Parallel Universes

Traditional Treatments vs
Emerging Disease-modifying Therapies
for Neuromuscular Disorders
MARCH
Day 1
25
March 25, 2021 | Time: 1:00 PM EST – 4:00 PM EST
x Lambert-Eaton Myasthenic Syndrome (LEMS)

x Myasthenia Gravis
Watch archived

x Amyotrophic Lateral Sclerosis (ALS)

sessions on-demand at:
NeuroSeriesLive.com
APRIL
Day 2
11 April 1, 2021 | Time: 2:00 PM EST – 4:00 PM EST
x Spinal Muscular Atrophy (SMA)

Current
 Rett Syndrome Session

This activity is supported by educational grants from Acadia Pharmaceuticals Inc.; Alexion Pharmaceuticals, Inc.; 1
Biogen; Catalyst Pharmaceuticals; and Mitsubishi Tanabe Pharma America, Inc.
Rett Syndrome: Early Recognition and
Emerging Agents to Reduce Disease
Burden
Presented by:

David N. Lieberman, MD, PhD

Attending Child Neurologist
Assistant, Department of Neurology
Instructor of Neurology, Harvard Medical School
Boston Children’s Hospital
Department of Neurology

Julie A. Parsons, MD
Haberfeld Family Endowed Chair in Pediatric Neuromuscular Disorders
Professor of Clinical Pediatrics and Neurology
University of Colorado School of Medicine
Children’s Hospital Colorado

This activity is supported by educational grants from Acadia Pharmaceuticals Inc.; Alexion Pharmaceuticals, Inc.; 2
Biogen; Catalyst Pharmaceuticals; and Mitsubishi Tanabe Pharma America, Inc.
Faculty Disclosures

 David N. Lieberman, MD, PhD

− Consulting Fees: AveXis, Taysha Gene Therapies
− Contracted Research: Site PI for clinical trials
supported by Acadia Pharmaceuticals, Anavex Life
Sciences, GW Research Limited, and the Rett Syndrome
Research Trust

 Julie A. Parsons, MD
− Consulting Fees: Biogen, Genentech Roche, Novartis,
Scholar Rock
− Contracted Research: AveXis, Biogen, Scholar Rock
3
Learning Objectives

 Recognize the subtle signs and symptoms of Rett

syndrome to confirm diagnosis early in the disease
course
 Appraise the therapeutic potential of agents
currently being investigated for the treatment of
patients with Rett syndrome
 Describe the need for coordinated comprehensive
care provided at a specialty clinic, including
neurology, developmental pediatrics,
gastroenterology, orthopedics, speech, and
occupational- and physical-therapy specialists
4
Rett Syndrome Overview

 Historical perspective
 Clinical description and clinical course
 Genetic etiology
 Criteria for a clinical diagnosis
 Medical management of Rett syndrome
 Clinical trials: Risks/benefits, therapeutic
rationale, and mechanism of action

5
Audience Polling Question

How confident are you in

diagnosing Rett syndrome?

A. Very confident
B. Confident
C. Somewhat confident
D. Not at all confident

6
Historical Note

 In 1954, Dr. Andreas Rett, a pediatrician in Vienna, Austria, first noticed

two girls making the same repetitive hand-washing motions as they sat in
his waiting room with their mothers.
 After noticing similarities in their clinical and developmental histories, he
learned that he had 6 other girls with similar behavior in his practice.

Dr. Andreas Rett presenting a lecture December 16, 1987 Andreas Rett in front of the newly opened habilitation center in Vienna

Wertes unwertes Leben. Available at: www.bizeps.or.at/shop/leben2012.pdf.

