A Novel Approach To Treating Huntington's Disease Using AAV To Deliver Gene Editing Tools To The Brain

LETI-101 is a preclinical-stage gene editing candidate designed to address Huntington’s disease through a one-time, intrastriatal administration of an AAV5-packaged CRISPR system. The approach targets the mutant huntingtin gene (mHTT) while preserving wild-type HTT, a critical consideration given its role in neuronal health. LETI-101 leverages Life Edit’s proprietary compact nucleases and diverse PAM recognition sites to enable allele-selective editing, with demonstrated efficacy in patient-derived cells, transgenic rodent models, and non-human primates. In BACHD mice, LETI-101 achieved dose-dependent reductions in mHTT protein, and in NHPs, it showed broad brain biodistribution with minimal systemic exposure and no detection in gonadal tissues.

The asset also details a robust CMC strategy, including construct screening, transfection optimization, and downstream purification, resulting in high vector productivity and capsid quality. A ddPCR-based potency assay was developed to quantify editing in heterozygous CNS-derived cell lines. Importantly, off-target analysis revealed no liabilities, supporting the precision of the editing system. The UK’s MHRA reviewed the preclinical package and deemed it sufficient and comprehensive, aligning with the proposed clinical trial design.

For teams exploring CNS-targeted gene therapies, LETI-101 offers a compelling case study in integrating early manufacturability with therapeutic innovation.