This proposal focuses on development of new potential treatments for patients with heart failure and preserved ejection fraction (HFpEF). Among symptomatic patients with HF, approximately half have preserved ejection fraction, and their mortality is similar to those with HF with reduced EF (HFrEF). However, unlike the case with HFrEF, there is currently no treatment for HFpEF that prolongs life, and few that reduce hospitalization rates for heart failure. We need new therapies to address this unmet medical need. Discovering and developing such an approach is the purpose of this proposal. Cardiovascular gene transfer is conceptually an attractive method for treating heart failure, but difficulty in obtaining high yield transgene expression in the heart in a manner that can be easily and safely applied has been challenging. However, we recently have demonstrated the effectiveness of intravenous (IV) delivery of a long-term expression vector encoding a peptide, urocortin-2 (UCn2), with favorable cardiovascular effects through its paracrine action. A single intravenous injection in normal mice of an adeno-associated virus vector (AAV8) encoding murine UCn2 (AAV8.UCn2) has favorable effects on Tau and LV peak -dP/dt, two measures of left ventricular (LV) diastolic function. This approach solves the problem of attaining high yield cardiac gene transfer and ultimately would enable patients to be treated by intravenous injection during an office visit, and provides a novel means to increase diastolic function. The goal of this proposal is to test the safety and efficacy of this method of therapy in animal models of HFpEF. In the 4-year tenure of our present VA Merit, we have published three papers on the effectiveness of gene transfer of UCn2: one in normal mice, a second in mice with HFrEF, and a third that focuses on the safety and metabolic effects of UCn2 gene transfer. Gene transfer of AAV8 encoding UCn2 yielded persistent increases in plasma UCn2 (18 months following a single IV injection) and improved LV function in severe HF induced by myocardial infarction. In these studies, we noted that UCn2 gene transfer increased LV peak -dP/dt (p<0.0001) and reduced Tau (p=0.05). We now propose to test the safety and efficacy of IV delivery of AAV8.UCn2 in two models of HFpEF: 1) trans-aortic constriction (TAC), which imposes a LV pressure stress and HFpEF in the early phase; and 2) aged mice (18-months-old) many of which have diastolic dysfunction and meet criteria for HFpEF. Although our primary goal is to improve LV diastolic function and to test this in physiological studies after gene transfer, we also will determine mechanisms for the anticipated increase in diastolic function. In the final year, we will initiate testing in rabbits as a segue to an eventual Investigational New Drug (IND) application to initiate a clinical trial using AAV8.UCn2 to treat patients with HFpEF, a transition we have made in our laboratory twice previously (ClinicalTrials.gov: NCT00787059 and NCT00346437).

Public Health Relevance

Six million people have heart failure in the US, and 550,000 new cases are diagnosed annually. Despite current optimal therapy, there are 300,000 deaths every year in the US due to heart failure. Among these 6 million patients, 3 million have heart failure with normal ejection fraction, a measure of the heart?s ability to pump blood. However, conventional therapies, which have been shown to prolong life in patients with heart failure with low ejection fraction, fail to prolong life in patients with normal ejection fraction heart failure. Because the prevalence of heart failure with normal ejection fraction is increasing, and outlook is dismal, we need new treatments. We propose, based on studies performed in the previous tenure of our VA Merit award, that intravenous delivery of a virus vector encoding urocortin-2 is a promising approach for these patients. The proposed work will test this in animal models of heart failure with normal ejection fraction.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Non-HHS Research Projects (I01)
Project #
1I01BX003774-01A1
Application #
9351275
Study Section
Cardiovascular Studies A (CARA)
Project Start
2017-04-01
Project End
2021-03-31
Budget Start
2017-04-01
Budget End
2018-03-31
Support Year
1
Fiscal Year
2017
Total Cost
Indirect Cost
Name
VA San Diego Healthcare System
Department
Type
Independent Hospitals
DUNS #
073358855
City
San Diego
State
CA
Country
United States
Zip Code
92161
Giamouridis, Dimosthenis; Gao, Mei Hua; Lai, N Chin et al. (2018) Effects of Urocortin 2 Versus Urocortin 3 Gene Transfer on Left Ventricular Function and Glucose Disposal. JACC Basic Transl Sci 3:249-264
Ichikawa, Yasuhiro; Zemljic-Harpf, Alice E; Zhang, Zheng et al. (2017) Modulation of caveolins, integrins and plasma membrane repair proteins in anthracycline-induced heart failure in rabbits. PLoS One 12:e0177660
Gao, Mei Hua; Lai, N Chin; Giamouridis, Dimosthenis et al. (2017) Cardiac-directed expression of a catalytically inactive adenylyl cyclase 6 protects the heart from sustained ?-adrenergic stimulation. PLoS One 12:e0181282
Penny, William F; Hammond, H Kirk (2017) Randomized Clinical Trials of Gene Transfer for Heart Failure with Reduced Ejection Fraction. Hum Gene Ther 28:378-384
Gao, Mei Hua; Lai, N Chin; Giamouridis, Dimosthenis et al. (2016) Cardiac-Directed Expression of Adenylyl Cyclase Catalytic Domain Reverses Cardiac Dysfunction Caused by Sustained Beta-Adrenergic Receptor Stimulation. JACC Basic Transl Sci 1:617-629