Ronen GM et al. J Child Neurol. 2009;24(1):115-127.
7
Historical Note

Hagberg B et al. Ann Neurol. 1983;14(4):471-479. 8

Clinical Description

 A postnatal neurological disorder first recognized in infancy in girls

after an uneventful pregnancy
− Normal initial development
− Typical onset of regression at 6 and 18 months of age
− A slowing of the normal rate of head growth
 All racial and ethnic groups
− Worldwide in roughly 1 in 10,000 female births
 Age when various symptoms first appear and severity both vary
from one girl to another
 Common features: epilepsy, gross and fine motor impairment,
dysregulated breathing, growth retardation, dystonia, GERD,
constipation, feeding difficulties, scoliosis, and communication
disorder 9
Developmental Course

Hagberg Stages of Rett Syndrome

Stage I Stage III
 Early-onset stagnation  Plateau sage (pseudostationary)
 Age: 6 months to 1.5 years  Age: preschool to adulthood
 Developmental delay appears  Behavioral symptoms may improve
 Duration: months  Duration: decades

Stage II Stage IV
 Active developmental  Late-motor deterioration stage
regression: onset can occur  Age: when ambulation is lost
over weeks to months (those who never ambulate move
 Age: 1 to 4 years from Stage II to IV, 5-25+ years)
 Loss of motor function and  Rigidity, dystonia, spinal issues
coordination  Duration: up to decades
 Duration: weeks to months

Hagberg B. Ment Retard Dev Disabil Res Rev. 2002;8(2):61-65. 10

Clinical Description

 It is not a neurodegenerative disorder.

 There is no pronounced death of neurons, but a reduction in
the size of the neuron, the extent of branching of the
dendrites, and the extent of connections between neurons.
 In the early years, there may be a period of isolation or
social withdrawal, female may be irritable, disliking physical
contact, avoiding eye gaze, becoming indifferent to visual
and aural stimulation and crying inconsolably.
 May be misdiagnosed as autism, Angelman syndrome,
cerebral palsy, neuronal ceroid lipofuscinosis, or non-
specific developmental delay/intellectual disability.

11
Clinical Description (cont)

 With appropriate care, >70% of affected individuals live to at least

50 years of age.
 The most frequently reported causes of death (one-quarter of
deaths) are variations of sudden, unexplained death with no
apparent underlying cause, likely due to uncontrolled seizures,
fatal arrhythmia, aspiration, and pneumonia associated with lack
of mobility.
 Most individuals require substantial assistance with every aspect
of daily living.
 Over time, motor problems may increase, irritability may lessen,
and eye contact, interaction, and communication improve.
− Seizures and irregular breathing may improve.

12
Genetic Etiology

 1999: Mutations in the methyl-CpG-binding protein 2 (MeCP2)

gene at Xq28 on the X chromosome (lab of Huda Zoghbi, MD at
Baylor)
 X-linked dominant disorder
 Sporadic due to de novo mutations in the MECP2 gene in 99% of
cases
 MeCP2 protein is a member of a family of proteins known to bind
specifically to methylated DNA CpGs and capable of regulating
transcription
− The MeCP2 protein is believed to be both a transcriptional
repressor and activator, regulating the expression of many other
genes

Amir RE et al. Nat Genet. 1999;23(2):185-188.

Chahrour M et al. Science. 2008;320(5880):1224-1229. 13
Eight Common Mutations (i.e., “hot spots”)
Account for ~65% of Total Number of Mutations

 The closer the mutation is to the N-terminus, the more the severe the
phenotype is typically (“severe”: R106W, R168X, R255X, R270X)
 Severity of symptoms is thought to be due to the degree to which
there is residual MeCP2 function (milder vs more severe mutations)
and the degree of skewed X-inactivation
− Two same-age girls with the same mutation can appear different

Pejhan S et al. Biomolecules. 2021;11(1):75. 14

Diagnosis and
Experience
Caregiver Story
Diagnostic Criteria
Typical Rett
Main Criteria:
1. Partial or complete loss of acquired purposeful hand skills
2. Partial or complete loss of acquired spoken language
3. Gait abnormalities: impaired (dyspraxic) or absence of ability
4. Stereotypic hand movements, such as hand wringing/squeezing,
clapping/tapping, mouthing, and washing/rubbing automatisms

Neul JL et al. Ann Neurol. 2010;68(6):944-950. Boston Children’s Hospital Rett Syndrome Program Website. 16
Diagnostic Criteria
Atypical or Variant Rett
Required for atypical or variant Rett syndrome:
 A period of regression followed by recovery or stabilization
 At least 2 of the 4 main criteria
 Also needs to have 5 out of 11 supportive criteria fulfilled:

