Taysha Gene Therapies presents preclinical in-vitro data on TSHA-102

Taysha Gene Therapies announced new preclinical in vitro data on TSHA-102 in Rett syndrome as part of a poster presentation at the European Society of Gene & Cell Therapy 30th Annual Congress. TSHA-102 is a self-complementary intrathecally delivered AAV9 investigational gene transfer therapy that utilizes a novel miRNA-Responsive Auto-Regulatory Element technology designed to mediate levels of MECP2 in the CNS on a cell-by-cell basis without risk of overexpression. These data demonstrate the function of the miRARE-RHD1pA regulatory element and its impact on MECP2 transgene and protein expression in human and mouse cell lines, providing further support for the regulatory control of miRARE. The preclinical study presented at ESGCT used human and mouse cell culture models to explore the function of miRARE and its impact on MECP2 transgene and protein expression in the presence or absence of cellular MeCP2 using both viral AAV9 transduction and plasmid transfection containing either miRARE-regulated or SV40 elements. In vitro data showed post-transcriptional gene silencing by miRARE in response to cellular MeCP2 levels can be recapitulated in human and mouse cell lines: miRARE controlled dose-dependent transgene expression of MeCP2 protein via a similar mechanism in both human and mouse cell lines miRARE partially silenced transgene expression in neuronal and non-neuronal cell lines; the expression and subsequent downregulation were 4-5-fold higher in neuronal cell lines, supporting tissue-specific expression of MeCP2 Transgene protein expression was highest in homozygous cells and slightly greater than wild-type in heterozygous cells, demonstrating transgene expression of MeCP2 protein is sensitive to cellular levels of MeCP2 and increases in human cells with both endogenous MECP2 copies disrupted Transgene silencing occurred in part by inducing mRNA decay but more substantially by reducing miniMeCP2 protein accumulation, suggesting that the miRARE technology also acts in cis to prevent translation