Poster X5 - Enhancer Particle for Increased Heart-Targeting of Gene Therapy

Introduction: Gene therapy is not yet clinically approved for cardiac applications because of the dangerously high dose required to reach efficacy. We have developed an adjuvant particle, “enhancer polymer (ePL),” which increases heart uptake and transduction, thereby enabling cardiac gene therapy. ePL is used in conjunction with existing gene therapy technology.

Materials and

Methods: ePL is a cargo-less, spherical particle composed of poly (lactic-co-glycolic acid) (PLGA). Screening a series of particles resulted in the following key characteristics: a diameter of 200 nm, a viscosity of 0.6 dL/g, a 65/35 lactic-to-glycolic acid ratio, and 100% of lactic acid being the L enantiomer of the monomer. The particles are synthesized by nanoprecipitation using poly (vinyl acetate) (PVA) as a surfactant. ePL is not a component of any gene therapy particle and does not alter existing gene therapy technology; rather, it is a separate, adjuvant particle that increases heart delivery and decreases liver delivery.

Results, Conclusions, and Discussions: ePL improves heart-targeting of adeno-associated virus (AAV). We measured the uptake of serotypes AAV1 and AAVrh74 carrying the transgene for common biomarkers with and without ePL in vivo. ePL increased heart-targeting of both serotypes, shown by PCR and Western blot (AAVrh74: 14-fold change, AAV1: 1.5-fold change). Further, ePL decreased the amount of dose delivered to the liver. This encompasses the overall effect of ePL: AAV is redirected from the liver to the heart. The mechanism by which ePL does this is by temporarily overwhelming the liver, thereby blocking its uptake of AAV. This increases the circulation half-life of AAV, allowing it to be taken up by the heart. Further, our data shows that ePL induces the release of cell-signaling factors that directly increase uptake of AAV in the heart. Overall, ePL has the potential to enable cardiac gene therapy by improving delivery and reducing harmful off-targeting.

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