 Breathing disturbances when  Growth retardation

awake  Small cold hands and feet
 Bruxism when awake  Inappropriate
 Impaired sleep pattern laughing/screaming spells
 Abnormal muscle tone  Diminished response to pain
 Peripheral vasomotor  Intense eye communication
disturbances (aka “eye pointing”)
 Scoliosis/kyphosis

17
Neul JL et al. Ann Neurol. 2010;68(6):944-950.
Diagnostic Criteria
MECP2-Related Disorder
 An individual who does not satisfy the
requirements for classic or atypical/variant Rett
syndrome:
− May or may not have a period of regression
followed by recovery or stabilization
− May or may not have at least 2 of the 4 main criteria
− May or may not have 5 out of 11 supportive criteria
fulfilled
 And if that individual has a pathogenic MECP2
variation (mutation), then the patient is diagnosed
with an MECP2-related disorder

Neul JL et al. Ann Neurol. 2010;68(6):944-950. 18

Factors Affecting Early Diagnosis

 Diagnosis is typically made by a neurologist (35%), developmental

pediatrician (30%), or geneticist (22%), and infrequently by a
primary care provider (5%)*
 Median age of diagnosis: 2.7 years for classic and 3.8 years for
atypical
 Earlier diagnosis: delayed acquisition of basic gross motor skills or
finger feeding
 Later diagnosis: delayed acquisition of higher-level fine motor
skills, later onset of supportive features, and normal head
circumference
 Odds of a pediatrician making the diagnosis are higher if the child
has lost the ability to be consoled by being held or has stopped
reacting to the parents’ voice or the command “no”
*Tarquinio DC et al. Pediatr Neurol. 2015;52(6):585-591.e2. 19
Audience Polling Question

How confident are you in

managing a patient with Rett
syndrome?

A. Very confident
B. Confident
C. Somewhat confident
D. Not at all confident

20
Treatment and
Management
Caregiver Story
Natural History Study

 As part of the Rare Diseases Clinical Research Network,

the Rett Syndrome, MECP2 Duplication, and Rett-Related
Disorders Consortium (including FOXG1 syndrome and
CDKL5 Deficiency Disorder) is conducting the Rett
Syndrome Natural History Study (NHS)
− Ongoing since 2006, currently performed at 14 clinical sites in
the US
− Conduct longitudinal clinical assessment of the natural history
of Rett syndrome
− Develop phenotype-genotype correlations
− Set the stage for conduct of translational studies and emerging
clinical trials leading to disease modification

22
Percy AK et al. Ann Neurol. 2010;68(6):951-955.
Medical Management of Rett Syndrome

 Epilepsy: seizures vs Rett spells (episodes of autonomic

dysfunction)
 GI issues: feeding issues, GERD, constipation, abdominal
distention/gas
 Growth and nutrition: short stature and underweight
 Movement disorders: dystonia, chorea, tremor
 Autonomic dysfunction: breath-holding, hyperventilation, Rett spells
 Orthopedic: scoliosis/kyphosis, hip displacement, frequent fractures
 Endocrine: low bone density
 Cardiac issues: risk of QT prolongation
 Behavior: anxiety, mood swings, aggression, self-injury
 Sleep difficulties: sleep initiation, sleep maintenance
Fu C et al. BMJ Paediatr Open. 2020;4(1):e000717.
Fu C et al. BMJ Paediatr Open. 2020;4(1):e000731.
23
Medical Management of Rett Syndrome (cont)

Fu C et al. BMJ Paediatr Open. 2020;4(1):e000717. 24

Medical Management of Rett Syndrome
and MECP2-related Disorders
Epilepsy
 Most girls have abnormalities on baseline EEG by age 2
years
 ~60%-90% of those with either typical or atypical Rett will
have at least one seizure
 Age of onset of epilepsy: 25% by age 3 years, 50% by age
6 years, and 75% by age 13 years
 Those with atypical Rett and a severe clinical phenotype
had the highest prevalence of epilepsy
 No particular antiepileptic medication is more effective in
Rett syndrome

