2. Academic Validation
  3. Cross-species tropism of AAV.CPP.16 in the respiratory tract and its gene therapies against pulmonary fibrosis and viral infection

Cross-species tropism of AAV.CPP.16 in the respiratory tract and its gene therapies against pulmonary fibrosis and viral infection

  • Cell Rep Med. 2025 Jun 17;6(6):102144. doi: 10.1016/j.xcrm.2025.102144.
Zhi Yang 1,  Yizheng Yao 2,  Xi Chen 3,  Victoria Madigan 4,  Shanrui Pu 3,  Xianqun Fan 5,  Jun Pu 6,  Fengfeng Bei 7
Affiliations

Affiliations

  • 1 Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Department of Ophthalmology, Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai 200011, China.
  • 2 Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Jiangsu Key Laboratory of Neuropsychiatric Diseases and Institute of Neuroscience, Soochow University, Clinical Research Center of Neurological Disease, The Second Affiliated Hospital of Soochow University, Suzhou 215123, China.
  • 3 Department of Neurosurgery, The Second Affiliated Hospital of Kunming Medical University, Kunming 650106, China; NHC Key Laboratory of Drug Addiction Medicine, Kunming Medical University, Kunming 650500, China.
  • 4 Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
  • 5 Department of Ophthalmology, Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai 200011, China. Electronic address: fanxq@sjtu.edu.cn.
  • 6 Department of Neurosurgery, The Second Affiliated Hospital of Kunming Medical University, Kunming 650106, China; NHC Key Laboratory of Drug Addiction Medicine, Kunming Medical University, Kunming 650500, China. Electronic address: pujun137@126.com.
  • 7 Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. Electronic address: fbei@bwh.harvard.edu.
PMID: 40409263 DOI: 10.1016/j.xcrm.2025.102144
Abstract

Efficient gene delivery vectors are crucial for respiratory and lung disease therapies. We report that AAV.CPP.16, an engineered adeno-associated virus (AAV) variant derived from AAV9, efficiently transduces airway and lung cells in mice and non-human primates via intranasal administration. AAV.CPP.16 outperforms AAV6 and AAV9, two wild-type AAVs with demonstrated tropism for respiratory tissues, and efficiently targets key respiratory cell types. It supports gene supplementation and editing therapies in two clinically relevant mouse models of respiratory and lung diseases. A single intranasal dose of AAV.CPP.16 expressing a dual-target, vascular endothelial growth factor (VEGF)/transforming growth factor (TGF)-β1-neutralizing protein protected lungs from idiopathic pulmonary fibrosis, while a similar application of AAV.CPP.16 carrying an "all-in-one" CRISPR-Cas13d system inhibited transcription of the SARS-CoV-2-derived RNA-dependent RNA polymerase (Rdrp) gene. Our findings highlight AAV.CPP.16 as a promising vector for respiratory and lung gene therapy.

Keywords

AAV; CRISPR; lung gene therapy; pulmonary fibrosis.

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