Trial for Rett Syndrome Gene Therapy TSHA-102 Doses First Patient


The REVEAL trial is being carried out in Canada under a CTA that was cleared by Health Canada in March 2022.

The first patient has been dosed in the phase 1/2 REVEAL clinical trial (NCT05606614) evaluating Taysha Gene Therapies’ TSHA-102, an investigational adeno-associated virus (AAV) vector-based gene therapy, for the treatment of adult patients with Rett syndrome.1

TSHA-102, which is administered intrathecally, delivers a copy of miniMECP2, a truncated version of the disease-targeted MECP2 gene, via an AAV9 vector.1,2 The gene therapy product also incorporates use of the company's novel miRNA-Responsive Auto-Regulatory Element (miRARE) platform, which is intended to enable regulation of cellular expression for both endogenous and exogenous MECP2. The REVEAL trial is currently being carried out at CHU Sainte-Justine, the Université de Montréal mother and child university hospital center in Montreal, Canada, under a clinical trial application (CTA) that was cleared by Health Canada in March 2022.1,3 

Taysha noted that it will present initial safety data from the trial at its R&D Day on June 28, 2023. Taysha also plans to submit a CTA for TSHA-102 to the United Kingdom’s Medicines and Healthcare products Regulatory Agency in mid-2023 in order to conduct a trial there for children with Rett syndrome. Submission of an investigational new drug application for TSHA-102 to the FDA is additionally planned for the second half of this year.

“Dosing of the first adult patient marks the beginning of clinical evaluation of TSHA-102 in the phase 1/2 REVEAL trial, and, to our knowledge, the first time a gene therapy has ever been evaluated in a clinical setting for the treatment of Rett syndrome,” Sukumar Nagendran, MD, the president and head of R&D at Taysha Gene Therapies, said in a statement.1 “By targeting the regulation of gene expression on a cell-by-cell basis, we believe our miRARE technology has the ability to enable safe expression of MECP2, which may help address the risks associated with both under and overexpression resulting from the mosaic pattern of MECP2 silencing. This is a significant milestone that furthers our quest to bring a potentially transformational gene therapy to patients and families living with Rett syndrome. We look forward to sharing initial available clinical safety data from the phase 1/2 REVEAL trial at our R&D Day on June 28, 2023.”

The dose-escalation portion of the open-label REVEAL trial will evaluate a lower dose of 5x1014 total vector genomes (vg) and a higher dose of 1x1015 vg. At approximately 6 weeks following the treatment of the first patient with TSHA-102, an independent data monitoring committee will assess the safety findings in order to determine whether the second patient can be dosed. The trial is expected to enroll approximately 12 female participants in total. Participants are required to be at least 18 years of age and must have a clinical diagnosis of classical/typical Rett syndrome with a documented loss-of-function mutation in MECP2. Patients with unrelated neurodevelopmental disorders; any other genetic syndrome with a progressive course; a history of brain injury causing neurological problems; uncontrolled seizures; a history of status epilepticus within the 3 months before enrollment; those who had a grossly abnormal psychomotor development in the first 6 months of life; and those who require invasive ventilatory support are excluded from participation.

TSHA-102 has previously been granted orphan drug designation by both the FDA and the European Commission. It has also received rare pediatric disease designation from the FDA. In addition to TSHA-102, Taysha also has gene therapies in clinical development for CLN1 disease and giant axonal neuropathy (GAN).3 Earlier this year, in January, Taysha announced that the FDA had recommended the company to dose additional patients with TSHA-120, its investigational AAV vector-based gene therapy intended to treat GAN, in order to support a biologics license application submission.4

"Based on its unique and compelling technology targeting the genetic root cause of Rett syndrome, TSHA-102 has the potential to transform care by addressing a significant unmet medical need for patients with this devastating and currently incurable disease,” Elsa Rossignol, MD, FRCP, FAAP, an associate professor of neuroscience and pediatrics and the principal investigator on REVEAL, added to the statement.1 “The dosing of the first patient in this important clinical trial represents a critical advancement in evaluating the potential of gene therapy for Rett syndrome. It is a privilege to be part of this important endeavor. In the name of all affected families, I thank Taysha for bringing this potentially transformative therapy from the bench to the bedside.”

1. Taysha Gene Therapies announces first patient dosed with TSHA-102 in the reveal phase 1/2 trial under investigation for the treatment of Rett syndrome. News release. Taysha Gene Therapies, Inc. June 5, 2023. Accessed June 6, 2023.
2. Pipeline. Taysha Gene Therapies. Website. Accessed June 6, 2023.
3. Taysha gene therapies announces initiation of clinical development of TSHA-102 in Rett syndrome. News release. Taysha Gene Therapies, Inc. March 29, 2022. Accessed June 6, 2023.
4. Taysha Gene Therapies provides update on TSHA-120 program in giant axonal neuropathy and a 2023 corporate outlook. News release. Taysha Gene Therapies, Inc. January 31, 2023. Accessed February 1, 2023.
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