Tarquinio DC et al. Brain. 2017;140(2):306-318. 25

Medical Management of Rett Syndrome
and MECP2-related Disorders (cont)
GI issues
 Gastrointestinal dysmotility (92%)
 Feeding difficulties (81%)
 Constipation (80%)
 Chewing dysfunction (56%)
 Gas bloating (51%)
 Swallowing dysfunction (43%)
 Gastroesophageal reflux (38%)
 Delayed gastric emptying (14%)
 Biliary tract disease (4%)

Motil KJ et al. J Pediatr Gastroenterol Nutr. 2012;55(3):292-298. 26

Medical Management of Rett Syndrome
and MECP2-related Disorders (cont)
Growth and Nutrition
 Rett-specific growth curves; No pubertal growth spurt
seen
 May initiate puberty earlier (adrenarche/thelarche
i.e., Tanner 2 reached at 6-7 years vs 9 years), but
have menarche later (median age 13 years vs 12.5
years)
 Gastrostomy (1/3 cases) for extremely poor growth to
augment fluid intake, if there is risk of aspiration
(dysfunctional swallow) and/or if feeding times are
prolonged
Tarquinio DC et al. Neurology. 2012;79(16):1653-1661.
Killian JT et al. Pediatr Neurol. 2014;51(6):769-775. 27
Medical Management of Rett syndrome
and MECP2-related Disorders (cont)
Growth and Nutrition
Height and Weight in unaffected children (orange) and Head Circumference and Body Mass Index (BMI) in unaffected
children with classic Rett syndrome (blue) children (orange) and children with classic Rett syndrome (blue)

Height Head
Circumference

Weight
BMI

Tarquinio DC et al. Neurology. 2012;79(16):1653-1661. 28

Medical Management of Rett Syndrome
and MECP2-related Disorders (cont)
Scoliosis
 Most common orthopedic comorbidity, ~75% of individuals
 Onset ~11 years (80% have significant scoliosis by age 16
years)
− Progression is reduced when there is capacity to walk
independently or with assistance
 A Cobb angle of 40o prior to the age of 12 years indicates
progression to a very severe scoliosis by age 16 years is
likely
 Surgery should be considered when the Cobb angle is
approximately 40o to 50o

Downs J et al. Spine. 2016;41(10):856-863. 29

Medical Management of Rett Syndrome
and MECP2-related Disorders (cont)
Enriched Environment
 Physical therapy: use of a stander and/or gait trainer
 Occupational therapy: hand-under-hand guidance
 Speech therapy: use of augmentative and alternative communication
approaches
− Tablet-based: Proloquo2go, GoTalkNOW, TouchChat
− Eye-gaze-based devices: Tobii Dynavox and PRC Accent device

 When housed in an enriched environment, MECP2 null mice improved

motor abilities and increased levels of BDNF in the brain
 When girls with Rett syndrome were provided motor learning and exercise
supplemented with social, cognitive, and other sensory experiences over
a 6-month period, there was an increase on average of 8 points on the 45-
point motor scale and an increase in BDNF blood levels 1
30
Downs J et al. Orphanet J Rare Dis. 2018;13(1):3.
Medical Management/Intervention for
Rett Syndrome
 Epilepsy: divalproex sodium, oxcarbazepine, levetiracetam,
zonisamide
 GI Issues: omeprazole, PEG 3350, senna, docusate sodium, G-tube
 Growth and nutrition: nutritional calorie supplement, calorically-dense
complete nutrition formula via tube feeding
 Movement disorders: trihexyphenidyl, carbidopa/levodopa
 Autonomic dysfunction: sertraline, escitalopram, citalopram,
fluoxetine
 Scoliosis/kyphosis/impaired gait: TLSO brace, AFOs
 Bone health: vitamin D3, calcium carbonate, zoledronic acid
 Cardiac issues: propranolol, betaxolol
 Behavior: fluoxetine, guanfacine
 Sleep difficulties: clonidine, trazodone 31
Medical Management/Intervention for
Rett Syndrome (cont)
 Parents most interested in better treatments for:
− Seizures and Rett spells, communication, hand function,
ambulation, sleep, and constipation
 How do we cut down on the number of medications and
interventions used to treat and manage complications?
 How do we improve core features of Rett syndrome that
current medications cannot treat?
 When do we have to intervene?
 Need to look toward basic molecular pathways that are
altered in Rett syndrome

32
Feasibility of Therapeutic Intervention
in Rett Syndrome
Question: Does MECP2 deficiency during development lead to
permanent impairment of neuronal function, or can restoration of
MECP2 function even at older ages rescue some of the neuronal
deficits?
Genetic “trick” of silencing MECP2 expression during development
… then turning it on in adolescence (when symptomatic)
Male Mice Drug that turns on

MECP2
Impairments in
motor function,
No drug breathing, and
movement disorders
MECP2
can be reversed.

