Taysha’s Rett Syndrome Gene Therapy TSHA-102 Continues to Show Promise in Adult and Pediatric Patients


Various improvements were seen in 2 adult patients and 2 pediatric patients treated in separate clinical trials.

Taysha Gene Therapies’ TSHA-102, an investigational adeno-associated virus (AAV) vector-based gene therapy, has continued to generate positive efficacy and safety data in updated results from the phase 1/2 REVEAL adolescent and adult clinical trial (NCT05606614) and the separate phase 1/2 REVEAL Pediatric Study clinical trial (NCT06152237).1

With regard to the adolescent and adult clinical trial, Taysha reported updated results from a 20 year-old patient (adult patient 1) with severe phenotype disease who has a large MECP2 deletion and a 21 year-old patient (adult patient 2) with milder phenotype disease who has a missense mutation in the MECP2 gene. Both patients, who received the trial’s low dose of 5.7x1014 total vg, have stage 4 Rett syndrome with late motor deterioration. Relative to baseline, adult patient 1, who now has 52 weeks of posttreatment follow-up, has shown improved hand function; the ability to sit unassisted for the first time in over 10 years; the ability to move her legs and use an eye-gaze driven communication device; improved social interest, vocalization, breathing patterns, and circulation; normalization of sleep quality and duration for the first time in 20 years; and stable seizure events while taking lower levels of antiseizure medication. With regard to instrument measures, adult patient 1 showed sustained improvement at 52 weeks posttreatment in Clinical Global Impression–Improvement (CGI-I), Clinical Global Impression–Severity (CGI-S) ,and Seizure Diaries scores, and new improvement in Revised Motor Behavior Assessment (R-MBA), Parental Global Impressions–Improvement (PGI-I), and Rett Syndrome Behavior Questionnaire (RSBQ) scores after completion of a steroid and sirolimus taper.

Meanwhile, adult patient 2, who now has 36 weeks of follow-up, in relation to her baseline has shown improved hand stereotypies for the first time since she was 3 years old; improved breathing patterns, circulation, posture, stability, and social interest; an increased response to spoken words and eye contact; and a significant decrease in seizures while taking 25% lower levels of antiseizure medication. Taysha noted that she previously had approximately 2 to 4 seizures per week and that she has now been seizure free for 8.5 months. The company also stated that at 25 weeks posttreatment, the patient shows sustained improvement in CGI-I and PGI-I scores and new improvement in R-MBA and Seizure Diaries scores following completion of a steroid taper.

In terms of safety, Taysha characterized TSHA-102 as “generally well-tolerated" in both adult patient 1 and adult patient 2. Neither patient experienced any serious adverse events (SAEs) related to the gene therapy and there were no dose-limiting toxicities (DLTs).

Thus far, 2 patients have also been dosed in the REVEAL Pediatric Study. The patients include a 6 year old girl with an MECP2 deletion associated with moderate phenotype disease (pediatric patient 1) and a 7 year old girl with a missense MECP2 mutation associated with milder phenotype disease (pediatric patient 2). The patients have stage 3 Rett syndrome and pseudo stationary symptoms. They were both treated with 5.7x1014 total vg of TSHA-102.

At 12 weeks posttreatment, pediatric patient 1 showed changes relative to baseline that included improved hand function, truncal stability and balance, swallowing and oral intake, communication; the ability to hold an object for 3 minutes as opposed to 12 seconds, ability to move her leg, ability to sit without assistance for a longer period of time, ability to use an eye-gaze driven communication device, and the gain of new abilities including visual reception and receptive language skills; reduced breath holding; and clinical improvements on instruments including CGI-I, PGI-I, R-MBA, Adapted Mullen Scales of Early Learning, and Seizure Diaries. It was noted that her frequency of seizure events remained stable in relation to her baseline at 22 weeks posttreatment.

