PROJECT 2 ABSTRACT PI: Daniel J. Rader, M.D. Recent evidence supports the potential of adeno-associated virus (AAV)-mediated liver-directed gene therapy as an effective therapeutic intervention for a variety of metabolic disorders. Monogenic lipid disorders are excellent models for the development of liver-directed gene therapy. Based on previous work funded by this P01 we are now poised to use a first-generation AAV8 clinical candidate to launch a clinical trial (Project 1) for one such disorder, Homozygous Familial Hypercholesterolemia (hoFH). This lipid disorder is caused by loss- of-function mutations in the LDL receptor (LDLR) and is associated with severe hypercholesterolemia and markedly premature atherosclerotic cardiovascular disease (ASCVD). In this Project 2, we propose to expand on our preclinical proof-of-concept studies for the treatment of hoFH by developing a second-generation AAV clinical candidate vector expressing an engineered LDLR transgene of superior efficacy for the correction of hoFH. Another serious lipid disorder is Familial LCAT Deficiency (FLD), which results in accumulation of unesterified cholesterol and chronic kidney disease progressing to end-stage renal failure. In contrast to the LDL receptor, LCAT is a secreted protein and restoration of a small fraction of the normal levels in blood would be expected to ameliorate the disease and prevent progressive renal disease. In this Project 2, we will develop an optimized clinical candidate vector for the treatment of FLD. Our goal is to optimize the hLDLR and hLCAT transgenes and work closely with Project 3 to optimize AAV-based vectors for correction of hoFH and FLD, such that the minimum efficacious dose of the clinical candidate vector is as low as possible. The overall intent of Project 2 is to lay the preclinical groundwork for conducting Phase 1 clinical trials using a second generation AAV-hLDLR for treatment of hoFH and the first AAV8-hLCAT for the treatment of FLD.

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PROJECT 2 NARRATIVE The studies proposed in this project will expand on our earlier preclinical proof of concept studies for the treatment of two life-threatening lipid disorders, Homozygous Familial Hypercholesterolemia (hoFH) and Familial LCAT Deficiency (FLD), using adeno-associated viral (AAV) vectors. The present goals are: 1) to develop a second-generation clinical candidate AAV vector of superior efficacy than that which currently exists for the correction of hoFH; and 2) to develop and optimize the first clinical candidate vector for the treatment of FLD. The objective is to optimize the transgene such that the minimum efficacious dose of both clinical candidate vectors is as low as possible. The overall intent of Project 2 is to lay the preclinical groundwork for conducting Phase I clinical trials using a second generation AAV-hLDLR for treatment of hoFH and the first AAV8-hLCAT for the treatment of FLD.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
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Heart, Lung, and Blood Initial Review Group (HLBP)
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Mcdonald, Cheryl
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University of Pennsylvania
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Ai, Jianzhong; Tai, Phillip W L; Lu, Yi et al. (2017) Characterization of adenoviral transduction profile in prostate cancer cells and normal prostate tissue. Prostate 77:1265-1270
Ai, Jianzhong; Li, Jia; Gessler, Dominic J et al. (2017) Adeno-associated virus serotype rh.10 displays strong muscle tropism following intraperitoneal delivery. Sci Rep 7:40336
Calcedo, Roberto; Somanathan, Suryanarayan; Qin, Qiuyue et al. (2017) Class I-restricted T-cell responses to a polymorphic peptide in a gene therapy clinical trial for ?-1-antitrypsin deficiency. Proc Natl Acad Sci U S A 114:1655-1659
Ajufo, Ezim; Cuchel, Marina (2016) Recent Developments in Gene Therapy for Homozygous Familial Hypercholesterolemia. Curr Atheroscler Rep 18:22
Ibrahim, Salam; Somanathan, Suryanarayan; Billheimer, Jeffrey et al. (2016) Stable liver-specific expression of human IDOL in humanized mice raises plasma cholesterol. Cardiovasc Res 110:23-9
Calcedo, Roberto; Wilson, James M (2016) AAV Natural Infection Induces Broad Cross-Neutralizing Antibody Responses to Multiple AAV Serotypes in Chimpanzees. Hum Gene Ther Clin Dev 27:79-82
Rashnonejad, Afrooz; Chermahini, Gholamhossein Amini; Li, Shaoyong et al. (2016) Large-Scale Production of Adeno-Associated Viral Vector Serotype-9 Carrying the Human Survival Motor Neuron Gene. Mol Biotechnol 58:30-6
Xie, Jun; Burt, Daniel Robert; Gao, Guangping (2015) Adeno-associated virus-mediated microRNA delivery and therapeutics. Semin Liver Dis 35:81-8
Ahmed, Seemin S; Gao, Guangping (2015) Making the White Matter Matters: Progress in Understanding Canavan's Disease and Therapeutic Interventions Through Eight Decades. JIMD Rep 19:11-22
Wang, Lili; Bell, Peter; Somanathan, Suryanarayan et al. (2015) Comparative Study of Liver Gene Transfer With AAV Vectors Based on Natural and Engineered AAV Capsids. Mol Ther 23:1877-87

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