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 non-CRISPR nucleases expanding therapeutic applications.

• New gene editing platforms, such as ARCUS and engineered recombinases, enable precise gene insertion, deletion, and inversion at targeted genomic sites.

• These technologies are being leveraged for large gene insertions, addressing diseases with multiple mutations and enabling multi-gene therapies.

• Gene insertion approaches offer advantages over traditional gene therapy by ensuring durable expression in dividing cells, especially in pediatric indications.

Optimization and application of gene insertion

• Delivery modality, nuclease/recombinase choice, insertion site, and construct design are tailored to each indication for optimal therapeutic outcomes.

• Safe harbor loci, such as PCSK9, are targeted for gene insertion due to their established safety and potential side benefits.

• ARCUS nucleases enable high-efficiency gene insertion in both dividing and non-dividing cells, and can simultaneously insert and remove DNA.

• Clinical data from a phase 1/2/3 trial in neonatal OTC deficiency showed durable biochemical efficacy, discontinuation of standard care, and removal from liver transplant list.

Safety, off-target effects, and regulatory landscape

• Off-target editing is closely monitored, with regulatory expectations well established; risk-benefit is balanced by indication severity.

• Recombinases offer high specificity due to large recognition sites and avoid double-stranded breaks, reducing risk of indels and translocations.

• Regulatory agencies are increasingly supportive and pragmatic, especially for indications with high unmet need and transformative potential.