Taysha Gene Therapies, Inc. Announces Publication of Preclinical Data for TSHA-102 in Rett Syndrome in Brain
May 10, 2021 at 07:00 am EDT
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Taysha Gene Therapies, Inc. announced the publication of new preclinical data for TSHA-102 in Rett syndrome. The data were published online and will be included in the May edition of Brain, a highly esteemed neurological science peer-reviewed journal. The preclinical study was conducted by the UT Southwestern Medical Center (UT Southwestern) laboratory of Sarah Sinnett, Ph.D., and evaluated the safety and efficacy of regulated miniMECP2 gene transfer, TSHA-102 (AAV9/miniMECP2-miRARE), through intrathecal (IT) administration in adolescent mice between four and five weeks of age. TSHA-102 was compared to unregulated full length MECP2 (AAV9/MECP2) and unregulated miniMECP2 (AAV9/miniMECP2). TSHA-102 extended knockout survival by 56% through IT delivery. In contrast, the unregulated miniMECP2 gene transfer failed to significantly extend knockout survival at either dose tested. Additionally, the unregulated full-length MECP2 construct did not demonstrate a significant extension in survival and was associated with an unacceptable toxicity profile in wild type mice. In addition to survival, behavioral side effects were explored. Mice were subjected to phenotypic scoring and a battery of tests including gait, hindlimb clasping, tremor and others to comprise an aggregate behavioral score. miRARE attenuated MECP2-mediated aggravation in wild type aggregate phenotype severity scores. Mice were scored on an aggregate severity scale using an established protocol. AAV9/MECP2- and AAV9/miniMECP2-treated wild type mice had a significantly higher mean (worse) aggregate behavioral severity score versus that observed for saline-treated mice (p <0.05; at 6–30 and 7–27 weeks of age, respectively). TSHA-102-treated wild type mice had a significantly lower (better) mean aggregate severity score versus those of AAV9/MECP2- and AAV9/miniMECP2-treated mice at most timepoints from 11–19 and 9–20 weeks of age, respectively. No significant difference was observed between saline- and TSHA-102-treated wild type mice. Of note, miRARE-mediated genotype-dependent gene regulation was demonstrated by analyzing tissue sections from wild type and knockout mice treated with AAV9 vectors given intrathecally. TSHA-102 demonstrated regulated MECP2 expression in different regions of the brain. In the pons and midbrain, miRARE inhibited mean MECP2 gene expression in a genotype-dependent manner as indicated by significantly fewer myc(+) cells observed in wild type mice compared to knockout mice (p<0.05), thereby demonstrating that TSHA-102 achieved MECP2 expression levels similar to normal physiological parameters.
Taysha Gene Therapies Inc is a clinical-stage biotechnology company, which is focused on advancing adeno-associated virus (AAV)-based gene therapies for severe monogenic diseases of the central nervous system. The Companyâs lead clinical program, TSHA-102, is in development for the treatment of Rett syndrome, a rare neurodevelopmental disorder. The Company is evaluating TSHA-102 in the REVEALPhase I/II adolescent and adult clinical trial, which is a first-in-human, open-label, randomized, dose escalation and dose-expansion, multicenter study evaluating the safety and preliminary efficacy of TSHA-102 in female patients aged 12-years and older with Rett syndrome. It has acquired a worldwide right to a clinical-stage, intrathecally dosed AAV9 gene therapy program, TSHA-120, for the treatment of giant axonal neuropathy (GAN). It received orphan drug designation from the European Commission for TSHA-120 for the treatment of GAN.
TAYSHA GENE THERAPIES, INC. 
