A Phase 1/2/3 Study of TSHA-102 Gene Therapy in Females With Rett Syndrome (REVEAL Pivotal Study)

An Open-label Phase 1/2/3 Study Consisting of a Phase 1/2 Safety and Dose-escalation and Phase 3 Dose-expansion Study to Evaluate Safety and Efficacy of a Single Intrathecal Administration of TSHA-102, an AAV9-Delivered Gene Therapy in Females With Rett Syndrome

The primary objectives of this study are to evaluate the safety of a single intrathecal (IT) dose of TSHA-102 in females with typical Rett syndrome, to select the TSHA-102 dose with the best benefit/risk profile based on the totality of safety and efficacy data and to evaluate the efficacy and safety of TSHA-102 at the selected dose.

Study Overview

• Status: Recruiting
• Conditions: Rett Syndrome
• Intervention / Treatment: Genetic: TSHA-102

Detailed Description

REVEAL Part A (Phase 1/2) is an open-label safety and dose-finding study designed to evaluate the safety and preliminary efficacy of two dose levels of TSHA-102 to establish initial safety of TSHA-102 and select a safe and efficacious dose for further evaluation. Enrollment of 6 participants in Part A is complete.

REVEAL Part B (Phase 3) will evaluate the efficacy and safety of TSHA-102 at the dose level 2 determined in Part A in 15 females ages 6 to <22 years with typical Rett syndrome. TSHA-102 is designed to target the genetic root cause of Rett syndrome by regulating the expression of MECP2 in cells.

Each participant will be followed for the observation period of 5 years after TSHA-102 administration in Part A and B.

• Study Type: Interventional
• Enrollment (Estimated): 15
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Taysha Gene Therapies Medical Information; Phone Number: 833-489-8742; Email: medinfo@tayshagtx.com

Study Locations

• Canada
  • Quebec
    • Montreal, Quebec, Canada
      • Recruiting
      • CHU St. Justine
• United States
  • California
    • La Jolla, California, United States, 92093
      • Recruiting
      • UC San Diego
      • Contact: Karen Ditslear, M.S.; Phone Number: 858-246-2288; Email: kditslear@ucsd.edu
  • Illinois
    • Chicago, Illinois, United States, 60612
      • Recruiting
      • Rush University Medical Center
      • Contact: Milana Milic; Email: milana_milic@rush.edu
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Recruiting
      • Boston Children's Hospital
      • Contact: Email: RettResearch@childrens.harvard.edu
  • Missouri
    • St Louis, Missouri, United States, 63110
      • Recruiting
      • Washington University, St. Louis
  • Texas
    • Dallas, Texas, United States, 75930
      • Recruiting
      • UT Southwestern Children's Medical Center
      • Contact: Phone Number: 214-456-2464; Email: PNTRCstudyrecruitment@utsouthwestern.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Child, Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Females between the ages of 12 and <22 in Part A (closed) and females between the ages of 6 and <22 in Part B (pivotal cohort).
• Participant has a clinical diagnosis of classic/typical Rett syndrome with a documented pathogenic mutation of the methyl-CpG-binding protein 2 (MECP2) gene that results in loss of gene function.
• Participants must be willing to receive blood or blood products for the treatment of an AE if medically needed.
• Participants and parent/caregiver must agree to reside within easy access to the study site prior to the baseline visit and at least 3 months after TSHA-102 treatment

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 or had grossly abnormal psychomotor development in the first 6 months of life.
• Participant has a diagnosis of atypical Rett syndrome or a MECP2 gene mutation that does not cause Rett syndrome.
• Participant requires invasive ventilatory support.

Note: Other protocol defined inclusion/exclusion criteria may apply

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: Single

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Part A Cohort 1; TSHA-102 Dose Level 1: 5.7×10¹⁴ total vector genomes (vg). Participants receive a single intrathecal (IT) administration of TSHA-102 at Dose Level 1 (fully enrolled, 2 participants).	Genetic: TSHA-102; 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.
Experimental: Part A Cohort 2; TSHA-102 Dose Level 2: 1.0×10¹⁵ total vector genomes (vg) Participants receive a single intrathecal (IT) administration of TSHA-102 at Dose Level 2 (fully enrolled, 4 participants).	Genetic: TSHA-102; 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.
Experimental: Part B Pivotal Cohort; TSHA-102 at Selected Dose (Dose Level 2): 1.0 × 10¹⁵ total vector genomes (vg) Participants receive a single intrathecal (IT) administration of TSHA-102 at Dose Level 2 (1.0 × 10¹⁵).	Genetic: TSHA-102; 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Part A: Safety and Tolerability of TSHA-102	Proportions of participants experiencing any treatment-emergent adverse events (AEs) and serious adverse events (SAEs)	Baseline through Week 52
Part B: Efficacy of TSHA-102	Change from baseline in percentage of participants who gain or regain any one or more of the 28 items from the Developmental Milestones Assessment (DMA), which are video recorded and scored by independent, blinded central raters.	Baseline through Week 52

Secondary Outcome Measures

Outcome Measure	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

Collaborators and Investigators

• Sponsor: Taysha Gene Therapies, Inc.
• Investigators: Study Director: Medical Monitor, M.D., Taysha Gene Therapies

Publications and helpful links

General Publications

• Jagadeeswaran I, Oh J, Sinnett SE. Preclinical Milestones in MECP2 Gene Transfer for Treating Rett Syndrome. Dev Neurosci. 2025;47(2):147-156. doi: 10.1159/000539267. Epub 2024 May 9.
• Sadhu C, Lyons C, Oh J, Jagadeeswaran I, Gray SJ, Sinnett SE. The Efficacy of a Human-Ready miniMECP2 Gene Therapy in a Pre-Clinical Model of Rett Syndrome. Genes (Basel). 2023 Dec 24;15(1):31. doi: 10.3390/genes15010031.

Study record dates

Study Major Dates

• Study Start (Actual): March 6, 2023
• Primary Completion (Estimated): June 1, 2031
• Study Completion (Estimated): June 1, 2031

Study Registration Dates

• First Submitted: October 28, 2022
• First Submitted That Met QC Criteria: November 2, 2022
• First Posted (Actual): November 7, 2022

Study Record Updates

• Last Update Posted (Actual): December 30, 2025
• Last Update Submitted That Met QC Criteria: December 29, 2025
• Last Verified: December 1, 2025

More Information

Terms related to this study

• Keywords: Gene Therapy; Nervous System Diseases; Intellectual Disability; Neurologic Manifestations; Neurodevelopmental disorder; Rett Syndrome; MECP2; RTT; AAV9; Genetic Diseases, X-Linked; Pathologic Process; Rett; Rett Disorder; Retts; Typical Rett Syndrome; Intrathecal Administration; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Classic Rett Syndrome; MECP2-Related Disorder; Developmental Regression; TSHA-102; miRARE; Self-complementary Vector; X-Linked Intellectual Disability
• Additional Relevant MeSH Terms: Mental Disorders; Genetic Diseases, Inborn; Neurobehavioral Manifestations; Heredodegenerative Disorders, Nervous System; Pathological Conditions, Signs and Symptoms; Signs and Symptoms; Neurologic Manifestations; Neurodevelopmental Disorders; Rett Syndrome; Pathologic Processes; Intellectual Disability; Nervous System Diseases; Genetic Diseases, X-Linked; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; X-Linked Intellectual Disability
• Other Study ID Numbers: TSHA-102-CL-101

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes