single gene defects. Examples of such single gene defect diseases are cystic fibrosis; sickle cell disease; hemophilia; alpha-1-antitrypsin deficiency; glucocorticoid remediable aldosteronism (GRA); Liddle’s syndrome; and cardiac myopathies, dysplasias, and arrhythmias that result in sudden cardiac death. The modifier genes are likely to encode a wide variety of proteins that either interact directly with the disease gene, influence pathways involving the disease gene, or affect metabolic processes altered as a result of the disease gene defect. Identification of the genes responsible for these differences should lead to a better understanding of disease pathogenesis, earlier diagnosis, and improved treatment.

Novel Approaches to Enhance Animal Stem Cell Research

A new PA, co-sponsored by ten institutes, encourages studies to isolate, characterize, and identify totipotent and multipotent stem cells from nonhuman biomedical research animal models and generate reagents and techniques to characterize and separate them from other cell types. The PA stresses innovative approaches to the problems of making multipotent stem cells available from a variety of nonhuman sources, and innovative approaches to creating reagents that will identify them across species and allow for separation of multipotent stem cells from differentiated cell types.

Pathogenesis and Treatment of Lymphedema

A new PA, initiated by NHLBI and co-sponsored by NICHD, NIAMS, and NCI, encourages investigation of the pathogenesis of, and new treatments for, primary and secondary lymphedema. The PA seeks to stimulate research on the biology of the lymphatic system and to characterize at the molecular, cellular, tissue, organ, and intact organism levels, the pathophysiologic mechanisms that cause the disease, and to discover new therapeutic interventions. Such knowledge will help to improve early diagnosis of affected individuals, the choice and timing of treatment, and genetic counseling.

Pediatric Heart Disease Clinical Research Network

A new RFA establishes a network of interactive pediatric clinical research centers to promote the efficient evaluation of new treatment methods and management strategies that offer potential benefit for children with structural congenital heart disease, inflammatory heart disease, heart muscle disease, and arrhythmias. Therapeutic trials and studies involve investigational drugs, drugs already approved but not currently used, as well as devices, interventional procedures, and surgical techniques. The network approach, consisting of five to six clinical centers and a data coordinating center, is an effective, flexible way to study adequate numbers of patients with uncommon diseases such as congenital cardiovascular malformations. Efficiencies are achieved through standardizing procedures to recruit, characterize, monitor, and follow-up patients. Approximately 2,000 patients are expected to participate in 6-12 different protocols over the 5-year project period. The network also serves as a platform to train junior investigators in pediatric clinical research and as a vehicle for rapid and wide-spread dissemination of findings.

Initiatives Planned for the Future

Animal Models of Antigen-Specific Tolerance for Heart and Lung Transplantation

A new PA in FY 2002 will encourage the development of large animal models of antigen-specific tolerance induction for heart and lung transplantation and small animal models of tolerance induction for lung transplantation. Development of stable immune tolerance between donor and recipient would decrease morbidity and mortality due to chronic rejection, toxic effects of immunosuppressive therapy, and graft versus host disease.

Chemical Screens for New Inducers of Fetal Hemoglobin for Treatment of Sickle Cell Disease
and Cooley’s Anemia

A new PA in FY 2002 will support high-throughput chemical activity screens for new pharmacologic inducers of fetal hemoglobin, with the long-term objective of developing better drugs to treat sickle cell disease and Cooley’s anemia. The screens should include but not be limited to compounds in the short chain fatty acid and carbonic acid classes. Promising compounds identified through these Small Business Innovation Research (SBIR) grants will later be subjected to toxicology and pharmacokinetic testing in primates.

Heritable Disorders of Connective Tissue

A new RFA, to be initiated by NIAMS and to be co-sponsored by NHLBI in FY 2002, will promote research on heritable disorders of connective tissue caused by abnormalities in the molecules involved in the biosynthesis, processing, and degradation of structural macromolecules, as well as abnormalities in regulatory and signaling molecules that reside within the extracellular matrix. This initiative should increase understanding of, and lead to novel therapeutic strategies for, the Mafan's and Ehler-Danlos syndromes, diseases that involve alterations of the integrity of the connective tissue compartments within the wall of the blood vessel and the subsequent formation of aneurysms in the aorta and smaller arteries.

