Grant: Project Grant

One million Canadians, many of them children, live with life-limiting rare genetic diseases. Only 6% of these diseases have a treatment. Monogenic lung diseases (MLDs) due to a defect in a single gene lead to failure to breathe at birth and early death, or lung scarring (fibrosis) in later life. There are no targeted therapies. Surfactant proteins (SP) B, C, and the ATP-binding cassette sub-family A member 3 (ABCA3) are critical for normal breathing by keeping the air sacs in the lung open for efficient oxygen intake. Gene therapy offers a promising solution to treat these life-threatening lung diseases by addressing the root cause of genetic diseases. Gene therapy uses a shuttle (vector) to bring the healthy version of the gene into the lung. The Adeno-Associated Virus (AAV) is the most commonly used vector. We have engineered an innovative vector (AAV6.2FF) that delivers the healthy gene exactly into the lung cells that produce surfactant. We previously demonstrated that targeted airway delivery of a normal SP-B gene improves lung function and survival in a mouse model lacking SP-B. Here, we target ABCA3 deficiency, the most common genetic surfactant disorder. ABCA3, similar to CFTR (the gene responsible for cystic fibrosis, the most lethal MLD) is a large gene that cannot be packaged into AAV6.2FF. We propose to solve the limited packaging ability of AAVs using novel split-vector technology. This will enable the expansion of AAV6.2FF gene therapy as a platform for the treatment of a variety of MLDs, including cystic fibrosis. The impact of our research lies in its potential to revolutionize the treatment of genetic lung diseases and other AAV-based gene therapies targeting oversized genes for genetic diseases beyond the lung to improve the health of the many patients with rare but life-limiting diseases.