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HIBM Hereditary Inclusion Body Myopathy

HIBM Hereditary Inclusion Body Myopathy. Daniel K. Darvish, MD December 12, 2007 IALSN, San Diego. 2007. Daniel & Babak. 1996. HIBM/IBM2/DMRV. Quadriceps Sparing Myopathy >80% on WC within 10-20y Prevalent in Jews of Iranian descent. Ten Tribes of Israel People of Judea.

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HIBM Hereditary Inclusion Body Myopathy

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  1. HIBMHereditary Inclusion Body Myopathy Daniel K. Darvish, MD December 12, 2007 IALSN, San Diego

  2. 2007 Daniel & Babak 1996

  3. HIBM/IBM2/DMRV • Quadriceps Sparing Myopathy • >80% on WC within 10-20y • Prevalent in Jews of Iranian descent

  4. Ten Tribes of IsraelPeople of Judea Iranian Jewish Migration

  5. Iranian Jewish MigrationFollowing Iranian Revolution 1979

  6. Personal Story • Rare disease, realization and acceptance • Meeting the experts, the hunt for gene-defect • Need for funds: Advancement of Research for Myopathies (ARM), non-profit org. • Need for bio-materials: HIBM Research Group, non-profit lab

  7. GNE Genomic region 62,000 bp Chr 9 GNE - mRNA = 3500-4500bp 722 AA UDP-GlcNAc 2-Epim / ManNAc Kinase IBM2 Genetics - GNE • IBM2 is associated with bi-allelic mutations on the GNE Gene. GNE codes for UDP-N-Acetylglucosamine 2-Epimerase / N-Acetylmannosamine Kinase, the rate limiting enzyme in sialic acid synthesis.

  8. ManNAc(Intermediate) ManNAc-6p(Intermediate) SialicCMP-Neu5Ac(Product) Biochemical Pathway GNE is the key enzyme for sialic (Neu5Ac) synthesis UDP-GlcNAc(Substrate)

  9. Role of Sialic • The only negatively charged sugar on glycoproteins. Vital cell-cell signaling. • Our understanding of role of Sia in muscle is incomplete (e.g. a-dystroglycan, ion channels, etc.) • Gne-/- mice do not survive gestation

  10. C303X -Ind A460V -Jap G134V -Ca R246W -Ca R246Q -Bah C303V -Jap A631T -Ga A631V -Jap D260K R266W,Q,X D225N -Bah R263L,Q A524V -Tx V572L -Jap V696M -Ind G576E -Ga Y675H -Tx M712T -Iran H2N- -COOH 722 AA 1 378 410 684 TLVLFPNIDAGSKEMVRVMRKKGIEHHPNFR A200V V331A zI557T R306Q H132Q P36L D378Y T587C F528C R177C D176V I472T Allosteric Domain Sialuria Mutations Found in man D255Y,X H273Y V249D N275T Sialuria (Hyperactive) Enzyme

  11. French Type Sialuria • Course faces, hepatospelomegaly, mild retardation. • At 10 months of age, urinary sialic acid 14,680umol/mmol creatinine (control <75umol/mmol). • Mother’s urinary sialic acid, 4,278 umol/mmol creatinine. • Physical strength in adult is near normal.

  12. Therapeutic Strategies • Administration of Sialic Acid biosynthesis pathway substrates, intermediates, or product (N-Acetylmannosamine). • Gene therapy using normal or Sialuria forms of GNE. • Cell therapy using own genetically modified myogenic stem cells.

  13. N-Acetylmannosamine • Advantages • High chance of correcting sialylation defects. • May work by oral route. • Disadvantages • Safety and cellular integration of oral, IV, or IM administration has not been established yet. • Assumes HIBM/DMRV is due to relative lack of Sia

  14. Gene Therapy HIBM/IBM2/DMRV maybe an ideal candidate • Skeletal muscle is the ideal tissue for gene therapy. • GNE is small enough to fit in safe and effective vectors • Low levels of expression may rescue the whole myofiber. • Hyperactive (sialuria) forms of the enzyme is available, and expression in limited number of fibers may be sufficient. • Treatment of only a few major muscle groups may be sufficient. • Host antibody response to the expressed protein is highly unlikely.

  15. Stem Cell Therapy • Advantages • Possible to use patients own genetically modified cells (autograph) • Technique has been used on numerous other patients (allographs) • Disadvantages • Numerous injections and repeat therapy may be needed • Requires complex ex-vivo techniques (not suitable for scale-up)

  16. Clinical Development Pipeline IND Application Process NDA Application Process Pre-Clinical I II III IV • Clinical Trials ($$$) • Phase I – Safety • Phase II – Efficacy • Phase III – Confirm • Phase IV- Post Market Monitoring / Sustain manufacturing of product. • Cell Culture Studies • Assay Development • Animal Studies • Toxicology/Safety Studies ($$) • Manufacturing, cGMP, GLP, ($$)

  17. Is Therapy Discovered? Virtual Pipelines

  18. Scientific Leaders

  19. Non-scientific (ARM) Public awareness, fundraising, and public relation. Raise scientific interest through competitive grant program. Scientific (HRG) Provide bio-materials and reagents specific for HIBM. ARM Grant administration. Patient relations, including registry, genetic counseling/testing. Challenges 2000

  20. Non-scientific (ARM) Lack common vision Lack of experienced non-profit leadership Personality conflicts Stigma Scientific (HRG) Rare disease Lack of interest Lack of bio-materials Lack of resources Lack of funding Challenges 2000 - 2004

  21. Non-scientific (ARM) Lack common vision Lack of experienced non-profit leadership Personality conflicts Stigma Lack of exposure Scientific (HRG) Rare disease Lack of interest Lack of bio-materials Lack of resources Lack of funding Challenges 2004 - 2007

  22. Non-scientific (ARM) Sustaining effective non-profit governance Sustaining interest Sustaining public exposure Scientific (HRG) Phase I/II, New Drug Application (NDA) Adjunctive Therapies: Myotrophic agents (IGF, Myostatin inhibition) Phase IV and manufacturing Future Challenges

  23. Other Patients (Media Kit)http://www.hibm.org

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