Multicenter Study of Hydroxyurea in Sickle Cell Disease: Patient Follow-Up Extension I

A renewal of an RFP in FY 2002 will continue the follow-up study of the 299 adult patients who participated in the Multicenter Study of Hydroxyurea in Sickle Cell Disease (MSH Trial) from 1992 to 1995 in order to ascertain the long term toxic effects of hydroxyurea usage in this patient population. The 240 patients known to be alive will be followed annually for five additional years at the 21 MSH clinical centers to determine health status, quality of life, incidence of malignancies, and birth defects in their offspring. Mortality rates will be compared to the mortality data from the Cooperative Study of Sickle Cell Disease adult cohort and the normal African-American population. In addition, long term efficacy of hydroxyurea will be estimated in terms of its effects on fetal hemoglobin levels (Hb F), blood cell counts, and selected organ function.

Plasticity of Human Stem Cells in the Nervous System

A new PA, to be co-sponsored by NHLBI and three other institutes in FY 2002, will encourage studies on the plasticity and behavior of human stem cells and the regulation of their replication, differentiation, and function in the nervous system. Because of their ability to generate neurons and glia, stem cells are promising candidates for the development of cellular and genetic therapies for neurological disorders, including neuroregulatory problems in heart, lung, and blood diseases, and sleep disorders. Studies will be encouraged to confirm, extend, and compare the behavior of human stem cells that are derived from different sources and ages or exposed to different regimes in vitro and in vivo. In addition, studies will be encouraged to develop methods for identifying, isolating, and characterizing specific human precursor populations at intermediate stages of differentiation into neurons and glia.

Stem Cell Plasticity in Hematopoietic and Non-Hematopoietic Tissue

A new RFA, to be initiated by NHLBI and to be co-sponsored by NIDDK and NINDS in FY 2002, will encourage studies to elucidate and characterize the molecular and cellular mechanisms that influence stem cell plasticity or versatility. Stem cells are the most primitive cells in the bone marrow from which all the various types of blood cells are derived. Studies are needed to identify genes responsible for the maintenance of "stemness" and genes responsible for initiating and/or maintaining the development of specific cell types. Human adult stem cells could potentially be exploited to become more embryonic-like and therefore useful for drug screening, replacement of diseased or injured tissue, and gene therapy.

Transactivation of Fetal Hemoglobin Genes for Treatment of Sickle Cell Disease and Cooley’s

A new RFA, to be initiated by NHLBI and co-sponsored by NIDDK in FY 2002, will encourage studies to identify the transcriptional regulatory proteins involved in fetal hemoglobin gene activation, determine their mechanisms of action and the induction mechanisms of the structural genes encoding the regulators, and identify drugs that induce fetal hemoglobin via action on the regulators. A better understanding of the molecular basis of fetal hemoglobin gene regulation, and of fetal to adult hemoglobin isoform switching in development, will facilitate the development of new approaches to cure beta-chain hemoglobinopathies such as SCD and Cooley's anemia.

Transfusion Medicine/Hemostasis Clinical Research Network

A new RFA will establish in FY 2002 a network of interactive clinical research groups to promote the efficient comparison of new management strategies of potential benefit for children and adults with hemostatic disorders and also to evaluate new as well as existing blood products and cytokines for the treatment of hematologic disorders. Hemostasis, the arrest of bleeding from an injured blood vessel, requires the combined activity of vascular, platelet, and plasma factors counterbalanced by regulatory mechanisms to limit the accumulation of platelets and fibrin in the area of injury. Hemostatic abnormalities may be congenital; immune-mediated, such as ITP and TTP; or due to coagulopathies resulting from chemotherapy, surgery, or trauma and can lead to excessive bleeding or thrombosis. The network will consist of a Data Coordinating Center and up to sixteen core clinical centers to perform multiple clinical trials.