At 8 weeks posttreatment, pediatric patient 2 showed changes relative to baseline that included improved hand function, gait, speed, stability when walking, breathing patterns, social interest and eye contact; gain of the ability to stand up from a chair and the ability to walk up a stair; and improvements on instruments including CGI-I, PGI-I, RSBQ, R-MBA, and Seizure Diaries. As of 11 weeks posttreatment, pediatric patient 2 also experienced more seizure-free days than before receiving TSHA-102, although it was noted that she also started use of a new antiseizure medicine at 4 weeks posttreatment that she has continued to take.

At 22 weeks of follow-up for pediatric patient 1 and 11 weeks of follow-up for pediatric patient 2, Taysha characterized TSHA-102's safety profile as “generally well-tolerated" in both patients. No SAEs deemed related to TSHA-102 occurred in these patients, but pediatric patient 2 experienced 2 SAEs that were considered related to the underlying disease, with 1 of these SAEs also considered related to her immunosuppression regimen.

“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 dose-limiting toxicities 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, an assistant professor of pediatrics at RUSH University Medical Center, said in a statement.1 “Specifically, at week 12 post-treatment, the first patient’s truncal stability and balance improved, which enabled her to sit unassisted for a longer duration and move her leg on her own to better take a step with assistance. Her hand function improved, and she was able to hold an object for 3 minutes following treatment compared to up to 12 seconds pretreatment. Additionally, she communicated new words using an eye-gaze driven communication device and gained the ability to identify object functions for the first time. At week 8 post-treatment, the second pediatric patient’s gait, speed and stability improved, resulting in the ability to walk longer distances. Her hand function showed initial improvement, and she gained some new skills that were previously lost, including the ability to stand up from a chair and walk up a stair. The initial improvements observed across multiple areas of disease in both pediatric patients are encouraging early signs of possible benefit.”

Taysha stated that the trial’s independent data monitoring committee has given the company the go-ahead to begin treating patients in cohort 2 of the REVEAL Pediatric Study, which is expected to include 3 patients and will utilize a dose of 1x1015 total vg, pending a review of 42-day safety data from the first patient in the high dose cohort of the REVEAL adolescent and adult study, who received treatment at a dose of 1x1015 total vg in Q2 of 2024. Notably, TSHA-102 recently received regenerative medicine advanced therapy designation from the FDA in May 2024.2

Further development of TSHA-102 is Taysha’s main focus at the moment.3 The company announced in February 2024 that it would be transferring other gene therapy programs that it has deprioritized to other companies. Therapies that the company has discontinued include TSHA-120, for giant axonal neuropathy; TSHA-101, which was being investigated in people with GM2 gangliosidosis; TSHA-104 for SURF1-associated Leigh syndrome; TSHA-112 in adult polyglucosan body disease; and TSHA-118 for CLN1 Batten disease. Taysha announced that it would be transferring the rights to TSHA-120 to National Institute of Neurological Disorders and Stroke; the rights to TSHA-101 to Queen’s University; and the rights to TSHA-104 and TSHA-112 back to their originating institutions.

"Creating options for these programs has been a focus since the Company completed a management change in December 2022, and the new loan and security agreement afforded the flexibility to implement certain opportunities,” Sean P. Nolan, the chairman and CEO of Taysha, said in a February 2024 statement.3 “As we continue to focus on advancing our lead TSHA-102 program for the treatment of Rett syndrome, we are pleased that we can ensure these programs are provided to the right advocates, clinicians and scientific experts who can potentially move these programs forward for the benefit of patients.”

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. Taysha Gene Therapies, Inc. June 18, 2024. Accessed June 28, 2024. https://ir.tayshagtx.com/news-releases/news-release-details/taysha-gene-therapies-announces-positive-clinical-data-across
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. Accessed June 28, 2024. https://www.biospace.com/article/releases/taysha-gene-therapies-announces-regenerative-medicine-advanced-therapy-rmat-designation-granted-by-u-s-fda-for-tsha-102-in-rett-syndrome/
3. Taysha Gene Therapies Provides Update on Deprioritized Pipeline Programs. February 15, 2024. Accessed June 28, 2024. https://www.globenewswire.com/news-release/2024/02/15/2830347/0/en/Taysha-Gene-Therapies-Provides-Update-on-Deprioritized-Pipeline-Programs.html
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