Cross-species evolution of a highly potent AAV variant for therapeutic gene transfer and genome editing.
Trevor J GonzalezKatherine E SimonLeo O BlondelMarco M FanousAngela L RogerMaribel Santiago MaysonetGarth W DevlinTimothy J SmithDaniel K OhL Patrick HavlikRuth M Castellanos RiveraJorge A PiedrahitaMai K ElMallahCharles A GersbachAravind AsokanPublished in: Nature communications (2022)
Recombinant adeno-associated viral (AAV) vectors are a promising gene delivery platform, but ongoing clinical trials continue to highlight a relatively narrow therapeutic window. Effective clinical translation is confounded, at least in part, by differences in AAV biology across animal species. Here, we tackle this challenge by sequentially evolving AAV capsid libraries in mice, pigs and macaques. We discover a highly potent, cross-species compatible variant (AAV.cc47) that shows improved attributes benchmarked against AAV serotype 9 as evidenced by robust reporter and therapeutic gene expression, Cre recombination and CRISPR genome editing in normal and diseased mouse models. Enhanced transduction efficiency of AAV.cc47 vectors is further corroborated in macaques and pigs, providing a strong rationale for potential clinical translation into human gene therapies. We envision that ccAAV vectors may not only improve predictive modeling in preclinical studies, but also clinical translatability by broadening the therapeutic window of AAV based gene therapies.
Keyphrases
- gene therapy
- genome editing
- crispr cas
- gene expression
- clinical trial
- genome wide
- copy number
- endothelial cells
- dna methylation
- mouse model
- sars cov
- stem cells
- dna damage
- randomized controlled trial
- high throughput
- type diabetes
- escherichia coli
- adipose tissue
- genome wide identification
- cell therapy
- anti inflammatory
- dengue virus
- multidrug resistant