Calcium Pump Activators for Heart Failure Therapy

用于心力衰竭治疗的钙泵激活剂

• 批准号: 9268662
• 负责人: Roger J. Hajjar
• 金额: $ 79.59万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9268662
• 关键词: ATP phosphohydrolase; Address; Affect; Affinity; Animal Model; Animal Testing; Back; Binding; Biological Assay; Biosensor; Ca(2+)-Transporting ATPase; Calcium; Cardiac; Cell Line; Cells; Clinical Trials; Collaborations; Color; Cytoplasm; Data; Defect; Detection; Development; Diastole; Engineering; Enzymes; Family suidae; Fluorescence; Fluorescence Resonance Energy Transfer; Gene Transfer; Genes; Goals; Grant; Heart; Heart failure; Human; Institution; Lead; Measures; Mediating; Membrane; Methods; Minnesota; Modeling; Mus; Muscle; Muscle Cells; Myocardium; Outcome; Phase; Phase I Clinical Trials; Play; Process; Protein Isoforms; Pump; Recombinant adeno-associated virus (rAAV); Research; Reticulum; Role; SERCA2a; Sarcoplasmic Reticulum; Somatic Gene Therapy; Structure; Syndrome; Testing; Therapeutic; Time; Treatment Failure; base; design; drug discovery; experience; feeding; gene therapy; high throughput screening; improved; in vivo; insight; instrumentation; loss of function; mouse model; mutant; novel; phospholamban; process optimization; public health relevance; reagent testing; research clinical testing; screening; small molecule; targeted treatment; therapeutic candidate; tool; trial design; uptake

 DESCRIPTION (provided by applicant): We aim to develop heart failure (HF) therapies that increase Ca uptake from the myocyte cytoplasm into the sarcoplasmic reticulum (SR). A key abnormality in both experimental and human HF is a defect in SR function, associated with decreased expression and/or specific activity of the SR Ca-ATPase (SERCA2a), the membrane enzyme that pumps Ca2+ into the SR lumen to relax muscle (diastole). Our hypothesis, validated by recent clinical trials, is that activation of SERCA is a powerful approach to treat HF We will increase SERCA activity by direct activation or by relieving inhibition of SERCA by phospholamban (PLB). Over the past decade, the group at Mount Sinai has systematically targeted Ca uptake for heart failure therapy by somatic gene transfer. In animal models of HF, they showed that increasing SERCA2a expression (using rAAV-based gene transfer) improves Ca cycling and contractility. They extended this approach to humans, now in Phase 2b/3 clinical trials, with very promising results for treatment of a wide range of HF syndromes. Thus SERCA activation has been clearly validated for treatment of HF in humans. In parallel, the group at Minnesota has played a leading role in the development of spectroscopic probes for structure- function analysis of SERCA and SERCA-PLB, leading to new mechanistic insights, and to the engineering of fluorescent biosensors that provide direct detection of functionally important SERCA structural changes and PLB interactions in living cells. In collaboration, the MN and MS groups have shown that these biosensors, used with novel fluorescence lifetime instrumentation, are powerful tools for designing small molecules or PLB mutants (PLBM) with potential for therapeutic activation of SERCA. In this project, the MN and MS groups will intensify their collaboration to activate SERCA for HF therapy. Two complementary approaches will be used. In Aim 1, we seek small molecules that activate SERCA directly (1a) or disrupt the inhibitory SERCA-PLB interaction (1b). In Aim 2, we pursue a gene therapy approach, using structure-based design to engineer PLB mutants that bind to SERCA with high affinity but do not inhibit the enzyme, thus displacing endogenous PLB and relieving SERCA inhibition. These projects take advantage of complementary world-class expertise in the two research teams - the Minnesota team will provide the structure-based insights and fluorescence-based screening methods to identify therapeutic candidates, and the Mount Sinai Group will test these reagents in animal models of HF. Based on excellent preliminary data and the unique capabilities of these two teams, expected outcomes are small molecules (lead compounds) and PLB mutants ready for Phase I clinical trials within 5 years.

 描述（由申请人提供）：我们的目标是开发心力衰竭（HF）疗法，增加从肌细胞胞质到肌浆网（SR）的Ca摄取。实验和人类HF中的关键异常是SR功能的缺陷，与SR Ca-ATP酶（SERCA 2a）的表达和/或比活性降低相关，所述SR Ca-ATP酶是将Ca 2+泵入SR腔以松弛肌肉的膜酶（肌松素）。我们的假设，通过最近的临床试验验证，是激活SERCA是治疗HF的有效方法。我们将通过直接激活或通过解除受磷蛋白（PLB）对SERCA的抑制来增加SERCA活性。 在过去的十年中，西奈山的研究小组通过体细胞基因转移系统地靶向钙摄取用于心力衰竭治疗。在HF动物模型中，他们发现增加SERCA 2a表达（使用基于rAAV的基因转移）可改善Ca循环和收缩性。他们将这种方法扩展到人类，目前处于2b/3期临床试验中，对于治疗各种HF综合征具有非常有希望的结果。因此，已明确验证了SERCA激活用于治疗人类HF。与此同时，明尼苏达州的小组在SERCA和SERCA-PLB的结构-功能分析的光谱探针的开发中发挥了主导作用，导致了新的机制见解，以及荧光生物传感器的工程设计，提供了直接检测功能重要的SERCA结构变化和活细胞中PLB相互作用。在合作中，MN和MS小组已经表明，这些生物传感器与新型荧光寿命仪器一起使用，是设计具有治疗激活SERCA潜力的小分子或PLB突变体（PLBM）的强大工具。 在这个项目中，MN和MS小组将加强合作，激活SERCA用于HF治疗。将采用两种相辅相成的办法。在目标1中，我们寻求直接激活SERCA（1a）或破坏抑制性SERCA-PLB相互作用（1b）的小分子。在目标2中，我们追求一种基因治疗方法，使用基于结构的设计来工程化PLB突变体，其以高亲和力结合SERCA但不抑制酶，从而取代内源性PLB并缓解SERCA抑制。这些项目利用了两个研究团队互补的世界级专业知识-明尼苏达团队将提供基于结构的见解和基于荧光的筛选方法来识别治疗候选人，而西奈山集团将在HF动物模型中测试这些试剂。基于出色的初步数据和这两个团队的独特能力，预期结果是小分子（先导化合物）和PLB突变体在5年内准备进行I期临床试验。