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DEX-M74 for Hereditary Inclusion Body Myopathy

Hereditary Inclusion Body Myopathy (HIBM) is a rare genetic disorder, characterized by progressive muscle weakness resulting in severe incapacitation. HIBM has been traced to specific mutations in the GNE gene and the biochemical pathways this gene affects within muscle cells. There are no approved therapies for HIBM, and treatment is limited to palliative care. This purpose of this project is to develop a small molecule (DEX-M74) specifically targeted to address the biochemical pathway deficits caused by the GNE mutations that lead to muscle wasting.

Scientific Synopsis

Hereditary Inclusion Body Myopathy (HIBM) is a rare adult-onset neuromuscular disorder characterized by progressive muscle weakness resulting in severe incapacitation within 10 to 20 years after onset. HIBM is a genetic disorder that has been traced to mutations in the gene GNE. GNE encodes an enzyme, UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase, which catalyzes the first two steps in the biosynthesis of sialic acid (SA). The subsequent deficiency of SA production is presumed to cause decreased sialylation of muscle glycoproteins resulting in muscle degeneration in the disease.

Recent studies have implicated the SA precursor N-acetyl-D-mannosamine (ManNAc, or DEX-M74) as a potential therapeutic agent for the treatment of HIBM. The National Human Genome Research Institute at the NIH filed a patent application on the use of ManNAc for the treatment of HIBM, and it filed an investigational new drug application with the Food and Drug Administration (FDA) in 2007 to conduct a Phase I/II clinical trial testing the safety and efficacy of ManNAc in HIBM patients. The FDA issued a hold on this clinical trial, citing the need for additional pre-clinical studies.

The purpose of this project is to complete these additional pre-clinical studies and prepare a complete response to the FDA clinical hold such that the clinical trial can move forward.

Key Investigator

National Human Genome Research Institute Intramural Research Program and NIH Clinical Center, Bethesda, Md.
William Gahl, M.D., Ph.D.

Public Health Impact

There are no FDA-approved therapies for HIBM, and treatment is limited to palliative care. There is a clear, high-priority unmet medical need. NIH owns related intellectual property for the use of the compound to treat HIBM patients, and has designed a Phase I/II clinical trial to do so. The regulatory affairs support required to move this project forward will provide important information adaptable to future TRND projects in the rare disease space.

Outcomes

TRND supported the completion of two pivotal animal toxicology studies necessary to prove drug safety. TRND also generated required data on the manufacturing processes employed to produce the final drug product. To gather the information on the disease required for a clinical trial, TRND began a natural history study of HIBM disease progression in 2011.

Press/Publications

  • Gleano, et al. Mutation in the key enzyme of sialic acid biosynthesis causes severe glomerular proteinuria and is rescued by N-acetylmannosamine. J Clin Invest., 117(6):1585-1594. 2007. [PubMed]
  • Malicdan, et al. Prophylactic treatment with sialic acid metabolites precludes the development of the myopathic phenotype in the DMRV-hIBM mouse model. Nature Medicine, 15(6):690-695. 2009. [PubMed]
  • Huizing and Krasnewich. Hereditary Inclusion Body Myopathy: A Decade of Progress. Biochim Biophys Acta, 1792(9):881-887. 2009. [PubMed]

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