Enhanced Gene Therapy Delivery Through Electric Pulsing Double-Balloon Catheter

Project Summary We propose to develop the novel Gene Therapy Catheter (GTC), an electrical pulsing (EP) device designed to deliver adeno-associated virus (AAV) gene therapy to the liver, increasing the efficiency of the viral vector to achieve safer, more affordable, therapeutic outcomes. Liver-directed gene therapies show great promise for the treatment of monogenic diseases due to the liver’s central role in metabolism. AAV has emerged as the leading vector for in vivo liver-directed gene therapy treatment with more than 24 US clinical studies using AAV completed or ongoing. However, to reach therapeutic effect, these treatments are often delivered systemically with high vector dosages, which can trigger lethal immune responses and are prohibitively expensive. This Phase I SBIR grant will explore an innovative approach to liver- directed gene therapy that, if successful, could unlock the potential for curing a multitude of monogenic liver diseases. The GTC is designed to safely increase the efficiency of AAV gene therapy to the liver. The GTC combines local delivery with an electrode for EP and double balloons to isolate local tissue from circulation, enabling the tissue to be flushed of preformed neutralizing antibodies (NAbs). The GTC features a novel combination of elements to increase AAV hepatocyte transduction while avoiding vector-mediated immunotoxicity. We hypothesize that the GTC will: a) enable these therapies to achieve clinical benefit using <10% of the current range of AAV dose relative to systemic administration; and b) reduce the risk of adverse events caused by high systemic doses.1 Proving feasibility of the GTC’s EP enhanced transduction of hepatocytes in a large animal model is the most compelling element of this work. Preliminary data justify building the GTC prototype in Aim 1, optimizing electric field parameters in Aim 2, and demonstrating safety and effectiveness in vivo in Aim 3. Phase II research, if awarded, will focus on developing the technology toward Phase III commercialization, including refining the EP parameters and functionality of the double balloons, leading to a fundamental advancement of care for many patients in need of gene therapy. 1 The 40x increase in transduction seen in vitro (see Preliminary Research) equates to a 97.5% decrease in vector requirement. We theorize that 40x understates the true effect due to: a) multiplicity of infection at high dosage; and b) and not having reached the dilution point where +EP and -EP groups achieve the same outcome.