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Research Update SRSA Family Meeting Alan K. Percy, MD August 3 , 2013

Research Update SRSA Family Meeting Alan K. Percy, MD August 3 , 2013. Why rare diseases are important. True burden difficult to estimate Little general information available Absence of reliable or consistent data Difficult research funding Inadequate health service coverage

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Research Update SRSA Family Meeting Alan K. Percy, MD August 3 , 2013

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  1. Research UpdateSRSA Family Meeting Alan K. Percy, MDAugust 3, 2013

  2. Why rare diseases are important • True burden difficult to estimate • Little general information available • Absence of reliable or consistent data • Difficult research funding • Inadequate health service coverage • Limited effective treatment • Biochemical and molecular facilities scarce

  3. Natural History Study Goals • Advance clinical research • Develop longitudinal data through uniform protocols for data collection • Assess phenotype-genotype correlation • Engage in pilot projects to set stage for randomized clinical trials • Engage patients and advocates as partners • Enhance training of new investigators

  4. The Past • Natural History Study I • Grant written in 2003 • Consisted of Angelman, Rett, and Prader-Willi Syndromes • Rett syndrome focus: Classic and Variant forms; MECP2 Duplication Disorder unknown • Enrollment began in March 2006 • Significant assistance from IRSA

  5. Natural History Study • Goal: Enroll 1000 girls or women with RS • Must meet criteria or have MECP2 mutation • Purpose: expand phenotype-genotype studies and set stage for clinical trials • Principal sites: Baylor, Greenwood Genetic Center, and UAB • Travel Clinics: Oakland, Chicago, NJ, Florida • DMCC: Contact Registry • rarediseasesnetwork.epi.usf.edu

  6. The Present • Natural History Study II • Continuation grant funded in 2009 • Rett syndrome now included Classic and Variant forms, MECP2 Duplication Disorder, and MECP2 positive, non-Rett individuals • Increased enrollment goal to 1350 • Principal sites: Children’s Hospital Boston, Baylor, Greenwood Genetic Center, and UAB • IRSF now provides support for Rett portion

  7. Natural History Study • Current enrollment = 1093 participants • ~40% enrolled at travel clinics • Rett syndrome = 853 • Variant forms = 149 • MECP2 positive, non-Rett = 91 • Females = 46 (8 with MECP2 duplications) • Males = 45 (26 with MECP2 duplications)

  8. MECP2 and Rett Syndrome! What we have learned • >95% of classic RTT have MECP2 mutations • 8 mutations account for ~ 60% • Deletion or insertions about 15-18% • Incidence: ~1:10,000 female births • Mainly sporadic: majority of paternal origin • Familial Rett syndrome is <<1% of total • Variant forms account for ~15% • MECP2 mutations in approximately 75% • And much more

  9. The Future • New application likely in Fall 2013 • Restrict to MECP2 and related disorders • Rett syndrome; MECP2 duplication disorder; MECP2-related disorders: CDKL5, FOXG1, and MECP2-positive-non-RTT • Travel clinics to be phased out; addition of enrollment sites in Chicago, Denver, California, and Philadelphia

  10. Future Goals • Improve early diagnosis • Expand biobank: X chromosome inactivation, whole exome sequencing, etc. • Develop and customize outcome measures • Expand clinical trials • Work with international sites to increase presence of uniform data collection and potential participants for clinical trials

  11. Importance of SRSA • Continued role in promotion of research and recruitment of participants • Promotion of information exchange between basic and clinical research to facilitate translational research pipeline • Continued opportunities to meet with and update families on progress

  12. A Major Challenge

  13. Framing Regression • The point at which an individual loses, either partially or completely, previously acquired skills. • In Rett syndrome, regression is related to loss, partially or completely, of previously acquired skills in fine motor function and spoken language or communication.

  14. Framing Regression in RTT

  15. Diagnosis and Enrollment

  16. Who is making diagnosis?

  17. What must be done? • If we are to begin treatment as early as possible, earlier diagnosis is required. • We need to make certain that primary care physicians are knowledgeable of and are empowered to diagnose RTT. • It is our responsibility as physicians, but IRSF and all interested individuals can make a major difference.

  18. Steps to accomplish the goal • Provide information through the American Academy of Pediatrics • Stress the importance of this information on education and training programs in medical and allied health schools. • Work with public health agencies at local, state, and federal levels to spread the word.

  19. RESEARCH TODAY

  20. MECP2 Mutations and CSS

  21. Research in Critical Transition • Increase in individuals with RTT and other MECP2-related disorders • Animal models of human mutations • Single cell culture: neurons or glia • Tissue slices: specific brain regions • Stem cells: from human skin fibroblasts • Differentiated to neurons or glia or cell type of interest • Testbeds for research and drug discovery • No viable direct therapy……..YET

  22. PHARMACOLOGIC APPROACHES

  23. Prior Clinical Trials • Lamotrigine for seizures • Bromocriptine for motor performance • Naltrexone for periodic breathing • Folate-betaine to increase methyl-binding • Little benefit aside from improved seizure management with lamotrigine

  24. Gene Therapy • Gene correction • Problem: Correcting only abnormal allele • Stem cell transplant • No effect in symptomatic male mice; some improvement in asymptomatic females • Noted positive response in microglia • Suggests role for pharmacologic approach • X chromosome activation of normal allele • Critical: activate normal allele in all cells

  25. Symptomatic Therapy • Serotonin reuptake inhibitors • ameliorate anxiety • NMDA receptor blocker: Memantine • reverse glutamate hyperexcitability • IGF-1: full length and tri-peptide • downstream effect in BDNF cascade • BDNF mimetics: TrkB agonists • restore BDNF levels • Read-through compounds: Stop mutations • produce full length MeCP2

  26. MeCP2 Restoration • Missense mutations: Reactivate full-length protein • Nonsense (Stop) mutations: Promote full-length protein; may require ‘reactivation’ • Deletions/insertions: More complicated – requires more thinking

  27. The Team • Baylor College of Medicine • Daniel Glaze • Kay Motil • Jeff Neul • Judy Barrish • Greenwood Genetic Center • Steve Skinner • Fran Annese • Lauren McNair Baggett • NIH: ORDR/NICHD • CHB • Walter Kaufmann • Daniel Tarquinio • Katherine Barnes • Heather O’Leary • UAB • Alan Percy • Jane Lane • Suzie Geerts • Jerry Childers • Girls and women with RTT and their families

  28. Young friend with Rett syndrome

  29. My first friend with Rett Syndrome

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