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
●Limited effective treatment
●Biochemical and molecular facilities scarce
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
The Past
●Natural History Study I
●Grant written in 2003
●Consisted of Angelman, Rett, and PraderWilli Syndromes
●Rett syndrome focus: Classic and Variant
forms; MECP2 Duplication Disorder unknown
●Enrollment began in March 2006
●Significant assistance from IRSA
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
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
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)
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
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
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
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
A Major Challenge
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.
Framing Regression in RTT
Age at
Regression
Classic
RTT
Variant RTT
Higher level
Lower level
< 6 months
13 (1.7%)
3 (4.4%)
27 (38%)
6 - < 12 mos
54 (7.0%)
2 (2.9%)
9 (12%)
12 - < 18 mos 281 (36%)
2 (2.9%)
15 (21%)
18 – 30 mos
351 (46%)
26 (38%)
10 (14%)
> 30 mos
74 (9.6%)
35 (52%)
11 (15%)
Total
773
68
72
Diagnosis and Enrollment
Group
Classic
Atypical
Group
Classic
Atypical
Age at Diagnosis
N
Mean
Standard
Deviation
852
4
5
149
6
6
Age at Enrollment
N
Mean
Standard
Deviation
852
149
9.8
9.1
8.9
8.1
Median
6.0
7.0
Who is making diagnosis?
Diagnosing
Specialist
Classic
Variant
Total
Neurologist
307 (36%)
48 (31%)
355 (35%)
Developmental
Pediatrician
276 (32%)
55 (36%)
331 (33%)
Geneticist
192 (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%)
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.
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.
RESEARCH TODAY
MECP2 Mutations and CSS
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
PHARMACOLOGIC APPROACHES
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
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
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
MeCP2 Restoration
●Missense mutations: Reactivate full-length
protein
●Nonsense (Stop) mutations: Promote fulllength protein; may require ‘reactivation’
●Deletions/insertions: More complicated –
requires more thinking
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
●
●
●
●
Alan Percy
Jane Lane
Suzie Geerts
Jerry Childers
● UAB
● Girls and women with
RTT and their families
Young friend with Rett syndrome
My first friend with
Rett Syndrome