Project II - Gene Therapy for Dyslipidemia Our goal in this project is to establish biological understanding, preclinical proof of concept;and safety data using AAV-based vectors for correction of familial hypercholesterolemia (FH) and abetalipoproteinemia (ABL) such that clinical trials of gene therapy for both disorders is a tangible reality by the final year of this P01. Dyslipidemia is a major risk factor for atherosclerotic cardiovascular disease (ASCVD), the most common cause of death and disability. Several common genetic forms of dyslipidemia exist and although many patients with dyslipidemia can be treated effectively with existing drugs, others are not effectively treated and remain at exceptionally high risk of premature ASCVD. A classic example is homozygous FH, in which patients have severe hypercholesterolemia that can't be effectively treated with current drugs and develop ASCVD in childhood or adolescence. Conversely, ABL, which is due to mutations in the microsomal triglyceride transfer protein (MTP), is associated with absent plasma LDL and apoB and progressive spinocerebellar degeneration and retinopathy. Therefore, understanding of the regulation of the secretion and catabolism of apoB-containing lipoproteins by the liver is of major importance to the development of new therapies targeted toward these pathways. Liver-directed somatic gene transfer is a useful biological tool that could be used as a strategy for treating severe dyslipidemia. In this project, we will utilize liver-directed gene transfer using vectors based on novel adeno-associated virus (AAV) pseudotypes to address questions related to the impact of specific gene products on the regulation of hepatic secretion of apoB- containing lipoproteins. Project I will identify the best AAV for liver-directed gene transfer (called AAVcc) which will be further evaluated in this project.
Specific Aim 1 will use mouse models of FH to test the hypothesis that AAVcc-mediated expression of the murine LDL receptor (LDLR) will stably normalize cholesterol levels and prevent, and regress, atherosclerosis.
Specific Aim 2 will test the hypothesis that AAV8-mediated expression of the rabbit LDL receptor (LDLR) will stably normalize cholesterol levels and prevent, and regress, atherosclerosis in LDLR-deficient WHHL rabbits.
Specific Aim 3 will test the hypothesis that AAVcc-mediated expression of the rhesus LDL receptor (LDLR) wilj stably normalize cholesterol levels in the heterozygous LDLR-deficient rhesus fed a high-fat high-cholesterol diet designed to downregulate the expression of the LDLR from the normal allele.
Specific Aim 4 will test the hypothesis that AAVcc-mediated expression of the murine MTP will stably permit secretion of apoB-containing lipoproteins by the liver in the liver-deficient MTP mouse. Effects on vitamin E metabolism and end-organ effects will also be determined.

Public Health Relevance

(Seeinstructions):

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
2P01HL059407-11
Application #
7595329
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
2009-07-01
Project End
2014-06-30
Budget Start
2009-07-01
Budget End
2010-06-30
Support Year
11
Fiscal Year
2009
Total Cost
$425,007
Indirect Cost
Name
University of Pennsylvania
Department
Type
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Giles, April R; Govindasamy, Lakshmanan; Somanathan, Suryanarayan et al. (2018) Mapping an Adeno-associated Virus 9-Specific Neutralizing Epitope To Develop Next-Generation Gene Delivery Vectors. J Virol 92:
Amengual, Jaume; Guo, Liang; Strong, Alanna et al. (2018) Autophagy Is Required for Sortilin-Mediated Degradation of Apolipoprotein B100. Circ Res 122:568-582
Giles, April R; Sims, Joshua J; Turner, Kevin B et al. (2018) Deamidation of Amino Acids on the Surface of Adeno-Associated Virus Capsids Leads to Charge Heterogeneity and Altered Vector Function. Mol Ther 26:2848-2862
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
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
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
Greig, Jenny A; Limberis, Maria P; Bell, Peter et al. (2017) Non-Clinical Study Examining AAV8.TBG.hLDLR Vector-Associated Toxicity in Chow-Fed Wild-Type and LDLR+/- Rhesus Macaques. Hum Gene Ther Clin Dev 28:39-50
Greig, Jenny A; Limberis, Maria P; Bell, Peter et al. (2017) Nonclinical Pharmacology/Toxicology Study of AAV8.TBG.mLDLR and AAV8.TBG.hLDLR in a Mouse Model of Homozygous Familial Hypercholesterolemia. Hum Gene Ther Clin Dev 28:28-38
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

Showing the most recent 10 out of 149 publications