Cell-Based Therapies for Heart, Lung, Blood, and Sleep Disorders and Diseases

A new RFA will encourage in FY 2003 basic research on stem cell biology and on the use of stem cells in cellular therapies for the treatment of cardiovascular, lung, blood, and sleep disorders and diseases. Because of their plasticity, adult, embryonic, and fetal stem cells hold great potential for use in new strategies to regenerate and repair damaged or diseased cardiovascular, lung, and blood tissues, and for sleep disorders. Areas supported would include the basic biology and characterization of embryonic, fetal, and adult stem cells and progenitor cells important for heart, lung, blood and sleep disorders; the use and differentiation of stem and progenitor cells for cell transplantation; stem cell homing to sites of tissue injury or specific tissue or organ sites, including the mechanisms underlying the homing process; and tissue engineering using stem or progenitor cells.

Comprehensive Sickle Cell Centers

A renewal of an RFA will continue in FY 2003 the operation of a nationwide network of collaborative, comprehensive centers in basic and translational research focused on the development of cures or significantly improved treatments for SCD. The network of ten centers and a statistics and data management core carries out basic research, inter-center collaborative clinical research, and local clinical research focused on the most promising biomedical and behavioral therapeutic modalities. The centers also support career development of young investigators in SCD research and support services including patient education, patient counseling, community outreach, and hemoglobin diagnosis. This is the eighth re-competition of a program that was established by a Presidential initiative and Congressional mandate in 1972.

Hutchinson-Gilford Progeria Syndrome (HGPS): Exploratory/Developmental (R21) Grants

A new PA with Review, to be co-sponsored by four Institutes, will encourage in FY 2003 studies to elucidate the molecular and mechanistic bases of HGPS, an incurable and terminal premature aging disorder characterized by short stature, abnormal skeletal and tooth development, scleroderma-like skin changes, and cardiovascular disease. Children with the disorder usually die of heart attacks or strokes at an average age of 13 years. Little research has been done on the syndrome because it is extremely rare (about 1 in 10 million births) and access to the patient population has been limited. Fibroblast and lymphoblastoid cell lines from HGPS patients from ten different families will be available to awardees. A better understanding of the mode of inheritance, molecular basis, and pathomechanisms of HGPS could lead to new insights into mechanisms of development, aging, and vascular occlusive diseases.

Mechanisms of Fetal Hemoglobin Gene Silencing for Treatment of Sickle Cell Disease and Cooley's Anemia

A new RFA will encourage studies in FY 2003 to delineate the mechanisms involved in fetal hemoglobin (gama-globin) gene silencing during normal human development and develop therapeutic approaches to inhibit silencing. Both cis- and trans-acting elements important in gamma-globin gene silencing will be identified and their mechanisms of action will be determined. Pharmacologic or gene-based approaches to interfere with silencing may ultimately be pursued. Increased understanding of the molecular basis of fetal hemoglobin silencing will facilitate the development of new gene-based therapeutic approaches to increase fetal hemoglobin in red blood cells and thereby cure beta-chain hemoglobinopathies.

Mesenchymal Stem Cell Biology

A new RFA will encourage studies in FY 2003 to conduct basic research on mesenchymal cell biology in order to provide the basis for clinical application of mesenchymal stem cells (MSCs) to hematopoietic and non-hematopoietic stem cell transplantation. MSCs are pluripotent progenitor cells located in bone marrow that can differentiate into a variety of non-hematopoietic tissues including bone, cartilage, tendon, fat, muscle, and early progenitors of neural cells. Preclinical studies suggest MSCs facilitate hematopoietic stem cell transplantation while decreasing immune rejection of allogeneic transplants. To realize the therapeutic potential of these results, the initiative will support the identification of population and assay methods to characterize the clinical potential of candidate human MSCs and the development of isolation and characterization standards for use in comparing.