Guy J et al. Science. 2007;315(5815):1143-1147. 33

Possible Therapeutic Interventions

Targets and treatment strategies: Downstream Targets of MECP2

1) Neurotransmitter signaling
a) Glutamate: ketamine, memantine
MECP2-mediated pathway: b) Monoamines: serotonin, desipramine,
1) Activate silent wild-type copy of citalopram, sarizotan
MECP2 c) GABA: midazolam
2) Introduce healthy MECP2 gene copy d) Acetylcholine: acetyl-L-carnitine
(AAV9 vector)
2) Growth factor signaling pathway
3) CRISPR-mediated gene editing a) BDNF/Trk-B: glatiramer, fingolimod
approaches b) IGF-1: rhIGF-1, (1-3) IGF-1 (trofinetide)
4) Read through compounds
3) Metabolic pathways
a) Lipids: statins: lovastatin
b) Glucocorticoids: corticosterone
c) Oxidative Stress/Mitochondrial Targets:
triheptanoin, sigma-1 receptors (blarcamesine)
d) Modulation of intracellular calcium and adenosine-
mediated signaling (cannabidiol)

Katz DM et al. Trends Neurosci. 2016;39(2):100-113. 34

Clinical Studies

 Ketamine: NMDA receptor antagonist

 Cannabidiol (CBD)
 Trofinetide (IGF-1 tripeptide)
 Blarcamesine (sigma-1 receptor agonist)
Many of these compounds aim to change the
excitatory/inhibitory balance in the brain

35
Ketamine

Glutamate function in Rett syndrome:

 Decreased excitatory drive in the neocortex thought to contribute to
cognitive and behavioral abnormalities
 Brainstem hyperexcitability is thought to cause paroxysmal
respiratory and autonomic events
− Both are reproduced in the MECP2 mutant mouse model
 In MECP2 mutant mice, acute treatment with ketamine can
increase cortical network function and decrease synaptic
excitability in brainstem networks important for respiratory and
autonomic control (lab of Dr. David Katz, Case Western)
 Daily exposure to ketamine ameliorated RTT symptoms and
extended the life span of treated MECP2-null mice without
adverse side effects (lab of Dr. Michela Fagiolini, Boston
Children’s Hospital)
Kron M et al. J Neurosci. 2012;32(40):13860-13872. 36
Ketamine Trial

A randomized, double-blind, placebo-controlled, cross-over

study to assess the safety, tolerability and efficacy of oral
ketamine for patients with Rett syndrome*
 Eligibility: age 6-12 years with either classic or atypical Rett
 48 participants over 6 sites in up to 4 ascending dose cohorts
(12 patients/cohort), each assessing 1 dose level of ketamine vs
placebo in 4-week cross-over design:
− 0.75 mg/kg BID for 5 days
− 1.5 mg/kg BID for 5 days
− 3.0 mg/kg BID for 5 days
− 4.5 mg/kg BID for 5 days
 Primary Outcome Measure:
− Dose-limiting adverse events

*ClinicalTrials.gov Identifier: NCT03633058. 37

Cannabidiol (CBD)

 CBD extracts are prepared from Cannabis sativa plants and

purified to ≥98% with <0.1% THC (the psychoactive component of
cannabis)
 CBD may affect intracellular Ca2+ mobilization via antagonism of
the G protein-coupled receptor 55 (GPR55), extracellular calcium
influx via transient receptor potential vanilloid type 1 (TRPV1)
channels, and adenosine-mediated signaling
 CBD demonstrates anticonvulsant, antipsychotic, anxiolytic,
neuroprotective, antioxidant, and anti-inflammatory activity and
received FDA approval for the treatment of epilepsy due to
Lennox-Gastaut syndrome or Dravet syndrome
 Side effects reported include sleepiness, loss of appetite,
diarrhea, vomiting, fever, and fatigue

