Fifty percent of patients with severe congestive heart failure (CHF) die within four years of symptom onset despite optimal therapy. Heart transplantation has an 80% 5-year survival rate, but only 3000 are performed in the US each year, and 5 million patients have CHF. Because the prevalence of CHF is increasing, and the outlook remains dismal, we need new ways to treat CHF. Insulin-like growth factor-I (IGF-I) has pleiotropic effects that may benefit the failing heart. For example, IGF-I, which is activated by growth hormone (GH), is thought to increase cardiac myocyte number and size, stimulate angiogenesis, improve calcium handling and have positive inotropic effects. Despite these putative benefits, no controlled trial of IGF-I/GH protein treatment in clinical CHF has been successful, perhaps due to the relatively short biological half life of IGF-I/GH and insufficient levels in the heart. This limitation, we predict, will be overcome by cardiac gene transfer of IGF-I. Our laboratory has used a variety of cardiac gene transfer methods in preclinical and clinical studies since 1993. In the proposed studies we will: 1) Use a long-term expression vector suitable to treat chronic CHF, which can be easily and efficiently deployed;2) Obtain regulation of gene transcription enabling us to turn on and off transgene expression quickly;3) Activate IGF-I transgene expression in the presence of severe CHF to test efficacy in a stringent manner. The vector that will best fulfill these criteria is the adeno-associated virus (AAV), which provides long-term expression in the heart after intracoronary delivery. The tet-regulation system will provide a suitable means to control transgene expression. Hypothesis. Activation of IGF-I expression will increase function of the failing heart.
Aim 1. To evaluate cardiac gene transfer and activation of IGF-I expression in the failing rat heart Aim 1A. Determine efficacy and mechanisms for effects Aim 1B: Survival study Aim 2. To determine if activation of IGF-I expression increases endothelial precursor cell migration to the failing LV Aim 3. To evaluate cardiac gene transfer and activation of IGF-I expression in the failing pig heart Aim 3A. Identify optimal AAV vectors for intracoronary deliver in rats Aim 3B. Confirm optimal AAV vector for intracoronary delivery in pigs Aim 3C. Determine the efficacy and safety of intracoronary AAV.IGFI-tet in pigs with CHF The proposed research is designed to determine the mechanisms by which increased expression of IGF-I has beneficial effects on the failing heart. We also will determine the efficacy and safety of IGF-I gene transfer in rodent and pig models of CHF. Studies have been designed to enable filing an IND application with the FDA during the 5 year tenure of the award, so that clinical trials of IGF-I gene transfer in patients with CHF can be initiated.

Public Health Relevance

In the US, congestive heart failure (CHF) is the only cardiovascular disease that is increasing in prevalence, and is the most common cause of urgent admission to the hospital. The mortality from CHF, when optimally treated, is worse than for most cancers. We need new treatments for patients with CHF. Identifying and testing new potential treatments for CHF is relevant to the 5 million patients in the US who have CHF (and millions more world‐wide), and is the focus of our proposed research.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL088426-02
Application #
7617661
Study Section
Cardiac Contractility, Hypertrophy, and Failure Study Section (CCHF)
Program Officer
Wang, Lan-Hsiang
Project Start
2008-05-01
Project End
2012-04-30
Budget Start
2009-05-01
Budget End
2010-04-30
Support Year
2
Fiscal Year
2009
Total Cost
$346,250
Indirect Cost
Name
Veterans Medical Research Fdn/San Diego
Department
Type
DUNS #
933863508
City
San Diego
State
CA
Country
United States
Zip Code
92161
Gao, Mei Hua; Giamouridis, Dimosthenis; Lai, N Chin et al. (2016) One-time injection of AAV8 encoding urocortin 2 provides long-term resolution of insulin resistance. JCI Insight 1:e88322
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
Lai, N Chin; Gao, Mei Hua; Giamouridis, Dimosthenis et al. (2015) Intravenous AAV8 Encoding Urocortin-2 Increases Function of the Failing Heart in Mice. Hum Gene Ther 26:347-56
Lee, Kristen L; Hoey, David A; Spasic, Milos et al. (2014) Adenylyl cyclase 6 mediates loading-induced bone adaptation in vivo. FASEB J 28:1157-65
Fenton, Robert A; Murray, Fiona; Dominguez Rieg, Jessica A et al. (2014) Renal phosphate wasting in the absence of adenylyl cyclase 6. J Am Soc Nephrol 25:2822-34
Gao, Mei Hua; Lai, Ngai Chin; Tang, Tong et al. (2013) Preserved cardiac function despite marked impairment of cAMP generation. PLoS One 8:e72151
Gao, Mei Hua; Lai, N Chin; Miyanohara, Atsushi et al. (2013) Intravenous adeno-associated virus serotype 8 encoding urocortin-2 provides sustained augmentation of left ventricular function in mice. Hum Gene Ther 24:777-85
Tang, Tong; Lai, N Chin; Wright, Adam T et al. (2013) Adenylyl cyclase 6 deletion increases mortality during sustained ?-adrenergic receptor stimulation. J Mol Cell Cardiol 60:60-7
Tang, Tong; Hammond, H Kirk (2013) Gene transfer for congestive heart failure: update 2013. Transl Res 161:313-20
Timofeyev, Valeriy; Myers, Richard E; Kim, Hyo Jeong et al. (2013) Adenylyl cyclase subtype-specific compartmentalization: differential regulation of L-type Ca2+ current in ventricular myocytes. Circ Res 112:1567-76

Showing the most recent 10 out of 29 publications