Targeting HDAC6 to Modulate Titin Stiffness for Dilated Cardiomyopathy Therapy

靶向 HDAC6 调节肌联蛋白硬度以治疗扩张型心肌病

基本信息

批准号：
10080922
负责人：
Frederick Albert Schroeder
金额：
$ 30万
依托单位：
EIKONIZO THERAPEUTICS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-01 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10080922
关键词：
Accounting Adrenergic Agents Adult Adverse effects Affect American Angiotensin II Angiotensin Receptor Biopsy Biotechnology Brain Cardiac Myocytes Cardiomyopathies Cardiovascular Diseases Cause of Death Cell surface Cessation of life Characteristics Chemicals Chronic Collaborations Country Cytoplasmic Protein Data Deacetylase Development Dilated Cardiomyopathy Disease Dose Drug Targeting EFRAC Echocardiography Elements Enzymes Functional disorder Genes Genetic HDAC6 gene Health Health Expenditures Healthcare Systems Heart Heart Diseases Heart Transplantation Heart failure Hospitalization Human Impairment Individual Investments Knock-out Knowledge Lead Left Malignant Neoplasms Massachusetts Measurement Medical Research Messenger RNA Mission Modeling Molecular Morbidity - disease rate Mus Mutation Myocardial dysfunction Myofibrils National Heart, Lung, and Blood Institute Nerve Degeneration Neurodegenerative Disorders Oxygen Patients Peripheral Nervous System Diseases Pharmaceutical Chemistry Pharmaceutical Preparations Population Positron-Emission Tomography Prevalence Protein Binding Domain Proteins Public Health Pump RNA Binding RNA Splicing Rattus Research Series Signal Transduction Societies Syndrome Testing Therapeutic United States United States National Institutes of Health Vascular blood supply Ventricular Ventricular Dysfunction Work alpha Tubulin base clinical development connectin cost design disability drug candidate drug discovery early onset efficacy testing familial dilated cardiomyopathy genetic approach heart function hemodynamics imaging agent improved in vivo inhibitor/antagonist innovation lead optimization mortality mouse model novel postnatal development preservation programs research clinical testing small molecule inhibitor standard of care

项目摘要

PROJECT SUMMARY/ABSTRACT Dilated cardiomyopathy (DCM) is associated with impaired systolic/pump function of the heart, which can lead to heart failure and death. It is estimated that 1 in 250 adults in the U.S. have DCM, with ~40% of these cases being attributed to genetic causes. A common characteristic of DCM is reduced stiffness of titin. Titin is a molecular spring that provides passive tension to the heart by functioning within contractile units known as myofibrils. It is believed that re-establishing titin spring function (i.e. stiffening titin) in DCM patients could provide an innovative, disease-modifying approach to treat cardiomyopathy. Unpublished findings from our collaborator, Dr. McKinsey, reveal a remarkable ability of the cytoplasmic protein, histone deacetylase 6 (HDAC6), to control the stiffness of titin. The long-term objective of the proposed work is to develop an HDAC6-selective small molecule inhibitor as a ‘titin stiffener’ to improve systolic function and treat DCM in humans. This is in-line with the mission of the NHLBI, which includes treatment of heart disease to enhance the health of individuals so they can live longer and more fulfilling lives. One specific aim is to rank-order novel HDAC6 inhibitors (discovered by Eikonizo Therapeutics) for their ability to increase titin stiffness in cultured adult rat cardiomyocytes, and for their ability to improve systolic cardiac function in a short-term mouse model of heart failure. In a second specific aim, compounds that advance through these initial filters will be tested for efficacy in a rat model of DCM characterized by severe titin softening. This rat model recapitulates many elements of RBM20 (RNA-binding motif protein 20, a splicing factor that targets titin) cardiomyopathy, an aggressive and early onset genetic DCM in humans. This drug discovery proposal has the potential to facilitate the development of transformative therapies to treat DCM in humans.

项目摘要/摘要扩张的心肌病（DCM）与心脏的收缩/泵功能受损有关心力衰竭和死亡。据估计，美国有250名成年人中有1个患有DCM，其中约有40％归因于遗传原因。 DCM的共同特征是降低钛的刚度。 Titin是一个分子弹簧通过在收缩单元中发挥作用，从而为心脏提供被动张力肌原纤维。据认为，DCM患者的重建锡弹簧功能（即僵硬的锡）可以提供一种创新的，修改疾病的方法来治疗心肌病。我们合作者未发表的发现，麦肯锡博士揭示了细胞质蛋白质蛋白脱乙酰基酶6（HDAC6）的显着能力钛的刚度。拟议工作的长期目标是开发HDAC6选择性小分子抑制剂作为“滴定加强剂”，以改善人类的收缩功能并治疗DCM。这与 NHLBI的使命，其中包括对心脏病的治疗以增强个人的健康，因此可以生活更长，更充实的生活。一个具体的目的是排序新颖的HDAC6抑制剂（由 eikonizo Therapeutics）由于其在培养的成年大鼠心肌细胞中增加滴定刚度的能力及其在短期小鼠心力衰竭模型中改善收缩性心脏功能的能力。在第二个特定目标中，通过这些初始过滤器进行前进的化合物将在DCM的大鼠模型中测试效率通过严重的滴定软化。该大鼠模型概括了RBM20的许多元素（RNA结合基序蛋白20，一种靶向钛titin）心肌病的剪接因子，这是人类的侵略性和早期发作遗传DCM。这药物发现建议有可能支持开发变革性疗法以治疗DCM 在人类中。