ElevateBio Unveils Promising Preclinical Data on LETI-101 for Huntington's Disease Treatment

ElevateBio, based in Waltham, Massachusetts, has announced promising new preclinical data for LETI-101, a novel gene-editing therapeutic designed for Huntington's disease (HD). This innovative treatment is being developed by Life Edit, ElevateBio's gene editing and research arm. LETI-101 employs Life Edit’s unique CRISPR nuclease technology, delivered via an AAV5 vector, to specifically target and modify the T allele of an exonic SNP in the HTT gene, which is implicated in HD.

Preclinical trials have shown that LETI-101 achieves remarkable reductions in disease-causing mutant huntingtin (mHTT) protein levels in a mouse model of Huntington’s disease. Notably, the treatment reduces mHTT protein levels by over 80% while maintaining the levels of the wild-type huntingtin protein, crucial for normal cellular functioning. These findings suggest that LETI-101 could be a leading candidate for the treatment of HD, a hereditary neurodegenerative disorder characterized by motor dysfunction, cognitive decline, and behavioral changes due to neuronal damage caused by mutant huntingtin protein accumulation.

The preclinical studies also indicate that LETI-101 is well-tolerated in nonhuman primates, with no adverse effects observed even at the highest tested doses. This safety profile further supports its potential as a therapeutic candidate for HD. Based on these encouraging results, Life Edit is advancing LETI-101 towards clinical development, having received constructive feedback on its CMC (Chemistry, Manufacturing, and Controls) and development plans from the UK’s Medicines and Healthcare Products Regulatory Agency (MHRA).

ElevateBio's approach integrates cutting-edge technology with comprehensive manufacturing capabilities to facilitate the development of genetic medicines. David Hallal, Chairman and CEO of ElevateBio, highlighted that the advancement of LETI-101 underscores the potential of their gene-editing platform and showcases the company's capabilities in driving forward genetic medicine development. The seamless integration of their technology stack at Life Edit and manufacturing prowess at BaseCamp enables ElevateBio to enhance the entire drug development process, from concept to clinic-ready candidates.

Huntington’s disease arises from a mutation in the huntingtin gene, specifically an expansion of the cytosine-adenine-guanine (CAG) trinucleotide repeat, leading to the production of a toxic form of the huntingtin protein. The mutant protein aggregates within the brain, causing neuronal damage and progressive neurodegeneration. Life Edit's technology focuses on precision, leveraging a vast array of nucleases with diverse protospacer adjacent motifs (PAMs) that allow for highly selective targeting of genetic sequences. This selectivity is crucial in ensuring that therapeutic interventions do not disrupt the normal huntingtin protein, a challenge that has hindered previous therapeutic efforts.

Tedd Elich, Ph.D., Chief Scientific Officer at Life Edit, emphasized that the selective targeting of mHTT protein, while preserving the wild-type form, exemplifies the unique capabilities of their platform. The recent preclinical results and positive regulatory feedback mark significant milestones in the development of LETI-101, paving the way for future partnerships to expedite the program's progress.

The promising data will be presented at the 20th Annual Huntington’s Disease Therapeutics Conference in Palm Springs, California. This presentation will highlight an AAV5-delivered Life Edit CRISPR system’s efficacy in editing and reducing mutant HTT protein in key brain regions affected by Huntington’s disease. These findings represent a significant advancement in the pursuit of effective treatments for complex genetic disorders, demonstrating the potential of ElevateBio’s innovative approach to revolutionize the future of medicine.