Mass General Brigham researchers have developed a groundbreaking gene therapy delivery system that can target the lungs and airways through a simple nasal spray, potentially revolutionizing treatment for respiratory diseases.
The team engineered a version of adeno-associated virus (AAV), dubbed AAV.CPP.16, which efficiently delivers therapeutic genetic material to lung tissue when administered intranasally. This innovation addresses one of the most significant challenges in gene therapy: delivering therapeutic molecules to the correct locations in the body.
"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."
Superior Performance Across Multiple Models
Through extensive testing, the researchers demonstrated that AAV.CPP.16 outperformed conventional vectors such as AAV6 and AAV9 in transduction efficiency and tissue specificity. The vector's effectiveness was validated across cell cultures, mouse models, and non-human primates, suggesting strong translational potential.
The intranasal administration route represents a significant advantage, as it bypasses systemic circulation, minimizing off-target effects and immune clearance while facilitating direct access to airway epithelial cells. This non-invasive delivery method is also more patient-friendly than traditional approaches.
Promising Applications in Pulmonary Diseases
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 showed significantly reduced fibrotic progression, providing hope for a disease that currently lacks effective treatments.
In a parallel investigation, the team explored AAV.CPP.16's antiviral potential. 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. This finding suggests new avenues for gene-based immunoprophylaxis and therapeutic intervention during respiratory viral outbreaks.
Mechanism and Advantages
The enhanced tropism of AAV.CPP.16 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 successfully targeting organs exposed to the external environment.
"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.
Future Implications
The translational potential of AAV.CPP.16 is particularly striking given its demonstrated effectiveness across species. This cross-species tropism significantly strengthens the argument for fast-tracking clinical development.
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 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.
The research has garnered support from multiple funding bodies, including Brigham and Women's Hospital sundry funds and several Chinese national science foundations, reflecting global interest in advancing respiratory gene therapies.
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 the multidisciplinary approach critical for tackling the complexities of gene delivery and therapeutic design.
The current data, published in Cell Reports Medicine, verify the transformative potential of AAV.CPP.16 in respiratory gene therapy, potentially opening doors to novel treatments for a spectrum of pulmonary conditions that can be treated at their genetic root using non-invasive gene delivery systems.
