Potential Gene Therapy TSHA-102 Does Well in Animal Study

Marta Figueiredo PhD avatar

by Marta Figueiredo PhD |

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gene therapy for Rett

TSHA-102, an experimental gene therapy for Rett syndrome, safely and effectively normalized levels of MeCP2 — the protein missing or defective in most Rett patients — in the brain and significantly improved survival in a mouse model of the disease, a study shows.

Notably, the data suggest this investigational treatment can overcome a common issue of MECP2-directed gene therapy strategies: excessive levels of MeCP2, which are toxic to cells.

“It has been a challenge finding an approach that can appropriately regulate MECP2 expression [activity] in Rett syndrome,” Sarah Sinnett, PhD, said in a press release. Sinnett is the study’s first author and an assistant professor in the department of pediatrics at University of Texas’ Southwestern Medical Center (UT Southwestern).

Steven Gray, PhD, the study’s senior author and chief scientific advisor at TSHA-102 developers Taysha Gene Therapies, said that “the built-in self-regulatory feedback loop mechanism in TSHA-102, work that was initiated in my laboratory in 2007, is a completely novel approach that allows for regulated expression of MECP2 on a cell-by-cell basis.”

This groundbreaking feature of TSHA-102 “significantly de-risks the developmental program in its translation to humans,” said Suyash Prasad, Taysha’s chief medical officer and head of research and development.


These preclinical findings support Taysha’s intent to file applications to regulatory agencies later this year seeking clearance to initiate clinical trials of the gene therapy. The company expects to launch the first Phase 1/2 clinical trial of TSHA-102 by the end of this year.

The study, “Engineered microRNA-based regulatory element permits safe high-dose miniMECP2 gene therapy in Rett mice,” was published in the journal Brain.

Rett syndrome is a rare neurodevelopmental disorder that affects females almost exclusively. It is caused mostly by mutations in the MECP2 gene, located on the X chromosome (one of the sex chromosomes).

This gene provides instructions to produce the MeCP2 protein, which is involved in nerve cell function and communication, and regulates other genes’ activities.

Typically, a person carries two copies of a gene, one inherited from the mother and the other from the father. A process that occurs only in females, called X-chromosome inactivation, leads to mosaicism, which refers to the presence of groups of cells in the body that are genetically distinct.

As such, female Rett patients typically show a mosaic pattern of cells producing a working MeCP2 protein, and cells with a defective or missing protein.

By delivering a healthy copy of a mutated, disease-causing gene to cells, gene therapy has emerged as a potential Rett treatment. However, developing a safe and effective gene therapy is further challenged by Rett-related “mosaicism and the need to regulate MECP2 such that it does not cause overexpression-related toxicity,” Prasad said.

Taysha’s TSHA-102 was designed to overcome both challenges. It uses a modified and harmless adeno-associated virus serotype 9 to deliver an optimized sequence of DNA to cells.

This sequence contains a shorter, but functional version of the MECP2 gene (miniMECP2), a “switcher” that allows the gene to be turned on exclusively in nerve cells, and a self-regulatory suppressor called miRNA-responsive auto-regulatory element, or miRARE.

This new element represents a built-in mechanism that suppresses miniMECP2 activation in the presence of high MeCP2 levels, thereby minimizing the possibility of producing excessive, toxic levels of MeCP2.

In the current study, Gray and his team compared the safety and effectiveness of TSHA-102 with those of two other strategies — one that delivers a full-length MECP2 gene and another that delivers the miniMECP2 without miRARE — in a mouse model of Rett syndrome.

All treatments were administrated directly into the animal’s spinal canal so to easily reach the brain and spinal cord.

Results showed that TSHA-102 significantly extended the mice’s survival by 56%, while no survival benefit was observed with the other two gene therapy strategies. Also, delivering a full-length MECP2 gene to healthy mice was associated with an unacceptable toxicity profile.

Behavioral side effects of each approach also were explored in healthy mice. Data demonstrated that animlas given TSHA-102 mice had significantly fewer behavioral abnormalities than those given either of the other two therapies.

Notably, behavioral scores of mice given TSHA-102 were comparable to those receiving a saline solution, suggesting that adding miRARE to the delivered DNA sequence attenuated behavioral worsening.

In addition, TSHA-102 treatment resulted in distinct levels of MECP2 activation in different regions of the brain, with significantly more nerve cells in the pons and midbrain — two regions affected by Rett — showing higher MECP2 activation in the mouse model of Rett than in healthy mice.

This suggested that TSHA-102 promoted MECP2 activation levels similar to normal.

The findings highlighted that “insertion of miRARE … greatly improved the safety of miniMECP2 gene transfer without compromising efficacy,” the researchers wrote.

“It is clear that the disease is reversible, and I am encouraged that this novel strategy may enable us to make a difference in the management of this disease,” Sinnett said.

Besides Rett syndrome, Taysha’s miRARE platform may be useful to treat “other [central nervous system] diseases requiring regulated gene expression,” Prasad added.

Taysha’s gene therapies are being developed in collaboration with the Cleveland Clinic, the UT Southwestern, Catalent, and Yale University.

In March, the company emphasized that Rett syndrome patients receiving the Johnson & Johnson or AstraZeneca-Oxford COVID-19 vaccines could still participate in future TSHA-102 clinical trials, due to the different virus used by each approach.