Taysha Launches Clinical Program to Test TSHA-102 Gene Therapy

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by Steve Bryson, PhD |

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Taysha Gene Therapies has launched the clinical development of TSHA-102, an investigational gene therapy for Rett syndrome.

The move follows the recent approval of a clinical trial application (CTA) by Health Canada. The Sainte-Justine Mother and Child University Hospital Center, in Montreal, will serve as the initial clinical site, under the direction of principal investigator Elsa Rossignol, MD, a pediatric neurologist specializing in neurogenetics.

Early Phase 1/2 clinical data for TSHA-102 are expected by the end of this year.

“We are excited to advance TSHA-102 as the first gene therapy in clinical development for the treatment of this devastating neurodevelopmental disorder and look forward to reporting preliminary Phase 1/2 clinical data by the end of 2022,” Suyash Prasad, chief medical officer and head of research and development of Taysha, said in a press release.

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Potential Gene Therapy TSHA-102 Does Well in Animal Study

Taysha also announced positive preclinical data supporting the CTA, including an efficacy study in a Rett mouse model and a toxicology study in nonhuman primates.

These preclinical data will be presented at the International Rett Syndrome Foundation (IRSF) Rett Syndrome Scientific Meeting, to be held April 26-27 in Nashville, Tennessee.

“We continue to be highly encouraged by the therapeutic potential of TSHA-102,” Prasad added.

Delivered by injection into the spinal canal fluid (intrathecally), the gene therapy uses a harmless adeno-associated virus to provide a copy of the MECP2 gene, which is defective in most Rett cases. This gene encodes the MeCP2 protein, which plays a vital role in brain development and function.

TSHA-102 comprises a shorter but functional version of MECP2 that is activated only in nerve cells. It also has a self-regulatory suppressor called a miRNA-responsive auto-regulatory element, or miRARE, which prevents the toxic overexpression (excess production) of the MECP2 protein.

“Treating Rett syndrome by gene replacement therapy requires an approach that can safely regulate transgene expression in a genotypic manner on a cell-by-cell basis without causing deleterious effects associated with overexpression,” Prasad said.

The pharmacological activity of TSHA-102 was assessed across three dose levels and three age groups in a Rett mouse model that lacked the mouse equivalent of the MECP2 gene. A one-time intrathecal injection significantly increased survival at all dose levels, with the mid-to-high dose levels improving survival in all age groups compared with controls.

Treatment also significantly improved body weight, motor function, and lung assessments in Rett mice. An additional study in newborn mice is ongoing, with preliminary data suggesting normal survival.

A six-month toxicology study, required by regulators under Good Laboratory Practice (GLP) standards, examined the distribution, toxicological effects, and mechanism of action of TSHA-102 in nonhuman primates across three dose levels. DNA analysis indicated the therapy was distributed in multiple areas of the brain and spinal cord.

Notably, the levels of MECP2 messenger RNA, the molecule that carries the genetic information to make MeCP2 protein, was low, despite the high levels of delivered DNA, suggesting the miRARE element limited MECP2 protein production as designed. Accordingly, there was no toxic overexpression, no change in primate behavior, and no adverse tissue findings.

“TSHA-102’s robust preclinical data package supports and validates the safe and controlled regulation of transgene expression using miRARE, a novel miRNA-responsive target sequence exclusively licensed to Taysha,” Prasad said.

These data “reinforced TSHA-102’s favorable safety profile across all dose levels tested including doses up to 4-fold above the presumed clinical starting dose,” added Prasad.

Taysha recently announced a strategic pipeline prioritization initiative to exclusively focus on developing gene therapies for Rett and giant axonal neuropathy — an inherited progressive neurodegenerative disorder caused by GAN gene mutations and characterized by motor and sensory nerve damage.

“We are sharpening our strategic focus to prioritize key value-driving registration-directed programs in GAN, which has an estimated addressable patient population of 5,000 worldwide, and Rett syndrome, which affects over 350,000 patients worldwide,” RA Session II, president, founder, and CEO of Taysha, in a separate press release.

“To increase operational efficiency, activities for other ongoing clinical programs will be minimized and all additional research and development will be paused,” Session added.