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

●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 Why rare diseases are important

●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 Natural History Study Goals

●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 The Past

●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 Natural History Study

●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 The Present

●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) Natural History Study

●>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 MECP2 and Rett Syndrome! What we have learned

●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 The Future

●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 Future Goals

●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 Importance of SRSA

A Major Challenge

●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. Framing Regression

Age at Regression Classic RTT Variant RTT Higher level Lower level < 6 months13 (1.7%)3 (4.4%)27 (38%) 6 - < 12 mos54 (7.0%)2 (2.9%)9 (12%) 12 - < 18 mos281 (36%)2 (2.9%)15 (21%) 18 – 30 mos351 (46%)26 (38%)10 (14%) > 30 mos74 (9.6%)35 (52%)11 (15%) Total Framing Regression in RTT

Age at Diagnosis GroupNMeanStandard Deviation Classic85245 Atypical14966 Age at Enrollment GroupNMeanStandard Deviation Median Classic Atypical Diagnosis and Enrollment

Diagnosing Specialist ClassicVariantTotal Neurologist307 (36%)48 (31%)355 (35%) Developmental Pediatrician 276 (32%)55 (36%)331 (33%) Geneticist192 (22%)39 (26%)231 (23%) Pediatrician 45 (5.3%) 4 (2.7%)49 (4.9%) Other 37 (4.3%) 7 (4.6%)44 (4.4%) Who is making diagnosis?

●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. What must be done?

●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. Steps to accomplish the goal

RESEARCH TODAY

MECP2 Mutations and CSS

●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 Research in Critical Transition

PHARMACOLOGIC APPROACHES

●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 Prior Clinical Trials

Gene correction Problem: Correcting only abnormal alle le 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 Gene 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 Symptomatic Therapy

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

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

Young friend with Rett syndrome

My first friend with Rett Syndrome