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Delivery of a functional CFTR transgene to airway epithelial cells (AEC) offers the potential to provide durable restoration of normal CFTR function. Adeno-associated virus (AAV) vectors are the leading platform for the delivery of in vivo gene therapy; however, wild-type AAV vectors exhibit a limited capacity to transduce airway cells and evade pre-existing human neutralizing antibodies (NAb). We therefore employed a directed evolution platform to invent a novel AAV capsid (A101) with the capacity to efficiently transduce AECs, including in the presence of NAbs, following aerosolized administration to nonhuman primates (NHP). We then engineered 4D-710, a gene therapy comprising the A101 vector and a CFTR transgene with a partial deletion in the regulatory domain (CFTR\u0394R) to facilitate vector packaging. 4D-710 exhibited efficient transduction of human bronchial epithelial (HBE) cell air\u2013liquid interface (ALI) cultures in vitro and robust functional activity in CF HBE ALI cultures. Aerosolized administration of 4D-710 to NHPs was well tolerated and resulted in dose-dependent transgene expression and increased CFTR protein in diverse AEC types compared with vehicle controls. No significant differences in CFTR\u0394R mRNA levels were observed in lung samples from NHPs with pre-existing serum anticapsid NAbs compared with NAb-negative NHPs. These findings demonstrate the tolerability and feasibility of A101-mediated transgene delivery and expression in primate airways. A clinical trial evaluating aerosol delivery of 4D-710 in adults with CF (NCT05248230) is underway.<\/jats:p>","DOI":"10.1165\/rcmb.2025-0243ma","type":"journal-article","created":{"date-parts":[[2025,10,22]],"date-time":"2025-10-22T18:03:31Z","timestamp":1761156211000},"page":"837-846","update-policy":"https:\/\/doi.org\/10.1164\/crossmarkpolicies","source":"Crossref","is-referenced-by-count":10,"title":["Design and characterization of 4D-710, an aerosolized gene therapy for cystic fibrosis lung disease"],"prefix":"10.1093","volume":"74","author":[{"given":"Melissa A","family":"Calton","sequence":"first","affiliation":[{"name":"4D Molecular Therapeutics , Emeryville, CA,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roxanne H","family":"Croze","sequence":"additional","affiliation":[{"name":"4D Molecular Therapeutics , Emeryville, CA,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Theodore 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