Researchers Develop Gene Therapy That Can Target Airway and Lungs via Nasal Spray

For gene therapy to work well, therapeutic molecules need to be efficiently delivered to the correct locations in the body—a job commonly given to adeno-associated viruses (AAV).

To improve the AAV’s ability to deliver therapeutics specifically to the lungs and airway, Mass General Brigham researchers developed and applied a new version, called AAV.CPP.16, that can be administered with a nasal spray. In preclinical models, the innovative tool outperformed previous versions by more effectively targeting the airway and lungs and showing promise for respiratory and lung gene therapy. Results are published in Cell Reports Medicine.  

“We noticed that AAV.CPP.16, which we initially engineered to enter the central nervous system, also efficiently targeted lung cells,” said senior author FengFeng Bei, PhD, of the Department of Neurosurgery at Brigham and Women’s Hospital, a founding member of the Mass General Brigham healthcare system. “This prompted us to further investigate AAV.CPP.16 for intranasal gene delivery to the respiratory airways.”

The researchers found AAV.CPP.16 outperformed previous versions (AAV6 and AAV9) in cell culture, mouse models, and non-human primate models. They then used the more efficient tool to deliver scar-preventing gene therapy for pulmonary fibrosis, using a mouse model of the respiratory disease. They also used the tool to delivery gene therapy for a viral infection, where the therapy prevented the replication of the SARS-CoV-2 virus in a mouse model of COVID-19.

“Although further research is needed, our findings suggest that intranasal AAV.CPP.16 has strong translational potential as a promising delivery tool for targeting the airway and lung,” said Dr. Bei.

Authorship: In addition to Bei, Mass General Brigham authors include Zhi Yang and Yizheng Yao. Additional authors include Xi Chen, Victoria Madigan, Shanrui Pu, Xianqun Fan, and Jun Pu.

Disclosures: Bei is a co-founder of and scientific advisor to Brave Bio Inc., a gene therapy startup, and an inventor on patents or patent applications related to AAV.CPP.16 (US11518787B2, US11981705B2, and US20240285804A1).

Funding: This study was supported by Brigham and Women’s Hospital sundry fund, the National Natural Science Foundation of China (82200961, 82302385 and 82473327), the Natural Science Foundation of Jiangsu Province (BK20241921), the National Basic Science Center Program of China (82388101), the Basic Research Program of Yunnan Province (202401AS070018), and the NHC Key Laboratory of Drug Addiction Medicine (K1323303).

Paper cited: Yang Z, et al. “Cross-species tropism of AAV.CPP.16 in the respiratory tract and its gene therapies against pulmonary fibrosis and viral infection” Cell Reports Medicine DOI: 10.1016/j.xcrm.2025.102144