Gene Therapy for Rett Syndrome Receives FDA Breakthrough Therapy Designation

The Food and Drug Administration (FDA) has granted Breakthrough Therapy designation to TSHA-102 (Taysha Gene Therapies, Dallas, TX) for the treatment of individuals with Rett syndrome. TSHA-102 is an intrathecally delivered adeno-associated virus 9 (AAV9) gene transfer therapy designed to mediate methyl CpG-binding protein 2 (MECP2) levels in the central nervous system. The FDA Breakthrough Therapy designation was based on positive results from part A of the phase 1/2 REVEAL clinical trial (NCT05606614).  

The REVEAL trial is a single-arm, open-label study evaluating a 1-time, high-dose TSHA-102 infusion (1×10¹⁵ total vector genomes [vg]) in 15 female participants aged 6 to <22 years within the developmental plateau population of Rett syndrome. The primary efficacy end point is the percentage of patients who gain or regain ≥1 defined developmental milestone(s) (DM) from a list of 28 milestones across the core functional domains of communication, fine motor and gross motor. Independent, blinded central raters will perform standardized milestone assessments in the treatment population. In part A of the trial, 12 participants received treatment with TSHA-102 at a low dose (5.7x10¹⁴ total vg, n=4) or high dose TSHA-102 (1.0x10¹⁵ vg, n=8), and 10 individuals were included in the efficacy evaluation.

The following results were reported from part A of the trial:

• 100% of individuals who were treated with TSHA-102 and evaluated for efficacy (n=10) gained or regained ≥1 defined DM, meeting the primary study end point.
• A dose-dependent effect was observed, with the high-dose cohort showing greater milestone gains and functional improvements by 6 months post-treatment.
• TSHA-102 was generally well-tolerated at both the low and high dose levels, with no treatment-related serious adverse events (AEs) or dose limiting toxicities reported. The most common AEs were mild-to-moderate liver enzyme elevations and pyrexia.

The observed milestone gains are unlikely to occur without treatment, with natural history data showing a <6.7% likelihood of spontaneous gain/regain in a natural history population. According to a press release from Taysha Gene Therapies, the company has finalized alignment with the FDA on the REVEAL trial protocol and statistical analysis plan (SAP) that are intended to support the planned Biologics License Application (BLA) submission for TSHA-102, with the inclusion of a planned 6-month interim analysis.

Sources: Rossignol E, Berry-Kravis E, Haas R, et al. Achieving developmental milestones and broad restoration of function in Rett syndrome: the potential of tSHA-102 gene therapy. Accessed October 14, 2025. https://ir.tayshagtx.com/static-files/a53890fd-8e16-4c61-b900-9444eb522051

Taysha gene therapies announces FDA Breakthrough Therapy designation and provides positive regulatory update on TSHA-102 in Rett syndrome. Accessed October 14, 2025. https://www.globenewswire.com/news-release/2025/10/02/3160308/0/en/Taysha-Gene-Therapies-Announces-FDA-Breakthrough-Therapy-Designation-and-Provides-Positive-Regulatory-Update-on-TSHA-102-in-Rett-Syndrome.html