Urocortin 2 Gene Transfer for Heart Failure with Preserved Ejection Fraction

尿皮质素 2 基因转移治疗射血分数保留的心力衰竭

• 批准号: 10620117
• 负责人: H. Kirk Hammond
• 金额: --
• 依托单位: VA SAN DIEGO HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10620117
• 关键词: Address; Aging; Award; Ca(2+)-Transporting ATPase; Cardiac; Cardiac Myocytes; Cardiovascular system; Cessation of life; Clinical; Clinical Trials; Corticotropin-Releasing Hormone Receptors; Dahl Hypertensive Rats; Development; Diagnosis; Disease; EFRAC; Effectiveness; Endocrine; Endoplasmic Reticulum; Exclusion; Funding; Gene Transfer; Grant; Heart; Heart failure; Hypertension; Intravenous; Laboratories; Left; Left Ventricular Function; Life; Link; Maps; Measures; Medical; Membrane; Methods; Modeling; Mus; Pathway interactions; Patients; Peptides; Persons; Prevalence; Proteins; Rattus; Risk Factors; Safety; Sarcomeres; Sarcoplasm; Series; Smooth Muscle; Testing; Time; Treatment Effectiveness; Vascular Smooth Muscle; Vasodilation; Vasodilator Agents; Ventricular; Veterans; Virus; Work; aged; blood pump; cardiovascular effects; clinical translation; conventional therapy; design; effectiveness evaluation; expression vector; heart function; heart preservation; hospitalization rates; hypertensive; improved; in vivo; mortality; mouse model; novel therapeutics; optimal treatments; paracrine; preclinical study; preservation; pressure; transgene expression; urocortin; vector

This proposal focuses on development of a new treatment for patients with heart failure and preserved ejection fraction (HFpEF). Among symptomatic patients with HF, half have HFpEF, and their mortality is similar to those with HFrEF. However, there are currently no treatments for HFpEF that prolong life, and few (if any) that reliably reduce HF hospitalization rates. We need new therapies to address this unmet medical need. Cardiovascular gene transfer is conceptually an attractive method for treating HF, but difficulty in obtaining high yield transgene expression in the heart in a manner that can be easily and safely applied has been challenging. However, we recently have demonstrated the effectiveness of intravenous (i.v.) delivery of a long-term expression vector (AAV8) encoding a peptide, urocortin 2 (Ucn2), which possesses favorable cardiovascular effects through its paracrine/endocrine actions. In our current VA Merit grant we have established the safety and efficacy of a 1-time i.v. administration of AAV8.Ucn2 in two murine models of HFpEF—aging and pressure overload, two risk factors for clinical HFpEF. However, there are several important issues that must be resolved prior to clinical translation of this much-needed therapy. Hypothesis: Ucn2/Ucn3 gene transfer, through paracrine/endocrine effects, will improve cardiac function and survival in two models of HFpEF (in different species) via corticotropin releasing hormone receptor 2 (CRHR2)-dependent enhancement of Ca2+ handling in cardiac myocytes Aim 1: To determine the effectiveness and survival advantage of Ucn2 vs Ucn3 gene transfer in a model of HFpEF due to hypertension (Dahl Salt-Sensitive Rat) Aim 2a: To determine if the beneficial effects of Ucn2 gene transfer on LV function in aged mice are abrogated by cardiac-targeted deletion of CRHR2 Aim 2b: To determine whether the beneficial effects of Ucn2 gene transfer on the aged LV result from enhanced Ca2+ handling and increased rates of sarcomere shortening and lengthening Aim 3: To determine the intracellular mechanisms linking Ucn2 and Ucn3 peptide activation of CRHR2 with enhanced Ca2+ handling in cultured cardiac myocytes These Aims are designed to answer key questions: 1) Will the benefits of Ucn2 gene transfer be seen in a second species in a second model of HFpEF (hypertensive Dahl Salt-Sensitive rats), will it confer a survival advantage, and will Ucn3 gene transfer have similar beneficial effects? These questions will be addressed in Aim 1; 2) To what degree are the beneficial effects of Ucn2 gene transfer due to cardiac CRHR2 activation vs systemic vasodilation due to activation of CRHR2 in smooth muscle and attendant systemic vasodilation? We will address this question by using cardiac-targeted deletion of CRHR2 (Aim 2); 3) Finally, we propose to map the intracellular pathways (mechanisms) from CM CRHR2 stimulation by Ucn2/Ucn3 to the predicted increase in Ca2+ handling in a series of studies conducted in isolated CMs (Aim 3). These preclinical studies, which are focused on mechanism of action and effectiveness of treatment in vivo will serve as a segue for an additional study in a large mammalian model of HFpEF under separate funding, and subsequently to the filing of an IND application for the initiation of a clinical trial, a transition we have made in our laboratory twice previously (ClinicalTrials.gov: NCT00787059 and NCT00346437).

本提案的重点是开发一种新的治疗心力衰竭和心力衰竭的方法

项目成果

Modulation of caveolins, integrins and plasma membrane repair proteins in anthracycline-induced heart failure in rabbits.

• DOI: 10.1371/journal.pone.0177660
• 发表时间: 2017
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Ichikawa Y;Zemljic-Harpf AE;Zhang Z;McKirnan MD;Manso AM;Ross RS;Hammond HK;Patel HH;Roth DM
• 通讯作者: Roth DM

Impact of blood factors on endothelial cell metabolism and function in two diverse heart failure models.

• DOI: 10.1371/journal.pone.0281550
• 发表时间: 2023
• 期刊: PloS one
• 影响因子: 3.7

Urocortin 2 Gene Transfer Reduces the Adverse Effects of a Western Diet on Cardiac Function in Mice.

尿皮质素 2 基因转移可减少西方饮食对小鼠心脏功能的不利影响。

• DOI: 10.1089/hum.2018.150
• 发表时间: 2019
• 期刊: Human gene therapy
• 影响因子: 4.2
• 作者: Kim,YoungChul;Giamouridis,Dimosthenis;Lai,NChin;Guo,Tracy;Xia,Bing;Fu,Zhenxing;Gao,MeiHua;Hammond,HKirk
• 通讯作者: Hammond,HKirk

Cardiac-Directed Expression of Adenylyl Cyclase Catalytic Domain Reverses Cardiac Dysfunction Caused by Sustained Beta-Adrenergic Receptor Stimulation.

• DOI: 10.1016/j.jacbts.2016.08.004
• 发表时间: 2016-12
• 期刊: JACC. Basic to translational science
• 作者: Gao MH;Lai NC;Giamouridis D;Kim YC;Tan Z;Guo T;Dillmann WH;Suarez J;Hammond HK
• 通讯作者: Hammond HK

Cardiac-Directed Expression of Adenylyl Cyclase Catalytic Domain (C1C2) Attenuates Deleterious Effects of Pressure Overload.

腺苷酸环化酶催化结构域 (C1C2) 的心脏定向表达可减轻压力过载的有害影响。

• DOI: 10.1089/hum.2018.176
• 发表时间: 2019
• 期刊: Human gene therapy
• 影响因子: 4.2
• 作者: Tan,Zhen;Giamouridis,Dimosthenis;Lai,NChin;Kim,YoungChul;Guo,Tracy;Xia,Bing;Gao,MeiHua;Hammond,HKirk
• 通讯作者: Hammond,HKirk