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（舒张期HF，DHF）的情况下。登革出血热的发病率正在迅速上升。到目前为止，没有治疗被证明可以改善DHF的症状或生存，因此DHF患者的生存率并没有随着时间的推移而改善。基于我们以前的研究和对DHF有效治疗的巨大未满足的临床需求，本提案的广泛目标是基于心脏中过表达的利钠肽受体（鸟苷酸环化酶A（GCA））开发一种高度新颖的、心脏特异性的和最终可翻译的DHF治疗方法。我们广泛的假设是，增加心脏GCA将改善DHF的不良重塑和舒张功能障碍。我们的高度新颖的方法将利用显着的亲心重组腺相关病毒血清型9（AAV-9）载体在我们建立良好的DHF犬模型的心脏中过表达GCA。我们的初步研究已经建立了过表达GCA作为DHF治疗的基本原理，建立了在啮齿动物中通过AAV-9-GCA基因递送增强心脏中GCA活性的能力，并建立了在犬中基因递送的可行性。我们提出的特定目的概述了通过AAV-9基因递送优化犬心脏中GCA过表达的策略，证明犬DHF中心脏GCA的恢复消除了不良重塑和舒张功能障碍，并确定了AAV-9-GCA对磷酸二酯酶5型抑制的相对和增量效应。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。具体目的1：优化AAV-9-cGCA基因在正常犬中的递送。假设：优化的AAV-9-cGCA基因递送导致心脏GCA蛋白和活性增加。具体目标2：确定AAV-9-cGCA是否增加GCA蛋白表达和活性，并改善犬DHF中的不良LV重塑和舒张功能障碍。假设：AAV-9-cGCA基因递送导致犬DHF中GCA蛋白和活性增加、肥大和纤维化减少以及舒张功能改善。具体目的3：确定犬DHF中AAV-9-cGCA和PDE-5抑制的相对和增量效应。假设：在犬DHF中，与单独的AAV-9-cGCA或单独的PDE-5抑制相比，伴随的PDE-5抑制和AAV-9-cGCA提供了肥大、纤维化和舒张功能的增量改善。

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.