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

通过 AAV-9 介导的基因转移治疗舒张性心力衰竭

• 批准号: 8534243
• 负责人: Margaret M Redfield
• 金额: $ 37.53万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8534243
• 关键词: Acceleration; Antibodies; Blocking Antibodies; Canis familiaris; Cardiac; Catabolism; Chronic; Clinical; Cyclic GMP; Dependovirus; Diastolic heart failure; Disease Progression; Dose; EFRAC; Elderly; Fibrosis; Foundations; Functional disorder; Future; Gene Delivery; Gene Transfer; Heart; Heart failure; Hospitalization; Human; Hypertrophy; Image; Impairment; Injection of therapeutic agent; Left Ventricular Remodeling; Measures; Mediating; Modeling; Mus; Muscle Cells; Myocardial; Natriuretic Peptides; Particulate; Patients; Peptide Receptor; Peptides; Phenotype; Practice Guidelines; Prevalence; Production; Proteins; Radioisotopes; Recombinant adeno-associated virus (rAAV); Relative (related person); Reporter; Residual state; Rodent; SCID Mice; Serotyping; Serum; Signal Transduction; Stress; Symptoms; System; Technetium 99m; Testing; Therapeutic; Time; Translations; Viral; atrial natriuretic factor receptor A; base; clinically relevant; design; effective therapy; improved; in vitro activity; in vivo; in vivo Bioassay; inhibitor/antagonist; novel; novel strategies; overexpression; phosphoric diester hydrolase; pressure; protein expression; response; restoration; single photon emission computed tomography; sodium-iodide symporter; vector; viral gene delivery

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.

描述（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保留 (EF)（舒张期 HF、DHF）的情况下。 DHF 的患病率正在迅速增加。迄今为止，尚无任何治疗方法被证明可以改善 DHF 的症状或生存率，因此 DHF 患者的生存率并未随着时间的推移而改善。基于我们之前的研究以及对 DHF 有效治疗的巨大未满足的临床需求，该提案的总体目标是开发一种基于过表达利尿钠肽受体（鸟苷酸环化酶）的高度新颖、心脏特异性且最终可转化的 DHF 治疗方法。 A（GCA））在心里。我们的广泛假设是，增加心脏 GCA 将改善 DHF 中的不良重塑和舒张功能障碍。我们高度新颖的方法将利用显着强心性的重组腺相关病毒血清型 9 (AAV-9) 载体在我们完善的犬 DHF 模型中过表达心脏中的 GCA。我们的初步研究已经确立了 GCA 过度表达作为 DHF 治疗方法的基本原理，确立了通过 AAV-9-GCA 基因递送在啮齿动物中增强心脏中 GCA 活性的能力，并确立了在犬科动物中进行基因递送的可行性。我们提出的具体目标概述了通过 AAV-9 基因传递优化犬心脏中 GCA 过度表达的策略，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 的相对和增量效应GCA对5型磷酸二酯酶有抑制作用。如果我们的假设被证明是正确的，这些研究将为未来研究中转化为人类 DHF 奠定基础。具体目标 1：优化正常犬科动物中的 AAV-9-cGCA 基因传递。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 是否会增加犬 DHF 中 GCA 蛋白的表达和活性并改善不良的 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、肥大和纤维化减少并改善舒张功能。具体目标 3：确定 AAV-9-cGCA 和 PDE-5 抑制对犬 DHF 的相对和增量影响。假设：与单独使用 AAV-9-cGCA 或单独抑制 PDE-5 相比，同时使用 PDE-5 抑制和 AAV-9-cGCA 可逐渐改善犬 DHF 中的肥厚、纤维化和舒张功能。