Seminar: Towards Nonviral, In Vivo Genome Editing Therapies: New Tools, Models, and Policy to Facilitate Translation

Genome editing tools have high potential to directly fix or disrupt gene mutations responsible for a wide variety of diseases. Developing safe and effective therapies using in vivo somatic genome editing, however, faces a number of challenges including efficient delivery, manufacturing at scale, and determination of unintended off-target effects in relevant biological systems.

We have developed new approaches to inform first-in-human studies that combine patient-derived, induced pluripotent stem cell models with new delivery nanocarriers and computational models. Our results indicate that mutation-specific, CRISPR-Cas9 genome editors can be designed to efficiently target mutant alleles without substantial off-target effects. Patients who are non-responders to frontline gene augmentation therapies are likely to be good candidates for such gene editing approaches. Further, tailored polymeric nanoparticles can efficiently deliver these editors, simplifying manufacturing by avoiding viral vectors.

Finally, computational models for in vivo somatic editing, grounded in empirical data from in vitro models and delivery studies, indicate that injectable off-the-shelf nonviral genome editors can be efficacious. Applications of these tools will be described for inherited ocular disorders in particular and are likely generalizable to many rare disorders.