MINUTES OF THE EIGHTY-FIRST MEETING OF THE SICKLE CELL DISEASE ADVISORY COMMITTEE

Bethesda, Maryland

November 5, 2001

COMMITTEE MEMBERS PRESENT

Dr. Gilda Barabino, J. Hoxi Jones-Carranza, Dr. Peter Lane, Dr. Herbert Meiselman, Dr. Jeanne Smith, Dr. Marie Stuart, Dr. Paul Swerdlow, Dr. Joseph Telfair, Dr. Tim Townes

COMMITTEE MEMBERS ABSENT

Dr. Oswaldo Castro

EX-OFFICIO MEMBERS PRESENT

Dr. Joseph DeSimone, Dr. Marie Mann, Dr. Robert Sheffler

EX-OFFICIO MEMBERS ABSENT

Dr. William Hannon

PROGRAM STAFF AND AFFILIATED ORGANIZATION REPRESENTATIVES:

Ms. Barbara Adam, (CDC); Dr. Barbara Alving, NHLBI/OD; Dr. Robert H. Broyles, Oklahoma Medical Research Foundation; Dr. Duane Bonds, DBDR/SCDSRG; Dr. Gregory Evans, DBDR/SCDSRG; Dr. Liana Harvath, DBDR/BRP; Dr. Steven Pavlakis, Beth Israel Hospital; Dr. Charles Peterson, DBDR/BDP; Ms. Sonya Ross, SCDAA, Dr. John Thomas DBDR/BDP, Dr. Ellen Werner, DBDR/BDP;

Executive Secretary - Dr. Charles M. Peterson

Secretary - Ms. Petronella A. Barrow

1. Dr. Charles Peterson called the meeting to order at 9:00 am and read the required notification regarding conflicts of interest and reminded those present to sign in on the required sign-in sheets.
2. Dr. Swedlow called for review of the minutes of June 4, 2001 they were reviewed and approved.
3. Dr. Swerdlow welcomed the members and guests. He recognized the difficulties in travel and would attempt to end the meeting in time for every one to make their travel connections.
4. Dr. Swerdlow introduced the Scientific Presentations.



A. Dr. Robert Broyles spoke on Specific repression of the beta-globin promoter (Proc. Natl. Acad. Sci. USA, Vol. 98, Issue 16, 9145-9150, July 31, 2001)


Developmental hemoglobin switching involves sequential globin gene activations and repressions that are incompletely understood. Earlier observations, described herein, led us to hypothesize that nuclear ferritin is a repressor of the adult -globin gene in embryonic erythroid cells. Our data show that a ferritin-family protein in K562 cell nuclear extracts binds specifically to a highly conserved CAGTGC motif in the -globin promoter at 153 to 148 bp from the cap site, and mutation of the CAGTGC motif reduces binding 20-fold in competition gel-shift assays. Purified human ferritin that is enriched in ferritin-H chains also binds the CAGTGC promoter segment. Expression clones of ferritin-H markedly repress -globin promoter-driven reporter gene expression in cotransfected CV-1 cells in which the -promoter has been stimulated with the transcription activator erythroid Krüppel-like factor (EKLF). We have constructed chloramphenicol acetyltransferase reporter plasmids containing either a wild-type or mutant -globin promoter for the 150 CAGTGC motif and have compared the constructs for susceptibility to repression by ferritin-H in cotransfection assays. We find that stimulation by cotransfected EKLF is retained with the mutant promoter, whereas repression by ferritin-H is lost. Thus, mutation of the 150 CAGTGC motif not only markedly reduces in vitro binding of nuclear ferritin but also abrogates the ability of expressed ferritin-H to repress this promoter in our cell transfection assay, providing a strong link between DNA binding and function, and strong support for our proposal that nuclear ferritin-H is a repressor of the human -globin gene. Such a repressor could be helpful in treating sickle cell and other genetic diseases.


B. Dr. Steven Pavlakis spoke on CNS imaging techniques for stroke prevention in SCD. The techniques available include MRI, quantitative MRI. T-1 analysis, Magnetic Resonance Spectroscpy, Diffuse Tensor Imagry, and Magnetic Resonance Angiography. These approaches are reviewed in the appended slides.



5. Chairman’s Report: Dr. Swerdlow gave an overview of October 2001 Council and the status of initiatives. In general, the initiatives involving hemoglobinopahties did quite well at Council.
6. DBDR Director’s Report: Dr Peterson reviewed the personnel changes at the Division of Blood Diseases and Resources. Dr. Alving has become Deputy Director of the Institute and Dr. Peterson is now Acting Director. Dr. Traci Mondoro has recently joined the Division and several additional staff are being sought. Dr. Alving noted that the monograph on Management and Therapy of Sickle Cell Disease is virtually complete and will be posted on the web for further review and comments. The availability of the monograph as a web document will also facilitate future additions and revisions.
7. Action Items from previous meeting were completed or discussed as follows:

A. Dr. Jeanne Smith represented the Sickle Cell Advisory Committee at the FDA meeting on leukoreduction. Se reported that the issues have gone away after it was pointed out that 90% of the problems with leukoreduction occur in donor units without hemoglobinopathies.