38
Cannabidiol

Efficacy and safety of cannabidiol oral solution in patients with

Rett syndrome*
 Eligibility: age 2-18 years with either classic (typical) or atypical Rett
 252 participants over 14 sites in a 24-week trial
 Cannabidiol 5 mg/kg/day vs 15 mg/kg/day vs placebo
 Primary outcome measures:
− Rett Syndrome Behavior Questionnaire (RSBQ)
− Clinical Global Impressions – Improvement (CGI-I)
 Secondary outcome measures:
− Rett Syndrome Behavior Questionnaire subscales
− Clinician Global Impressions – Severity Scale (CGI-S)
− 9-items Motor Behavioral Assessment (MBA-9)
− Children's Sleep Habits Questionnaire (CSHQ)
*ClinicalTrials.gov Identifier: NCT03848832. 39
Trofinetide

 Trofinetide (NNZ-2566): 2-methylproline-substituted

analogue of glycine-proline-glutamate, which is the
N-terminal tripeptide cleavage product of insulin-like growth
factor 1 (IGF-1)
 Systemic treatment of Mecp2 mutant mice with the active
tripeptide fragment of IGF-1 extends the lifespan of the
mice, improves locomotor function, improves breathing
patterns, reduces irregularity in heart rate, increases brain
weight of the mutant mice, partially restores spine density
and synaptic amplitude, increases PSD-95, and stabilizes
cortical plasticity to wild-type levels

Tropea D et al. Proc Natl Acad Sci USA. 2009;106(6):2029-2034 . 40

Trofinetide: Favorable Safety and Tolerability
Profile in Initial Studies
 Neu-2566-RETT-001 (NCT01703533); phase II in 56
adolescent and adult females (16-45 years) 1
• Tested 35 mg/kg BID vs 70 mg/kg BID vs placebo

 Neu-2566-RETT-002 (NCT02715115); phase II in 82

pediatric and adolescent females (5-15 years)2
• 50 mg/kg BID vs 100 mg/kg BID vs 200 mg/kg BID vs placebo
• Statistically significant difference from placebo at P<0.05 for
the 200 mg/kg BID dose group on the Rett Syndrome
Behavior Questionnaire (RSBQ), RTT-Clinician Domain
Specific Concerns–Visual Analog Scale (VAS), and Clinical
Global Impression Scale–Improvement (CGI-I)

1. Glaze DG et al. Pediatr Neurol. 2017;76:37-46.

2. Glaze DG et al. Neurology. 2019;92(16):e1912-e1925. 41
Trofinetide: Favorable Safety and Tolerability
Profile in Initial Studies (cont)

At the end of the dosing period, the

clinical benefit (change from treatment
Improvement is decrease in score baseline) was continuing to accrue

 Side effects: Diarrhea, vomiting, upper respiratory tract infection,

irritability, difficulty sleeping, sleepiness, drooling, seizures

Glaze DG et al. Neurology. 2019;92(16):e1912-e1925. 42

Trofinetide: LAVENDER and LILAC Studies

Phase III study in 184 girls with Rett syndrome across 17 sites
 LAVENDER:
− 12-week, placebo-controlled study, 200 mg/kg BID eligibility: girls
and women age 5-20 years1
− Co-primary efficacy endpoints:
• Rett Syndrome Behavior Questionnaire (RSBQ)
• Clinical Global Impression Scale-Improvement (CGI-I)
 LILAC: 40-week open-label extension2
− All participants completing the 12-week LAVENDER study may be
eligible to enroll in the LILAC study
− To evaluate long-term tolerability and safety of trofinetide
1. ClinicalTrials.gov. NCT04181723.
2. ClinicalTrials.gov. NCT04279314.
43
Blarcamesine (Sigma-1 Receptor Inhibitor)

