Grant: Project Grant

Surfactant protein B (SP-B) deficiency is a rare genetic disease that causes lethal respiratory distress in infants due to the absence of an essential surfactant protein that allows the lung to inflate. The disease results from mutations in the SP-B gene (SFTPB). Infants with SP-B deficiency exhibit early onset severe respiratory distress followed by progressive respiratory failure and death within the first year of life. The only effective treatment is lung transplantation. Due to the rapidly fatal nature of this disease and the lack of available treatment options, novel therapies for neonates suffering from SP-B deficiency are needed. Since SP-B deficiency is caused by mutations in a single gene, and the only organ affected by these mutations is the lung, targeted delivery of gene therapies to the respiratory tract is an attractive treatment option. Adeno-associated virus (AAV) is a highly effective gene therapy vector that infects both dividing and non-dividing cells and promotes long-term transgene expression, making it one of the most promising vectors in the field of gene therapy. We have developed a novel lung tropic AAV vector expressing the murine SFTPB gene (AAV-SPB) that when delivered to the respiratory tract of SP-B null mice significantly improves respiratory function and extends survival. Here we aim to investigate whether repeat administration of AAV-SPB will lead to longer-term expression of therapeutic levels of SPB, potentially even curing mice. In an effort to move this therapy toward human clinical trials, we have engineered an AAV vector expressing human SPB and aim to test it first in the mouse model of SP-B deficiency, followed by human induced pluripotent stem cell-derived lung cells from SP-B null patients and finally in human lung slices. If successful, this technology would have profound therapeutic implications for neonates suffering from SP-B deficiency and could impact how we treat other life-threatening monogenic lung diseases.