Grant: CIHR Fellowship

There is a need for effective lung-tropic viral gene delivery vectors for treatment of genetic lung disorders like Cystic Fibrosis, or for prophylactic delivery of broadly neutralizing antibodies against human respiratory pathogens (e.g. influenza or RSV) directly to the lung where they can be of greatest benefit. Such gene therapy is straightforward in concept, but challenging in application, due to issues with safety, host immune responses, and sufficient levels of gene expression in the right place. Sendai virus is a mouse Paramyxovirus with no known pathogenesis in humans. It is, however, fully capable of infecting the human respiratory tract, has no risk of integrating into the host genome or causing cancer, and has capacity to express high levels of foreign genes. Thus it is an excellent candidate for gene delivery to the respiratory tract, which is generally non-permissive to infection by other commonly-used virus vectors. Previously, inefficient systems for recombinant paramyxoviruses have limited the use of Sendai virus as a therapeutic vector, but recent advances in my sponsoring lab have overcome these barriers. I will take a combination of approaches to refine Sendai virus into an ideal viral vector. First, I will place the virus under selection pressures designed to render it immune-silent, so it does not induce an immune response that can cause pathology in the patient; and persistent, so that it can continue expressing the gene of interest for long periods of time. Second, I will engineer a "kill-switch" into the virus, so that if it is used in an immune-compromised patient, or there are unexpected complications from the virus or gene it bears, patient can be treated with an already clinically-available drug to eliminate the virus. Combined, these approaches will produce a Sendai virus vector that is safe, biologically-contained, capable of long-term, non-pathogenic infection, and is therefore ideal for respiratory gene delivery.