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C6 - Gene Targeting and Gene Correction New Technologies

15: Reduction in Triglycerides through a Novel Ultracompact CRISPR System: Efficacy in Mouse Models and NHP Studies

Type: Oral Abstract Session

Presentation Details
Session Title: New Technologies for Gene Targeting and Gene Correction

In the last decade, CRISPR-based therapies have made tremendous progress in cell therapy applications and selected diseases that can be targeted in the liver. However, correcting the vast majority of genetic diseases outside the liver has remained challenging due to the large size of the original CRISPR systems, such as Cas9 and Cas12a. Ultracompact CRISPR systems present an opportunity to overcome the challenge of in vivo delivery, enabling single-AAV delivery of genome editors, including next-gen editing techniques such as epigenetic editing, reverse transcriptase editing, and base editing. Although many compact CRISPR systems have been described, their application to therapeutic targets has been limited due to challenges in matching the efficacy of larger systems. Here, we describe the discovery of a novel ultracompact CRISPR platform and show it is a potent genome editor in vivo in mouse and nonhuman primate models. Through high-throughput screening of natural variants, extensive protein engineering, and guide optimization, we optimize this platform for robust editing with both AAV and LNP delivery. This ultracompact CRISPR system was effectively used to target the APOC3 gene, a key player in triglyceride metabolism, offering promising therapeutic potential for durable treatment of severe hypertriglyceridemia. In vivo studies in humanized mouse models demonstrated an 80% reduction in triglyceride levels. Complementing these findings, our nonhuman primate studies further confirmed significant genetic editing of APOC3 with no major safety concerns observed. In addition, we provide an update on leveraging these ultracompact CRISPR systems for single AAV delivery of epigenetic editing for muscular dystrophy. These results underscore the potential of ultracompact CRISPR systems for precise and efficient gene editing applications in diverse conditions and to enable single-aav compatible next-gen editing approaches such as epigenetic editing.

Plain Language Summary
Our study introduces a new, smaller version of the CRISPR gene editing tool, specifically designed to be easier to deliver inside the body. This tool was tested in mice and monkeys to target a gene linked to triglyceride levels in the blood. Triglycerides are a type of fat, and high levels can lead to health problems. The results were promising: in mice, triglyceride levels dropped by 80%. The tests in monkeys also showed effective gene editing without major safety issues. Additionally, we explored using this smaller CRISPR system to potentially treat diseases in the muscle through a different type of gene editing. This research shows the potential of our new CRISPR tool in treating diseases related to genes, like high triglyceride levels and muscular dystrophy.

Lucas B. Harrington, Janice Chen

Mammoth Biosciences, Brisbane, CA"

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