Safety and Efficacy of TSHA-102 in Adult Females With Rett Syndrome (REVEAL Adult Study)

Study Overview
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Brief Summary
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The REVEAL Adult Study is a multi-center, Phase 1/2 open-label, dose-escalation study of TSHA-102, an investigational gene therapy, in adult females with Rett syndrome. The safety, tolerability, and preliminary efficacy of two dose levels will be evaluated. The study duration is estimated to be up to 63 months.

Official Title
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Open-label, Randomized, Dose-escalation and Dose-expansion Study of the Safety and Preliminary Efficacy of a Single Intrathecal Administration of TSHA-102, an AAV9-Delivered Gene Therapy, in the Treatment of Adult Females With Rett Syndrome

Conditions
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Rett Syndrome

Intervention / Treatment
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* Genetic: TSHA-102


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participant has a clinical diagnosis of classical/typical Rett syndrome with a documented pathogenic mutation of the methyl-CpG-binding protein 2 (MECP2) gene that results in loss of function. Participants must be willing to receive blood or blood products for the treatment of an AE if medically needed. Exclusion Criteria: Participant has another neurodevelopmental disorder independent of the MECP2 loss-of-function mutation, or any other genetic syndrome with a progressive course. Participant has a history of brain injury that causes neurological problems. Participant had grossly abnormal psychomotor development in the first 6 months of life. Participant has a diagnosis of atypical Rett syndrome. Participant has a MECP2 mutation that does not cause Rett syndrome. Participant requires invasive ventilatory support. Participant has contraindications for IT administration of TSHA-102 or lumbar puncture procedure, or other medical conditions, or contraindications to any medications required for IT administration. Participant has uncontrolled seizures or a history of status epilepticus within the 3 months prior to enrollment.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1<br>Dose Level 1 | Genetic: TSHA-102<br>* TSHA-102 is a recombinant, non-replicating, self-complementary AAV9 (scAAV9) vector encoding for the miniMECP2 gene. TSHA-102 is a one-time intrathecal (IT) administration.<br>|
| Experimental: Cohort 2<br>Dose Level 2 | Genetic: TSHA-102<br>* TSHA-102 is a recombinant, non-replicating, self-complementary AAV9 (scAAV9) vector encoding for the miniMECP2 gene. TSHA-102 is a one-time intrathecal (IT) administration.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportions of participants experiencing any treatment-emergent adverse events (AEs) and serious adverse events (SAEs) |  | Baseline through Week 52 | 
| Change from baseline in participant's status after TSHA-102 administration as assessed by Clinical Global Impressions-Improvement (CGI-I) scale, adapted to Rett syndrome |  | Baseline through Week 52 | 
| Change from baseline in participant's status after TSHA-102 administration as assessed by the Revised Motor Behavior Assessment (R-MBA) |  | Baseline through Week 52 | 
| Change from baseline in participant's status after TSHA-102 administration as assessed by the Rett Syndrome Hand Function Scale (RSHFS) |  | Baseline through Week 52 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from Baseline in participant's status after TSHA-102 administration as assessed by Clinical Global Impressions-Severity (CGI-S) |  | Baseline through Week 52 | 
| Change from baseline in monthly seizure frequency (52 weeks) |  | Baseline through Week 52 | 
| Change from baseline in adaptive behavior as assessed by Vineland-3 |  | Baseline through Week 52 | 
| Change from Baseline in quantitative EEG findings with visual evoked potentials |  | Baseline through Week 52 | 
| Change from Baseline in quantitative EEG findings with auditory evoked potentials |  | Baseline through Week 52 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Rett Syndrome, Neurodevelopmental disorder, Rett, MECP2