Base-editing therapy for alpha-galactosidase variants in fabry disease

Overview

Fabry disease, often linked to mutations in the alpha-galactosidase A (GLA) gene, presents significant challenges for patients, especially those with variants like D313Y and A143T. These variants, prevalent in certain populations, cause neurological symptoms without typical biomarkers, excluding patients from standard enzyme replacement therapies. Our research proposes a novel base-editing therapy targeting these specific GLA variants, aiming to alleviate symptoms and improve life quality for these underserved patients.

Technical specifications

Our approach utilizes advanced base-editing technologies to specifically target the D313Y and A143T variants. For the A143T variant, adenine base editors are employed to induce an A-to-G substitution. The D313Y variant requires a T-to-G conversion, achievable through prime editing, which uses a special Cas9 coupled with reverse transcriptase and guide RNA. Additionally, glycosylase-based editing enhances efficiency for T-to-G conversions. The editing is delivered via AAV transduction, an established method in our laboratory, providing a robust proof of principle.

Technology readiness level

This innovative therapy is currently at Technology Readiness Level 2, indicating that the foundational technology is established, with ongoing research focused on in vitro validation using patient-derived fibroblasts and engineered cell lines. Further characterization of cellular damage and ER stress effects is planned to support the development of this therapeutic approach.