Molecular Target and Drug Discovery for Idiopathic Pulmonary Fibrosis

A new RFA will encourage studies in FY 2003 to develop new therapeutic approaches for IPF. One approach to inhibit progression or reverse fibrosis in IPF patients would be to identify new agents, ranging from small molecules to vaccines, that interact with previously identified molecules or pathways known to be involved in the development of fibrosis. Other promising approaches supported by this initiative would be to use new technologies to identify additional molecular targets for treatment and to identify agonists or antagonists that interact with the previously or newly identified targets to attenuate, halt, or reverse the fibrotic process.

SCOR in (a) Neurobiology of Sleep and Sleep Apnea and (b) Airway Biology and Pathogenesis of Cystic Fibrosis

A renewal of an RFA to foster multidisciplinary basic and clinical research in FY 2003 enabling basic science findings to be more rapidly applied to clinical problems of sleep and CF. The objective of the sleep SCOR is to integrate clinical research on the etiology and pathogenesis of sleep disorders, particularly sleep apnea, with molecular, cellular, and genetic approaches to the study of sleep. The objective of the CF SCOR is to use our current knowledge of the CF transmembrane conductance regulator (CFTR) as a focus to promote advances in research on the pathogenesis of CF, the role of CFTR in airway biology, and the development of new treatment strategies. Each SCOR must consist of three or more projects, all of which are directly related to the SCOR program topic. This will be the second and final 5-year solicitation for these two SCORs.

Rare Disease-Related Program Activities

A Task Force on “Research in Pediatric Cardiovascular Disease” was held in January 2001. The Task Force identified the following eight research priorities for the next 5 years:

• Fundamental studies of the formation of heart and blood vessels
• Development and use of new and improved technologies to image the heart
• Advanced repair of congenital heart defects in infants and children
• Refined surgical treatment of human fetuses with heart defects
• Exploration of stem cell biology for the repair of heart tissues
• Creation of improved biomaterials through tissue engineering
• Translational research to enhance clinical care
• Definition of the childhood antecedents and risk factors for atherosclerotic heart disease in adults.

A symposium called “Lamposium 2001", held in March 2001 in Cincinnati Ohio, was co-sponsored by NHLBI and the LAM Foundation.

An RFA meeting for “Clinical Research for Cooley’s Anemia and Biology of Iron Overload” was held in April 2001.

A workshop on “AAT Deficiency: The Challenge Of Genetic Conditions”, held in June 2001, and co-sponsored by the Alpha One Foundation, NHLBI, NIDDK, and ORD, was designed to promote a multi-disciplinary understanding of psychosocial and scientific challenges of AAT deficiency.

A workshop on “Host Response in Sickle Cell Disease”, held in June 2001, discussed the clinical manifestations of problems with the immune response in SCD. Specific topics included resistance to pneumococcus, genetic modifiers of the immune response, loss of splenic function in SCD, and the response to encapsulated bacteria, iron overload, autoimmune disorders, developmental immunity, white blood cell function in SCD, and consequences of chronic transfusions. It was recommended that research be pursued to ascertain the genetic factors that modify phenotypic differences in the responsiveness of SCD patients to infections.

A workshop on “Protein Processing and Degradation in Pulmonary Health and Disease”, held in September 2001, and cosponsored by NHLBI and ORD, was designed to evaluate the current state of knowledge of protein biosynthetic processing and intracellular degradation.

A working group on “Targeting Technologies for Repair of Single Nucleotide Mutations in Single Gene-Defect Blood Diseases”, held in September 2001, assessed the potential of various approaches for correction of pathogenic single nucleotide mutations in SCD, beta-thalassemia, hemophilia A and B, and hemochromatosis.

A research training program designed for clinicians interested in performing biomedical research related to PH will be co-sponsored by NHLBI and the Pulmonary Hypertension Association. The training will be supported by the “Mentored Clinical Scientist Development Award” (NIH activity code K08).

A working group on translational research in PPH, sponsored by the ORD and NHLBI, is planned for FY2003.

Problem Areas Related to Rare Diseases

Alpha-1-Antitrypsin Deficiency

Research needs include better animal models of the disease, identification of biomarkers, and development of chemical chaperones that could specifically enhance the secretion of the mutant alpha-1 antitrypsin protein.

