Rett Syndrome Gene Therapy Shows Clinical Benefit, Challenging Adverse Events in Pediatric Patients


An investigator noted challenging side effects related to immunosuppressant treatment.

Taysha Gene Therapies’ TSHA-102 gene therapy has demonstrated a long-term benefit in 2 adult patients with Rett syndrome treated in the phase 1/2 REVEAL trial (NCT06152237), as well as clinical improvements in 2 pediatric patients.1

“We are highly encouraged by the safety profile and broad clinical response observed across multiple domains in both the adult and pediatric patients with different genetic mutation severity treated with the low dose of TSHA-102,” Sean P. Nolan, Chairman and Chief Executive Officer, Taysha, said in a statement.1 “The longer-term follow up data indicate a durable response with sustained and new improvements across multiple clinical domains in both adult patients, and importantly, both pediatric patients showed initial improvements across consistent clinical domains, with early evidence of developmental gains following treatment with TSHA-102. We believe these improvements in adult and pediatric patients further reinforce the potential of TSHA-102 to be transformative for a broad range of patients with Rett syndrome.”

The new, longer-term data from the adult trial in the United States (US) and Canada are from a 20-year-old patient (patient 1) with a large MECP2 deletion associated with a severe phenotype of disease with 52 weeks of follow-up and a 21-year-old patient (patient 2) with a missense MECP2 mutation associated with a milder disease phenotype with 36 weeks of follow-up. In both patients, TSHA-102 was well-tolerated with no serious adverse events (AEs) or dose-limiting toxicities. The data update comes a month after the FDA granted Regenerative Medicine Advanced Therapy (RMAT) Designation to TSHA-102.2

READ MORE: Partnership With Patient Advocacy Groups Is Key to Clinical Trial End Point Selection

In terms of motor skills, patient 1 achieved improved hand function and gained the ability to sit unassisted for the first time in over 10 years while patient 2 had improved hand stereotypies for the first time since regression at age 3 and improved posture and stability. In terms of communication and socialization, patient 1 had improved social interest, vocalization and ability to use eye-gaze driven communication device while patient 2 had improved social interest with increased response to spoken words and eye contact. In terms of autonomic function, patient 1 had improved breathing patterns, normalized sleep quality and duration for the first time in 20 years and improved circulation while patient 2 had improved breathing patterns and circulation. Seizure events also stabilized in patient 1 and significantly reduced in patient 2. Both patients had sustained improvements in Sustained improvement in Clinical Global Impression–Improvement (CGI-I) and Parental Global Impressions–Improvement (PGI-I), with new improvements in Revised Motor Behavior Assessment (R-MBA) and seizure diaries following completion of steroid and sirolimus taper. Patient 1 also had sustained improvements in Clinical Global Impression–Severity (CGI-S) and Rett Syndrome Behavior Questionnaire (RSBQ).1

“TSHA-102 was well-tolerated in both adult patients treated, with no serious adverse events or dose-limiting toxicities as of week 52 and week 36 post-treatment for the first and second patient, respectively. It’s encouraging that we continue to see improvements across multiple clinical domains in the longer-term assessments with no diminution of effect,” Principal Investigator Elsa Rossignol, MD, FRCP, FAAP, Associate Professor in Neuroscience and Pediatrics, Université de Montréal, CHU Sainte-Justine added.1 “We believe these longer-term clinical data support the durability and broad clinical benefits of TSHA-102 in adult patients with the most advanced stage of Rett syndrome.”’

Data were also announced from the first 2 pediatric patients (6 and 7 years old; moderate and mild phenotypes; and 22 and 11 weeks of follow-up, respectively) in the REVEAL trial in the US and United Kingdom. One patient experienced serious AEs related to underlying disease and immunosuppression, with significant challenges with AEs due to the immunosuppression regimen.1

Patient 1 exhibited enhanced hand function, trunk stability, balance, swallowing, and oral intake, alongside better communication using an eye-gaze device and reduced breath-holding, with stable seizure events. Patient 2 showed progress in hand function, walking speed and stability, the ability to stand up from a chair and walk up stairs, increased social interest and eye contact, improved breathing patterns, and more seizure-free days since dosing. In terms of the study outcome measures, patient 1 had improvements in CGI-I, PGI-I, R-MBA, Adapted Mullen Scales of Early Learning (MSEL-A) and Seizure Diaries while patient 2 had improvements in CGI-I, PGI-I, RSBQ, R-MBA and Seizure Diaries.1

“Following treatment with TSHA-102, both pediatric patients with different genotypes and disease severity had challenging side effects related to immunosuppressant treatment but showed a well-tolerated safety profile with no SAEs or DLTs related to TSHA-102 as of week 22 and week 11 post-treatment for the first and second pediatric patient, respectively, as well as some initial improvements across multiple clinical domains and early evidence of new developmental gains,” Colleen Buhrfiend, MD, Assistant Professor of Pediatrics, RUSH University Medical Center, added.1 “The initial improvements observed across multiple areas of disease in both pediatric patients are encouraging early signs of possible benefit.”

1. Taysha Gene Therapies Announces Positive Clinical Data Across Adult and Pediatric Patients from Low Dose Cohort in Ongoing REVEAL Phase 1/2 Trials Evaluating TSHA-102 in Rett Syndrome. News release. June 18, 2024.
2. Taysha Gene Therapies Announces Regenerative Medicine Advanced Therapy (RMAT) Designation Granted by U.S. FDA for TSHA-102 in Rett Syndrome. May 2, 2024.
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