In a groundbreaking advance for respiratory medicine, researchers at Mass General Brigham have developed a novel gene therapy delivery system that promises to revolutionize treatment for lung diseases. Central to this breakthrough is an engineered version of the adeno-associated virus (AAV), dubbed AAV.CPP.16, which is designed to efficiently and selectively deliver therapeutic genetic material to the lungs and airways through a simple nasal spray. This innovative delivery system marks a significant step forward in targeting respiratory disorders at the genetic level, overcoming longstanding barriers in gene therapy.
AAVs have long been the workhorses of gene delivery due to their low pathogenicity and ability to target a variety of tissues. However, tailoring AAVs to precisely reach the respiratory tract has been a formidable challenge. The team at Mass General Brigham, led by Dr. FengFeng Bei of the Department of Neurosurgery at Brigham and Women’s Hospital, engineered AAV.CPP.16 initially to cross the blood-brain barrier for central nervous system targeting. Unexpectedly, they found this same viral vector had a high affinity for lung tissue, prompting further investigation into its respiratory potential.
The process of pulmonary gene therapy requires vectors that not only reach but also efficiently transduce cells in the complex environment of the respiratory tract. Mucosal barriers, immune surveillance, and cellular heterogeneity pose major hurdles. AAV.CPP.16 appears to overcome many of these obstacles almost effortlessly. Through meticulous experimental studies encompassing cell cultures, murine models, and non-human primates, the researchers demonstrated that AAV.CPP.16 outperforms conventional vectors such as AAV6 and AAV9 in transduction efficiency and tissue specificity.
One of the most compelling aspects of AAV.CPP.16 is its delivery via intranasal administration, a non-invasive and patient-friendly route. Intranasal gene delivery bypasses systemic circulation, minimizing off-target effects and immune clearance. This route also facilitates direct access to airway epithelial cells, the frontline defenders and principal viral entry points in many pulmonary diseases. By harnessing the upper respiratory tract’s natural pathways, AAV.CPP.16 maximizes gene therapy payload delivery with remarkable precision.
To demonstrate therapeutic relevance, the research team employed AAV.CPP.16 to deliver an antifibrotic gene therapy in a mouse model of pulmonary fibrosis, a debilitating condition characterized by excessive scarring that impairs lung function. Results indicated significantly reduced fibrotic progression, providing a hopeful outlook for a disease currently lacking effective treatments. This milestone not only underscores the vector’s efficacy but also illustrates its potential to address chronic and complex pulmonary pathologies.
In a parallel line of investigation, the team explored AAV.CPP.16’s antiviral potential, particularly pertinent to the ongoing challenges of respiratory viral infections. They administered gene therapy that effectively inhibited SARS-CoV-2 replication in a mouse model of COVID-19, highlighting the vector’s capability to combat acute viral illnesses. The implications of this finding are vast, suggesting new avenues for gene-based immunoprophylaxis and therapeutic intervention during pandemics.
Mechanistically, the AAV.CPP.16 vector’s enhanced tropism for respiratory tissue is believed to stem from modifications that enable better interaction with lung cell surface receptors, improved mucosal penetration, and evasion of neutralizing antibodies. These optimization strategies are critical for the success of gene therapies targeting organs exposed to the external environment, which are inherently more challenging than internal tissues to target safely and efficiently.
Beyond proof-of-concept, the translational potential of AAV.CPP.16 is particularly striking given its demonstrated effectiveness across species, as evidenced by comparable outcomes in cell lines, rodents, and non-human primates. Translating preclinical success into human therapies often falters due to interspecies differences, but this vector’s cross-species tropism significantly strengthens the argument for fast-tracking clinical development.
Dr. FengFeng Bei emphasized the promising future of this technology, stating that while additional safety and efficacy studies are necessary, the intranasal delivery approach with AAV.CPP.16 is poised to fill a crucial gap in gene therapy for respiratory diseases. Current gene delivery platforms lack the fine tissue-targeting capabilities and practical administration methods this vector offers, potentially opening doors to novel treatments for a spectrum of pulmonary conditions.
As gene therapy continues to evolve from experimental science toward mainstream medicine, innovations like AAV.CPP.16 are essential to overcoming technical and biological barriers. The delivery vector landscape is highly competitive, yet AAV.CPP.16 distinguishes itself with its unique delivery mode, enhanced cell specificity, and robust preclinical efficacy. These attributes collectively suggest a future where lung diseases, from idiopathic fibrosis to viral infections, can be treated at their genetic root using non-invasive gene delivery systems.
Moreover, the safety profile of AAVs has been well-characterized over years of research, and with targeted engineering, vectors like AAV.CPP.16 further mitigate risks related to immune responses or unintended tissue transduction. This focus on both efficacy and safety is pivotal to gaining regulatory approval and clinical adoption, positioning AAV.CPP.16 as a frontrunner in next-generation gene therapy vectors.
The research has garnered support from a constellation of funding bodies, illustrating the broad scientific and societal interest in advancing respiratory gene therapies. Among them are Brigham and Women’s Hospital sundry funds and several Chinese national science foundations, reflecting a truly collaborative and global effort to push the boundaries of medical science.
In addition to Dr. Bei, the team includes key contributors Zhi Yang and Yizheng Yao from Mass General Brigham, alongside Xi Chen, Victoria Madigan, Shanrui Pu, Xianqun Fan, and Jun Pu, underscoring a multidisciplinary approach critical for tackling the complexities of gene delivery and therapeutic design.
While the scientific community eagerly anticipates further clinical developments, the current data published in Cell Reports Medicine verify the transformative potential of AAV.CPP.16 in respiratory gene therapy. This vector represents a shining example of how cutting-edge bioengineering combined with strategic translational science can pave the way for more effective, non-invasive, and personalized treatments to improve lung health worldwide.
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Subject of Research: Cells
Article Title: Cross-species tropism of AAV.CPP.16 in the respiratory tract and its gene therapies against pulmonary fibrosis and viral infection
News Publication Date: 22-May-2025
Web References:
– Mass General Brigham: http://massgeneralbrigham.org
– Publication DOI: https://doi.org/10.1016/j.xcrm.2025.102144
– Dr. FengFeng Bei lab: https://www.brighamandwomens.org/neurosurgery/research/labs-and-bios/bei-laboratory-fengfeng-bei-phd
References:
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.
Keywords: Gene delivery, Gene editing, Gene therapy
