Treatment of Diastolic Heart Failure via AAV-9 Mediated Gene Transfer

描述(由申请人提供)：心力衰竭(HF)是老年人住院的主要原因，超过50%的病例发生在射血分数(EF)保留的情况下(舒张性HF，DHF)。DHF的患病率正在迅速增加。到目前为止，没有任何治疗方法被证明可以改善DHF的症状或存活率，因此，DHF患者的存活率并没有随着时间的推移而提高。基于我们以前的研究和对DHF有效治疗的巨大临床需求，本方案的总体目标是开发一种高度新颖的、心脏特异的、最终可翻译的基于心脏过度表达的钠尿肽受体(鸟苷环化酶A)的DHF治疗方法。我们的广泛假设是，增加心脏GCA将改善DHF患者的不良重构和舒张期功能障碍。我们的高度新颖的方法将利用明显嗜心的重组腺相关病毒血清9(AAV-9)载体在我们建立的DHF犬模型的心脏中过度表达GCA。我们的初步研究已经确立了GCA过度表达作为治疗DHF的理论基础，建立了通过AAV-9-GCA基因在啮齿动物体内增强心脏GCA活性的能力，并建立了在犬体内进行基因转移的可行性。我们提出的特定目标概述了通过AAV-9基因转移优化GCA在犬心脏中过表达的策略，证明了犬DHF心脏GCA的恢复可以消除不利的重构和舒张期功能障碍，并确定AAV-9-GCA对磷酸二酯酶5抑制的相对和递增作用。如果我们的假设被证明是正确的，这些研究为在未来的研究中翻译成人类DHF奠定了基础。特异性目的1：优化AAV-9-CGCA基因在正常犬体内的传递。假设：优化的AAV-9-cGCA基因传递导致心脏GCA蛋白和活性增加。特异性目的2：确定AAV-9-CGCA是否能增加DHF犬GCA蛋白的表达和活性，并改善DHF的不良左室重构和舒张期功能障碍。假说：携带AAV-9-CGCA基因的DHF犬GCA蛋白和活性增加，肥大和纤维化减轻，舒张期功能改善。特异性目的3：确定AAV-9-CGCA和PDE-5抑制犬DHF的相对和递增效应。假设：与AAV-9-CGCA单独或单独抑制PDE-5相比，联合应用PDE-5抑制和AAV-9-CGCA在犬DHF中可逐渐改善肥大、纤维化和舒缩功能。

DESCRIPTION (provided by applicant): Heart failure (HF) is the leading cause of hospitalization in the elderly and occurs in the presence of preserved ejection fraction (EF) (diastolic HF, DHF) in over 50% of cases. DHF is rapidly increasing in prevalence. To date, no therapy is proven to improve symptoms or survival in DHF and thus, survival of patients with DHF has not improved over time. Based on our previous studies and on the tremendous unmet clinical need for an effective therapy for DHF, the broad objective this proposal is to develop a highly novel, cardiac specific and ultimately translatable therapy for DHF based on over-expressing natriuretic peptide receptors (guanylyl cyclase A (GCA)) in the heart. Our broad hypothesis is that augmenting cardiac GCA will ameliorate adverse remodeling and diastolic dysfunction in DHF. Our highly novel approach will utilize the markedly cardiotropic recombinant adeno-associated virus serotype 9 (AAV-9) vector to over-express GCA in the heart in our well established canine model of DHF. Our preliminary studies have established the rationale for over-expression of GCA as a therapy for DHF, established the ability to enhance GCA activity in the heart via AAV-9-GCA gene delivery in the rodent and established the feasibility of gene delivery in the canine. Our proposed Specific Aims outline the strategy to optimize overexpression of GCA in the canine heart via AAV-9 gene delivery, demonstrate that restoration of cardiac GCA in canine DHF abrogates adverse remodeling and diastolic dysfunction and determine the relative and incremental effect of AAV-9-GCA to phosphodiesterase type 5 inhibition. These studies lay the foundation for translation to human DHF in future studies if our hypothesis is proven correct. SPECIFIC AIM 1: Optimize AAV-9-cGCA gene delivery in the normal canine. Hypothesis: Optimized AAV-9- cGCAgene delivery results in increased cardiac GCA protein and activity. SPECIFIC AIM 2: Determine if AAV-9-cGCA increases GCA protein expression and activity and ameliorates adverse LV remodeling and diastolic dysfunction in canine DHF. Hypothesis: AAV-9-cGCA gene delivery results in increased GCA protein and activity, less hypertrophy and fibrosis and improved diastolic function in canine DHF. SPECIFIC AIM 3: Determine the relative and incremental effects of AAV-9-cGCA and PDE-5 inhibition in canine DHF. Hypothesis: Concomitant PDE-5 inhibition and AAV-9-cGCA provides incremental improvement in hypertrophy, fibrosis and diastolic function as compared to AAV-9-cGCA alone or PDE-5 inhibition alone in canine DHF.