Broad Biodistribution And Expression Of Allele Selective LETI101 In Critical Brain Regions For Treatment Of Huntington's Disease Following Intrastriatal Delivery In NHP

By K. Tyler McCul Lough, Ph.D., Associate Director, Translational Biology

LETI-101 is a novel, precision-based CRISPR treatment designed to target Huntington's disease through allele-selective editing of the mutant HTT gene. Utilizing a proprietary compact CRISPR system packaged in an AAV5 vector, LETI-101 enables targeted central nervous system (CNS) delivery, offering a promising therapeutic approach. The technology leverages Type II V RNA-guided nucleases with diverse PAM sequences, allowing for broad genome access and a variety of editing modalities, including knock-out, insertion/repair, and base editing. Flexible delivery platforms such as AAV and lipid nanoparticles further enhance its therapeutic potential.

In preclinical studies, LETI-101 demonstrated potent allele-selective editing in patient-derived cells, significantly reducing the mutant HTT protein while preserving wild-type levels. In BACHD transgenic mice, the treatment achieved up to an 80% reduction of mutant HTT protein in a dose-dependent manner. A one-month biodistribution study in cynomolgus monkeys showed high expression in critical brain regions and minimal systemic exposure, with no detectable vector in the gonads, confirming a favorable safety profile. Furthermore, extensive off-target analysis confirmed the specificity of LETI-101, with no off-target edits at sequenced sites, supported by advanced bioinformatics and Digenome-Seq methodologies.

To learn more about the promising potential of LETI-101 for treating Huntington's disease, we invite you to access the full presentation.