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, increasingthe efficiency of the viral vector to achieve safer, more affordable, therapeutic outcomes. Liver-directed gene therapies show great promise for the treatment of monogenic diseasesdue to the liver's central role in metabolism. AAV has emerged as the leading vector for in vivoliver-directed gene therapy treatment with more than 24 US clinical studies using AAVcompleted or ongoing. However, to reach therapeutic effect, these treatments are oftendelivered systemically with high vector dosages, which can trigger lethal immune responses andare 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 ofmonogenic liver diseases. The GTC is designed to safely increase the efficiency of AAV gene therapy to the liver. TheGTC combines local delivery with an electrode for EP and double balloons to isolate local tissuefrom circulation, enabling the tissue to be flushed of preformed neutralizing antibodies (NAbs).The GTC features a novel combination of elements to increase AAV hepatocyte transductionwhile avoiding vector-mediated immunotoxicity. We hypothesize that the GTC will: a) enablethese therapies to achieve clinical benefit using <10% of the current range of AAV dose relativeto systemic administration; and b) reduce the risk of adverse events caused by high systemicdoses.1 Proving feasibility of the GTC's EP enhanced transduction of hepatocytes in a largeanimal model is the most compelling element of this work. Preliminary data justify building theGTC prototype in Aim 1, optimizing electric field parameters in Aim 2, and demonstrating safetyand effectiveness in vivo in Aim 3. Phase II research, if awarded, will focus on developing thetechnology toward Phase III commercialization, including refining the EP parameters andfunctionality of the double balloons, leading to a fundamental advancement of care for manypatients 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.
Public Health Relevance Statement: Project Narrative
Liver-directed gene therapies using adeno-associated virus vectors have shown tremendous
promise but lack safe, efficient, and economical means of delivery. This project aims to create a
specialized gene therapy medical device, the Gene Therapy Catheter, which combines several
mechanisms for increasing the uptake of adeno-associated viral vector into one novel device.
Based on preliminary data, we estimate that the Gene Therapy Catheter will be able to reduce
the cost and volume of adeno-associated viral vector required by 90% compared to systemic
delivery.
Project Terms: |
