Precision BioSciences (DTIL) Chardan’s 9th Annual Genetic Medicines Conference summary

Advances in genome editing technologies

• Genome editing has evolved beyond CRISPR-Cas9, with significant progress in protein engineering and the development of non-CRISPR nucleases and optimized DNA-modifying enzymes, expanding therapeutic applications.

• New gene editing platforms, such as ARCUS and engineered recombinases, enable precise gene insertion, deletion, and inversion at targeted genomic sites, offering solutions for complex genetic diseases.

• These technologies allow for large DNA fragment insertions, addressing diseases with multiple mutations and enabling multi-gene therapies, especially in inborn errors of metabolism and advanced CAR-T applications.

Clinical applications and proof of concept

• ARCUS technology demonstrated high-efficiency gene insertion in both dividing and non-dividing cells, with the ability to simultaneously insert and remove DNA, overcoming dominant negative mutations.

• In a phase 1/2/3 trial for neonatal-onset ornithine transcarbamylase deficiency, gene insertion into the PCSK9 locus led to discontinuation of standard care, normalization of ammonia levels, and removal from the liver transplant list.

• The PCSK9 locus was chosen as a safe harbor due to its benign loss-of-function profile in humans and potential cardiovascular benefits.

Safety, specificity, and regulatory considerations

• Off-target editing is a key safety focus, with regulatory expectations for comprehensive characterization and risk assessment; ARCUS and recombinase platforms offer high specificity due to unique recognition sites and mechanisms that avoid double-stranded breaks.

• Recombinases, especially tyrosine types, minimize genomic scars and allow preclinical mapping of potential off-target sites, enhancing safety profiles.

• Regulatory agencies are increasingly supportive and pragmatic, especially for indications with high unmet need, and are open to flexible trial designs and platform designations.