Preclinical data provide quantitative evidence of miRARE’s ability to exhibit genotype-dependent regulation of MECP2 gene expression across different brain regions in both wild type and knockout mouse models of Rett syndrome
TSHA-102 resulted in a statistically significant survival extension by 56% in 4-5-week-old knockout Rett mice with meaningful accumulated disease whereas unregulated constructs did not extend survival significantly in the validated MECP2 knockout Rett mouse model
Significant survival benefit in 4-5-week-old TSHA-102-treated knockout Rett mice with meaningful accumulated disease a more translatable model of the disorder in humans
These quantitative data, for the first time, demonstrated miRARE’s ability to regulate gene expression on a cell-by-cell basis, highlighting its potential application in numerous dose-sensitive diseases
Data support an IND/CTA filing for TSHA-102 in Rett syndrome in the second half of 2021, with initiation of a Phase 1/2 trial anticipated by year-end
Estimated 25,000 patients in
“Effective gene therapy targeting MECP2 for the treatment of Rett syndrome has been elusive due to the inability to properly regulate transgene expression,” said
“The complexities of developing an efficacious and well-tolerated gene therapy for the treatment of Rett syndrome are highlighted by phenotypic variability, mosaicism and the need to regulate MECP2 such that it does not cause overexpression-related toxicity. Today’s data give us confidence that we can achieve appropriate MECP2 expression in all cells in a genotype-dependent manner, which we believe significantly de-risks the developmental program in its translation to humans,” said
The preclinical study was conducted by the
TSHA-102 extended knockout survival by 56% via 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.
“It has been a challenge finding an approach that can appropriately regulate MECP2 expression in Rett syndrome but the preclinical data for TSHA-102 published today support the miRARE approach,” said
The publication is available by clicking on the following link: https://academic.oup.com/brain/advance-article-abstract/doi/10.1093/brain/awab182/6265600.
Drs. Gray and Sinnett have intellectual property interest in Taysha and UTSW has a financial interest in the company.
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