 May activate sigma receptors in endoplasmic reticulum

membrane and modulate the activity of ion channels and
signaling molecules, inositol phosphates, protein kinases,
and calcium channels to modulate calcium homeostasis and
mitochondrial function.
 Activation of sigma-1 receptors can attenuate oxidative
stress linked to inflammatory glial responses and increase
the release of brain-derived neurotropic factor (BDNF),
which are altered in MECP2 deficiency.
 Side effects: dizziness, headache, nausea, vomiting,
diarrhea, abdominal pain at high doses

44
Blarcamesine in Rett Syndrome

 Phase II safety, tolerability, and efficacy study

 Double-blind, randomized, placebo-control
 31 patients, 18 to 45 years
 7 weeks
 Voluntary option for all patients who meet the exposure
criteria for blarcamesine to continue on a 12-week open
label extension

ClinicalTrials.gov. NCT03758924. 45
Blarcamesine in Rett Syndrome (cont)

 Primary Outcome
− Incidence of adverse events
− Maximum plasma concentration [Cmax] of blarcamesine
− Area-under-the-curve [AUC] of blarcamesine
− Lipid panel
 Secondary Outcome
− Rett Syndrome Behavior Questionnaire (RSBQ)
− Clinical Global Impression of Improvement (CGI-I)
 Others: glutamate and GABA plasma concentration

ClinicalTrials.gov. NCT03758924. 46
Gene Therapy: What Is on the Horizon?

 OAV021 – seeking IND submission 2021

− Delivers MECP2 gene to the brain via an AAV9
viral vector (very similar to gene therapy SMA)
− Clinical trials after IND approval
 TSHA-102 – seeking IND submission 2021
− Uses a modified AAV9 viral vector to deliver a
working version of the MECP2 gene

Rett Syndrome Research Trust. 47

Thank You!

 To our patients
 To our families
 To the Rett Syndrome Association of Massachusetts (RSAM, now Rett
Syndrome Angels)
 To Rettsyndrome.org and the Rett Syndrome Research Trust for their
support

48
Q&A
with the experts

49
Patient Advocacy
•Collaborates with local, state, and federal agencies on policies that  Has supported the
encompass the needs of rare-disease patients
identification, treatment,
Patient Organization Mentorship
and cure of rare disorders
•Supports the establishment and growth of disease-specific for nearly 40 years
organizations so they can better serve their patients

 Partners with >300

Patient and Professional Education
•Educates patients and their families, physicians, and
disease-specific patient
other health care professionals about rare diseases
and their dedicated organizations organizations
Research Support  Access resources at:
•Provides grants to facilitate rare-disease research and
establish disease-specific registries − https://rarediseases.org

Patient Assistance Program

•Offsets the costs of treatment, clinical-trial participation,
and access to services

International Partnerships
•Represents the US and collaborates with global partners dedicated
to addressing the global health challenge of rare diseases
50
More Information and Support

www.rettsyndrome.org

https://reverserett.org www.childneurologyfoundation.org

51
What’s Available from the 2021
Neuromuscular Series?
Available Day 1
On-Demand at:
March 25, 2021 | Time: 1:00 PM EST – 4:00 PM EST
x 1:00pm
 Lambert-Eaton Myasthenic Syndrome (LEMS)
Earn up to 3 credits; x 2:00pm
 Myasthenia Gravis
CME/CE-certified x 3:00pm
 Amyotrophic Lateral Sclerosis (ALS)

Day 2
Available
April 1, 2021 | Time: 2:00 PM EST – 4:00 PM EST
x 2:00pm
On-Demand at:
 Spinal Muscular Atrophy (SMA)
x 3:00pm
 Rett Syndrome
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Considerations for AAV Gene Therapy
for Rett Syndrome

Goldilocks Principle

The amount of MECP2 protein:

 Can’t be too little
 Can’t be too much
 Needs to be just right

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Clarke AJ et al. Orphanet J Rare Dis. 2018;13(1):44.
Goldilocks Principle
The Amount of MECP2 Protein Needs to Be Just Right in Neurons

Too much protein can lead to symptoms of MECP2 duplication syndrome:

 intellectual disability
 limited to absent speech
 infantile axial hypotonia that often leads to progressive spasticity
 movement problems (including tremor)
 susceptibility to respiratory infections
 autistic features
 difficult-to-control epilepsy
Too little protein will result in Rett syndrome, though perhaps milder
phenotype

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