Arrhythmogenic Right Ventricular Dysplasia

A concerted multi-laboratory program, combining basic, clinical, and genetic approaches, is needed to identify the causes of this highly lethal form of cardiomyopathy. Once contributing factors are found, the next challenge will be to begin a search for therapies. Additional clinical centers, and perhaps a national registry, would be useful to investigators who are already studying the origins of ARVD and potential treatments.

Congenital Central Hypoventilation Syndrome

A significant limitation is the difficulty of recruiting CCHS subjects for clinical research. CCHS is a very rare condition often presenting within a few hours of birth. Only 150 surviving CHS patients are estimated to exist world-wide. Relocation to clinical research sites is made difficult by the spectrum of clinical symptoms associated with CCHS and related dysfunction of the autonomic nervous system.

Congenital Diaphragmatic Hernia

As a result of advances in ultrasonography, CDH is now diagnosed before birth with increasing frequency. Development of micro surgical techniques has made it possible to execute surgical repair in utero. With multiple options currently available to families, accurate counseling on the expected outcome is crucial. Scientific information must be provided to assist affected families in making decisions about management.

Congenital Heart Disease

Long-term follow-up studies are required to answer certain types of questions, but, because congenital heart disease is often repaired in infancy, such studies are difficult to initiate. Additional research is needed on adult congenital heart disease, pulmonary malformations in congenital heart disease, and pediatric ventricular assist devices.

Creutzfeldt-Jakob Disease

A standardized reference material repository is needed to validate assay systems to detect TSE. Materials under consideration to calibrate in-house reference materials of individual laboratories to a single international standard include human brain tissue, human blood, animal tissues, and animal blood. Blind panels are needed for validation of all assays, specifically the validation of their sensitivity, reproducibility, and predictive abilities. NHLBI is presently developing an initiative to support the establishment of a standardized reference TSE material repository.

Graft versus Host Disease

Promising agents that could be used to treat GvHD are also under investigation for use in other diseases, for example, arthritis. Pharmaceutical companies are reluctant to allow transplant research investigators access to these investigational drugs for fear that the complications experienced by HCT patients will interfere with the approval process for new agents.

Infectious Myocarditis

Dilated cardiomyopathy is thought to be a consequence of myocarditis in a subgroup of genetically predisposed people. Identification of the genetic basis for more severe disease may allow clinicians to target patients who would benefit from more aggressive therapy. There is a need for more specific and sensitive noninvasive methods for diagnosis. The current gold standard is endomyocardial biopsy but this procedure suffers from limited specificity and sensitivity. Also, the concept of myocarditis as an autoimmune phenomenon is supported by studies linking persistence of viral RNA in the myocardium to the induction of autoantibodies. More research is needed to determine the effectiveness of immunosuppressive modalities in myocarditis. NHLBI-supported investigators are tackling several of these problem areas.

Long QT Syndrome

Access and identification of sufficient numbers of new patients for studies remain a problem. Identification of mutant gene carriers would be greatly facilitated by accurate means of screening individuals in afflicted families for specific founder mutations. Improved means of identifying new mutations in the various genes involved would also be helpful. Investigators are working to increase the visibility of an international LQTS registry in minority communities.


LAM tissue is scarce and cell lines are difficult to establish and maintain. Currently no animal models of LAM exist.

Primary Pulmonary Hypertension

A detailed understanding of the function of the BMPR-2 gene has not yet been achieved, and how this gene may cause the structural and functional changes in the lungs of PPH patients is not clear. Although progress is being made, no animal models have been developed that completely mimic PPH in humans. The etiology and pathogenesis of PPH must be understood before successful therapies can be developed. Current therapies are cumbersome and expensive and are not effective for all patients. Innovative mechanisms are needed to accelerate the translation of new findings into better treatments for PPH.

Systemic Lupus Erythematosus (SLE)

The fear of miscarriage is a great concern for many pregnant women with SLE. Anticoagulation therapy of high risk pregnant women with antibodies to phospholipids needs to be evaluated.

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