Yang Zhi, Yao Yizheng, Chen Xi, Madigan Victoria, Pu Shanrui, Fan Xianqun, Pu Jun, Bei Fengfeng
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.
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.
Cell Rep Med. 2025 Jun 17;6(6):102144. doi: 10.1016/j.xcrm.2025.102144. Epub 2025 May 22.
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.
高效的基因递送载体对于呼吸道和肺部疾病的治疗至关重要。我们报告称，AAV.CPP.16是一种源自AAV9的工程化腺相关病毒（AAV）变体，通过鼻内给药可有效转导小鼠和非人类灵长类动物的气道和肺细胞。AAV.CPP.16优于AAV6和AAV9这两种对呼吸道组织具有明确嗜性的野生型AAV，并能有效靶向关键的呼吸道细胞类型。它在两种与临床相关的呼吸道和肺部疾病小鼠模型中支持基因补充和编辑治疗。单次鼻内给予表达双靶点血管内皮生长因子（VEGF）/转化生长因子（TGF）-β1中和蛋白的AAV.CPP.16可保护肺部免受特发性肺纤维化的侵害，而类似应用携带“一体化”CRISPR-Cas13d系统的AAV.CPP.16可抑制严重急性呼吸综合征冠状病毒2（SARS-CoV-2）衍生的RNA依赖性RNA聚合酶（Rdrp）基因的转录。我们的研究结果突出了AAV.CPP.16作为呼吸道和肺部基因治疗的一种有前景的载体。