B. Dr. Swerdlow noted the importance of pain therapy for patients with sickle cell disease and volunteered to attend the FDA meeting of the Anesthetic and Life Support Drugs Advisory Committee and coordinate a response of the Sickle Cell Disease Advisory Committee as necessary. The meeting has been rescheduled for the end of January 2002.

C. The Protocol Review/DSMB Committees of BABY HUG are requested to report to the Committee regarding development of the protocol, age of participants, and considerations of therapeutic endpoints and potential toxicities. Since DSMB deliberations are ongoing, this discussion was postponed until the next meeting. This item is on hold due to a re-revision again by NHLBI and others.

D. The Committee concurred on the lack of data regarding quality of life issues and health services utilization and encouraged development of a workshop and a working group in the area. Members interested in serving on the working group are: Dr. Paul Swerdlow, Dr. Marie Mann, Dr. Joseph DeSimone, Dr. Joseph Telfair, Dr. Peter Lane Dr. Kenneth Bridges, Dr. Jeanne Smith, Dr. Lennette Benjamin, Dr. Jim Eckman, Ms. J. Hoxi Jones-Carranza, and Ms. Sonya Ross.

E. Dr. Swerdlow will convene an ad hoc committee to draft a statement on behalf of the Committee prior to the next meeting regarding ICD 9 codes for diagnoses of hemoglobinopathies as well as various sequelae of the main diseases. Dr. Lane will assist.

F. Dr. Joseph DeSimone distributed the funding opportunity from the VA entitled Research Training Initiative for historically Black Colleges and Universities and Hispanic Serving Institutions.

G. Dr. Bonds was encouraged to proceed with efforts in the area of Sickle Cell Disease and the Lung.

8. Agency Reports

A. Department of the Army: Dr. Sheffler’s report focused on the evolution of the army’s approach to screening for sickling blood disorders among new recruits. The present approach appears similar to that conducted by the U.S. Air Force. He will keep the committee advised regarding this issue.

B. Centers for Disease Control: Ms. Adams noted the many changes occurring in the methods of testing being used for neonatal screening. A laboratory has been established at the CDC to address issues in newborn screening quality assurance and quality control.

C. Health Resources and Services Administration: Dr. Marie Mann suggested that there were some potential to have grants of $300,000 for three years involving issues of neo-natal screening. At present none of the Agencies of DHHS has a budget so the exact programs have not been developed to date.

D. Veterans Administration: Dr. Joseph DeSimone noted that the VA is developing new funding opportunities for those that historically treat minority populations. The research training initiative for Historically Black Colleges and Universities and Hispanic-serving institutions was distributed to committee.

9. Update on Program Activities

Ask Dr. Bonds and Evans to send a summary of their updates???

10. Dates of Next Meetings

November 5, 2001

June 3, 2002

11. Summary List of Action Items

A. Dr. Swerdlow noted the importance of pain therapy for patients with sickle cell disease and volunteered to attend the FDA meeting of the Anesthetic and Life Support Drugs Advisory Committee and coordinate a response of the Sickle Cell Disease Advisory Committee as necessary. Rescheduled for the end of January 2002.

B. The Protocol Review/DSMB Committees of BABY HUG are requested to report to the Committee regarding development of the protocol, age of participants, and considerations of therapeutic endpoints and potential toxicities. Still under review by NHLBI.

C. The Committee recommended that a working group be formed regarding quality of life issues and health services utilization and encouraged development of a workshop in this area. Participants are: Dr. Paul Swerdlow, Dr. Marie Mann, Dr. Joseph DeSimone, Dr. Joseph Telfair, Dr. Lane and Ms. J. Hoxi Jones-Carranza.

D. Dr. Swerdlow would also convene an ad hoc committee to draft a statement on behalf of the Committee prior to the next meeting. Dr. Swerdlow noted that he would coordinate an outreach for the Committee to the AMA regarding the ICD 9 codes for SC disease and sickle beta thalassemia disorders, Dr. Lane will assist.

E. Dr. Bonds was encouraged to proceed with efforts in the area of Sickle Cell Disease and the Lung.




_____________________________ _______________

Paul Swerdlow, M.D. Date

Chairman

Sickle Cell Disease Advisory Committee




_____________________________ _______________

Charles M. Peterson, M.D. Date

Executive Secretary

Sickle Cell Disease Advisory Committee

Last updated: October 18, 2007