Gene transfer for the treatment of cardiovascular diseases is conceptually attractive, but difficulty in obtaining high yield transgene expression in the heart in a manner that can be easily and safely applied has been a chief impediment to progress. Current methods of gene transfer for heart disease include intramuscularinjection into heart muscle or intracoronary delivery, approaches that typically provide limited expression or are cumbersome to apply. Consequently, we have considered the usefulness of a vector encoding a paracrine-type transgene. In this approach, the transgene acts as a hormone, having cardiac effects after being released to the circulation from a distant site. This approach would circumvent the problem of attaining high yield cardiac gene transfer and enable patients to be treated by a systemic injection during an office visit. Furthermore, the approach proposed would eliminate the need for intravenous delivery of therapeutic peptides and thereby circumvent repeated and prolonged hospital stays, high morbidity, and enormous economic costs. The most suited vector to achieve these goals is the adeno-associated virus (AAV), which provides long term and extensive expression after intravenous delivery in rodents, pigs, and primates. Finally, by using regulated expression of the transgene in the AAV vector, one can achieve control of the level of transgene expression. To develop and optimally refine this approach is the focus of this proposal. Insulin-like growth factor-I (IGFI) is a peptide with protean favorable cardiovascular effects (inotrope, angiogenic, anti-apoptotic). Proof-of-concept studies in our laboratory recently showed that skeletal muscle injection of an AAV5 vector encoding IGFI improved function of the failing rat heart. IGFI will be an ideal therapeutic transgene in the proposed studies. To develop and refine such an approach, we propose to determine: a) mechanisms by which IGFI gene transfer increases contractile function;b) the optimal AAV vector and promoter for intravenous delivery that will provide maximal transgene expression with minimal immune response and off-target effects in rats;c) the optimal regulated transgene expression system to enable fine-tuning of serum transgene levels, and turning expression off and on as needed;d) the safety, efficacy, and survival advantage of IGFI gene transfer, using this optimal, paracrine-based approach in a rat model of congestive heart failure;and e) e) the minimally effective doses of AAV and activators of transgene expression following intravenous delivery of this optimal vector in normal pigs, using serum IGFI and immune response as end-points. These mechanistic and proof-of-concept studies are designed to be sufficient in scope to launch, under separate funding, a study in pigs with CHF, and subsequently to file an IND application to the FDA for the penultimate study: a clinical trial in veterans with congestive heart failure.
Gene transfer for the treatment of cardiovascular diseases is conceptually attractive, but difficulty in obtaining high yield expression in the heart in a manner that can be easily and safely applied has been an impediment to progress. We propose to develop and test a long-term regulated expression virus vector encoding a paracrinetype transgene, Insulin-like Growth Factor-I (IGFI), which has pronounced beneficial effects on the failing heart. In this approach, the transgene acts as a hormone, having cardiac effects after being released to the circulation from a distant site. This approach would circumvent the problem of attaining high yield cardiac gene transfer and enable patients to be treated by a systemic injection during an office visit. To develop and optimally refine this approach is the focus of this proposal. In addition, we will determine the mechanisms by which IGFI increases function of the failing heart. Our goal is to develop a novel treatment for congestive heart failure, a common disease in our veteran population.
|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|
|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; 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|
|Pandey, Amit K; Penny, William F; Bhargava, Valmik et al. (2016) Clinical Evaluation of Heart Failure: Agreement among Tests. PLoS One 11:e0161536|
|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|
|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|
|Tang, Tong; Hammond, H Kirk (2013) Gene transfer for congestive heart failure: update 2013. Transl Res 161:313-20|