(533a) Synergistic Cancer Gene Therapy Using Multi-Modal Gene Carriers in Combination with Chemotherapy

Bcr-Abl translocation (aka Ph) is a common underlying molecular cause of chronic myeloid leukemia (CML) and other forms of hematological malignancies. In Ph+ leukemia, the pro-apoptotic gene, Bim, is down-regulated, which is further complemented by and the up-regulation of pro-survival Mcl-1. To engineer Ph+ leukemia for facilitated apoptosis, hybrid particles is developed containing an adeno-associated virus (AAV) core expressing Bim and a stimuli-degrading polymeric shell co-delivering MCL-1 siRNA (BIM/MCL-1 hybrid gene carriers). AAV has become a key gene vector with multiple FDA-approved drugs but still offers challenges of immunogenicity and limited capability of genetic modifications. BIM/MCL-1 hybrid gene carriers are developed to avoid immune recognition and also incorporate a second, synergistic therapeutic component to expand the platform's potency. The ketalized polymeric shell that encapsulates the AAV core avoids immune recognition, enhances endosomal escape, and releases the therapeutic payloads in target intracellular destinations. Bim/Mcl-1 hybrid gene carriers were able to synergistically induce apoptosis of Ph+ leukemia via simultaneously up-regulating Bim and silencing Mcl-1, effectively eradicating Ph+ cells in vitro and in vivo. To further synergize the therapeutic efficacy, dasatinib, a tyrosine kinase inhibitor (TKI), was co-administered withBIM/MCL-1 hybrid gene carriers, allowing for nearly full eradication of Ph+ cells, while having minimal effect on Ph- cells as well as reducing the required dasatinib dosage. This talk will cover the synthesis and characterization of Bim/Mcl-1 hybrid gene carriers, and their proof-of-concept demonstration on effective treatment of Ph+ leukemia by themselves and in combination with targeted chemotherapeutics.