Vivet Therapeutics Showcases Cerebrotendinous Xanthomatosis Program and New AAV Gene Delivery at 2024 ESGCT Congress

Vivet Therapeutics, a biotechnology company at the clinical stage, has unveiled significant pre-clinical results for its VTX-806 gene therapy, aimed at treating Cerebrotendinous Xanthomatosis (CTX). This was presented through three posters at the European Society for Gene and Cell Therapy (ESGCT) 2024 Congress in Rome, Italy. These findings showcase the company's pioneering advancements in long-term gene therapies targeting rare inherited liver metabolic disorders.

Dr. Gloria Gonzalez-Aseguinolaza, the Co-Founder and Chief Scientific Officer of Vivet Therapeutics, emphasized the significance of their advancements. She pointed out that their diversified gene therapy pipeline, which utilizes precision-engineered viral vectors and gene constructs, holds substantial promise for developing durable treatments for CTX and other rare liver metabolic diseases. Dr. Jean-Philippe Combal, Co-Founder and Chief Executive Officer, also highlighted the limitations of the current CTX treatments, which necessitate lifelong administration of chenodeoxycholic acid. Although this treatment reduces toxic metabolites, it does not completely prevent neurodegeneration, indicating a clear unmet medical need. The promising preclinical data for VTX-806, which received European Orphan Drug Designation in September, suggests potential for a more effective treatment option.

The first poster, titled "Long-term metabolic, phenotypic, and neuropathological characterization of the Cyp27a1-/- mouse model of cerebrotendinous xanthomatosis," delves into the detailed evaluation of the CTX mouse model, B6.129-Cyp27a1tmlEl t/J. This study extended up to 18 months and revealed that Cyp27a1-/- mice, compared to their wild-type counterparts, experienced hepatomegaly, elevated plasma ALT levels, and increased expression of Cyp7a1 and Cyp3a11. Moreover, by six months, these mice exhibited reduced weight gain, steatosis, and an increase in toxic bile acid precursors in both blood and brain. Notably, female mice displayed signs of ataxia, marking the first instance of observable motor alterations in a CTX mouse model, which mirrors the human condition and thereby holds significant translational research value.

The second poster, "S/MAR-Containing AAV Vectors Result in an Increase in AAV Episomes and a Reduction in AAV Integration Sites in a Mouse Model With a High Rate of Hepatocyte Proliferation," focuses on an HT1 mouse model study involving S/MAR (scaffold/matrix attachment region) containing AAV vectors. Results demonstrated that these vectors achieved a more substantial therapeutic effect compared to control vectors. Surviving mice showed normalization of body weight and serum biomarkers roughly 50 days post-injection. Additionally, expression levels of viral genomes and the disease-associated enzyme Hfah were consistent across test groups. Immunohistochemistry indicated FAH expression in hepatocyte clusters of recovered mice, suggesting potential AAV integration and clonal expansion.

The third poster, "Liver-directed gene therapy normalizes toxic bile acid metabolite levels in the blood and brain of mice with cerebrotendinous xanthomatosis," outlines the optimization of VTX-806, an AAV vector designed to be highly potent with minimal immunogenicity. Using liver-specific promoters and additional regulatory elements, the AAVs were fine-tuned to prevent immune response activation. Results showed that VTX-806 elevated Cyp27a1 expression in vitro and in vivo, restoring normal levels of circulating 7αC4 and hepatic bile acid synthesis-related genes, and correcting hepatomegaly. Importantly, the AAV gene therapy also normalized 7αC4 levels in the brain, offering a potential curative approach for CTX patients.

These findings underscore Vivet Therapeutics' progress in developing innovative gene therapies to address significant gaps in treatment options for rare metabolic disorders, particularly CTX. The detailed research presented at the ESGCT Congress highlights the potential impact of their work on patient care and the broader field of gene therapy.