TSHA-102 is an investigational gene transfer therapy presented by Taysha Gene Therapies to treat Rett Syndrome.
This therapy utilizes a novel miRNA-Responsive Auto-Regulatory Element (miRARE) platform to regulate levels of MECP2 in the central nervous system (CNS) on a cell-by-cell basis. This approach aims to restore appropriate levels of MeCP2 without the risk of over-expression, addressing the underlying cause of Rett Syndrome.
What is Rett Syndrome?
Rett Syndrome is a rare neurodevelopment disorder that affects thousands of patients worldwide. It is caused by mutations in the MECP2 gene, which is crucial for neuronal and synaptic function in the brain. Currently, there are no approved disease-modifying therapies for Rett Syndrome.
Primarily affecting females, it is characterized by:
- intellectual disabilities
- loss of communication
- seizures
- developmental regression
- motor impairments
- respiratory problems
The mosaic pattern of MECP2 silencing in females with Rett Syndrome poses a challenge for developing effective treatments. The MECP2 gene provides instructions for producing the MeCP2 protein, which is essential for normal brain function. Mutations disrupt the production or function of MeCP2, leading to the symptoms associated with Rett Syndrome.
Studies
The miRARE technology incorporated in TSHA-102 allows for the precise control of MECP2 expression based on cellular levels of MeCP2. In vitro studies using human and mouse cell culture models have demonstrated the ability of miRARE to down-regulate MECP2 transgene and protein expression in response to cellular MeCP2 levels. The results showed that miRARE can finely tune the expression of MeCP2 protein, with higher expression in neuronal cell lines compared to non-neuronal cell lines. This tissue-specific expression of MeCP2 is a significant advantage in targeting the CNS in Rett Syndrome.
In vivo studies conducted in neonatal mice further support the regulatory control of miRARE. These findings demonstrate that TSHA-102 can effectively regulate MeCP2 expression in deficient CNS cells without causing toxic over-expression. The ability of TSHA-102 to modulate MeCP2 levels in a cell-specific manner provides hope for developing a safe and effective gene therapy for Rett Syndrome.
The first cohort of the REVEAL Phase 1/2 adult trial has already been dosed with TSHA-102, and clinical data from the two adult patients are expected to be reported in mid-November. Additionally, the dosing of the first pediatric patient with TSHA-102 is anticipated to occur in the first quarter of 2024. These clinical trials will provide valuable insights into the safety and efficacy of TSHA-102 in treating Rett Syndrome.
TSHA-102 has received Fast Track designation from the U.S. Food and Drug Administration (FDA). This designation expedites the development and review process, allowing for more frequent communication with the FDA and the potential for accelerated approval. TSHA-102 has also been granted Orphan Drug and Rare Pediatric Disease designations by the FDA, highlighting its potential to address unmet medical needs in the pediatric population.
By addressing the underlying cause of the disease, TSHA-102 has the potential to improve the quality of life for thousands of patients. With ongoing clinical trials and regulatory designations, there is hope that TSHA-102 could become the first approved disease-modifying therapy for Rett Syndrome.
For more information on Rett’s Syndrome and other neurological diseases click here, checkrare.com/diseases/neurology-nervous-system-diseases/
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