Optimized AAV capsids robustly transduce airway epithelial cells.

Area of Science:

• Pulmonary Medicine
• Gene Therapy
• Virology

Background:

• Gene therapy holds promise for genetic disorders but faces challenges in airway disease treatment.
• Efficient gene delivery to airway epithelial cells is crucial for treating conditions like cystic fibrosis (CF).
• Current adeno-associated virus (AAV) vectors need high doses for airway efficacy, posing safety concerns.

Purpose of the Study:

• To develop novel AAV capsid variants with enhanced transduction efficiency in airway epithelial cells.
• To overcome limitations of existing AAV vectors for pulmonary gene delivery.
• To create a versatile platform for treating CF and other respiratory diseases via gene therapy.

Main Methods:

• Utilized unbiased peptide-modified AAV libraries for screening.
• Employed round-over-round screening in primary human airway epithelia (HAE) cultures.
• Identified and characterized novel AAV capsids (AAV-AE) for improved airway transduction.

Main Results:

• Discovered 20 novel AAV capsids (AAV-AE) with 10- to 100-fold lower dose requirements.
• Achieved efficient gene transduction in HAE, human basal cells, and nonhuman primate tracheal explants.
• Demonstrated high transgene expression in murine airways in vivo using optimized AAV capsids.

Conclusions:

• Developed optimized AAV capsids significantly enhance gene delivery efficiency to airway epithelia.
• These AAV-AE variants offer a safer and more effective approach for pulmonary gene therapy.
• The novel capsids provide a versatile platform for gene addition and editing in respiratory diseases like CF.