(137c) Synergistic and Multimodal Cancer Gene Therapy Using Viral/Nonviral Chimeric Vectors

Gene therapy has become increasingly prevalent in the field of targeted medicine. Viral and nonviral vectors have been developed for treatment, but both have disadvantages, including immune activation for viruses and inefficient delivery for nonviral vectors. We have developed a hybrid particle that incorporates an adeno-associated virus (AAV) encapsulated within a polymer shell. Within this shell, siRNA is also encapsulated in order to form a multimodal system, capable of upregulating one gene through AAV and silencing another with the siRNA. The polymeric shell is comprised of a ketalized monomers and crosslinkers that break down in the acidic environment of the endosome, releasing AAV and siRNA. Particle formation was confirmed through DLS, and encapsulation was confirmed through hydrolysis, finding virus titer, and siRNA content.

As a therapeutic model, Ph+ leukemia, caused by a Bcr-Abl translocation, was explored. Bcr-Abl translocation causes down-regulation in the pro-apoptotic gene Bim and up-regulation in the pro-survival gene Mcl-1. To treat Ph+ leukemia, Bim expressing AAV and Mcl-1 silencing siRNA were encapsulated in the ketalized shell. Bim expression and Mcl-1 down-regulation synergistically induced apoptosis and suppressed proliferation, specifically in diseased cells. To enhance the efficacy of the hybrid system, the tyrosine kinase inhibitor, dasatinib (current standard of care for Ph+ leukemia), was co-delivered with the particles. The combined delivery of particles with dasatinib acted synergistically, and allowed for much smaller doses of the drug for the same effect. The smaller dosage reduces the risk of acquired resistance to dasatinib and presents a possibility to permanently cure leukemia, instead of just stopping disease progression. This talk will detail the creation of hybrid particles and their use as a specific and effective treatment alone, or in combination with dasatinib, against a Ph+ leukemia and potentially other cancers.