Calcium Pump Activators for Heart Failure Therapy

用于心力衰竭治疗的钙泵激活剂

• 批准号: 9096874
• 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/9096874
• 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; Health; Heart; Heart failure; Human; Institution; Lead; Life; 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; 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; reagent testing; research clinical testing; screening; small molecule; targeted treatment; 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（由适用提供）：我们旨在开发心力衰竭（HF）疗法，从而增加从心肌细胞质中的CA摄取到肌浆网（SR）。实验性和人HF中的关键绝对是SR功能的缺陷，与SR CA-ATPase（SERCA2A）的表达降低和/或特定活性有关，SR CA-ATPase（SERCA2A）是将Ca2+泵入SR腔内的膜酶，以放松肌肉（舒张）。通过最近的临床试验验证的我们的假设是，SERCA的激活是治疗HF的强大方法，我们将通过直接激活或缓解磷团（PLB）来增加SERCA活性。在过去的十年中，西奈山的小组通过体细胞基因转移有系统地针对心力衰竭治疗的CA摄取。在HF的动物模型中，他们表明，增加SERCA2A表达（使用基于RAAV的基因转移）可以提高CA循环和收缩力。他们将这种方法扩展到了现在在2B/3期临床试验中的人类，并有希望治疗广泛的HF综合征的结果。同时，明尼苏达州的小组在SERCA和SERCA-PLB的结构函数分析的发展中发挥了领先作用，从而导致了新的机械见解，以及荧光生物传感器的工程，这些生物传感器可以直接检测到功能上重要的SERCA结构变化和PLB相互作用。在合作中，MN和MS组表明，这些生物传感器与新型荧光寿命仪器一起使用，是设计小分子或PLB突变体（PLBM）的强大工具，具有SERCA治疗激活的潜力。该项目，MN和MS组将加强其协作，以激活SERCA进行HF治疗。将使用两种完整的方法。在AIM 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AIM 2中，我们采用一种基因治疗方法，使用基于结构的设计来工程师PLB突变体，这些突变体与具有高亲和力但不抑制酶的SERCA结合，从而置换了内源性PLB并缓解SERCA抑制。这些项目利用了两个研究团队中互补的世界一流的专业知识 - 明尼苏达州团队将提供基于结构的见解和基于荧光的筛查方法来识别治疗候选者，而西奈山组将在HF动物模型中测试这些试剂。基于这两个团队的出色初步数据和独特的功能，预期的结果是小分子（铅化合物）和PLB突变体，可在5年内准备进行I期临床试验。