Safe, Rapid Telomere Extension to Prevent and Treat Hypertension

安全、快速的端粒延长可预防和治疗高血压

基本信息

批准号：
8665856
负责人：
Helen M Blau
金额：
$ 19.71万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-06-01 至 2015-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8665856
关键词：
Affect Age Age-Months Aging Alzheimer&apos s Disease Autologous Biodistribution Biological Assay Blood Blood Vessels Body Fluids Cause of Death Cell Aging Cell Cycle Cell Cycle Regulation Cells Chromosomes Clinic Conscious Control Animal DNA Sequence Dendritic Cells Disease Dose Electroporation Endothelial Cells Endothelin-1 Enzyme-Linked Immunosorbent Assay Exhibits Functional disorder Generations Genome Genomics Goals Half-Life Heart Heart failure High Density Lipoprotein Cholesterol Histology Hour Human Human body Hypertension Image Immune response Injection of therapeutic agent Insertional Mutagenesis Interferon-alpha Interphase Cell Intravenous Knockout Mice Left Length Letters Libraries Longevity Luciferases Malignant Neoplasms Maps Measurement Measures Mediating Messenger RNA Methods Mus Nucleic Acids Nucleosides Nucleotides Organ Harvestings Partner in relationship Pharmaceutical Preparations Phenotype Population Post-Translational Regulation Prevention Production RNA Reactive Oxygen Species Resolution Risk Risk Factors Safety Signal Pathway Sphygmomanometers Tail Telomerase Telomere Shortening Testing Therapeutic Time Tissues Translations Vascular Dementia Vascular Endothelial Cell Vasoconstrictor Agents Veins Vesicle Work age related base bioluminescence imaging brief intervention cytokine hypertension treatment hypertensive heart disease immunogenicity immunosenescence mast cell mouse model novel pressure prevent progenitor public health relevance response safety testing senescence telomere tumor two-photon

项目摘要

DESCRIPTION (provided by applicant): We recently demonstrated a novel, uniquely-enabling drug for telomere extension: nucleoside-modified mRNA encoding telomerase. Our mRNA drug extends telomeres in six days by approximately the amount by which telomeres shorten over 15 years of normal human aging on average, and our drug is transient, being turned over within a few days. Uniquely, this approach has the potential to enable safe telomere extension therapy, because it extends telomeres so rapidly that the treatment can be very brief (a few days), leaving the normal anti-cancer telomere-shortening mechanism intact immediately after the brief treatment ends. Our drug does not integrate with the genome, is non-immunogenic as it comprises the same modified nucleosides recently discovered to comprise mature mammalian mRNA, and can encode forms of telomerase which avoid post- translational regulation enabling telomere extension even in slowly-cycling cell populations such as some progenitors. We and our collaborators are applying our drug to several age-related conditions mediated by short telomeres: hypertension and heart failure (Cooke and Blau labs), immunosenescence (Weyand lab), and vascular dementia (Yesavage lab) (see supporting letters). Each of these applications will be facilitated by this project: here we propose to initiate translation of our drug toward human studies by optimizing its intravenous delivery and demonstrating its safety and efficacy. To optimize i.v. delivery of our drug we will compare the best current and cutting-edge RNA vehicles. In 2007 it was discovered that in the human body, exosomes transport mRNA between cells via body fluids including blood, and in 2011 autologous exosomes were used to deliver nucleic acid via i.v. injection. We will test autologous exosomes as vehicles for i.v. delivery of our drug. We will use our best i.v. delivery method to extend telomeres of vascular endothelial cells to prevent or treat hypertension in the short-telomere mTERC-null mouse model of hypertension. Hypertension is the major risk factor in heart failure, and mice with short telomeres exhibit both hypertension and heart failure, and short telomeres predict both conditions in humans. In both mice with short telomeres and in humans, a key causative mechanism of hypertension is excess endothelin-1 production by senescent endothelial cells, and we (the Cooke lab) have shown that telomere extension prevents endothelial cell senescence. Thus there is strong evidence supporting the hypothesis that extension of endothelial cell telomeres by our drug will help prevent or treat hypertension. We will also test the safety of our drug by quantifying immune response, tumor formation, and effect on lifespan in the short-telomere hypertensive mice. If successful, this work will initiate translation of our rapid, safe telomere extension therapy toward the clinic for prevention and treatment of hypertension and other age-related conditions by us and our collaborators (see supporting letters).

描述（由申请人提供）：我们最近展示了一种新颖、独特的端粒延伸药物：编码端粒酶的核苷修饰 mRNA。我们的 mRNA 药物可在六天内延长端粒，其延长量大约相当于人类正常衰老 15 年期间端粒平均缩短的量，而且我们的药物是短暂的，在几天内就可以恢复。独特的是，这种方法有可能实现安全的端粒延长治疗，因为它延长端粒的速度如此之快，以至于治疗可以非常短暂（几天），在短暂的治疗结束后立即保持正常的抗癌端粒缩短机制完好无损。我们的药物不与基因组整合，不具有免疫原性，因为它包含最近发现的包含成熟哺乳动物mRNA的相同修饰核苷，并且可以编码端粒酶形式，避免翻译后调节，即使在缓慢循环的细胞群中也能实现端粒延伸比如一些祖辈。我们和我们的合作者正在将我们的药物应用于由短端粒介导的几种与年龄相关的疾病：高血压和心力衰竭（Cooke 和 Blau 实验室）、免疫衰老（Weyand 实验室）和血管性痴呆（Yesavage 实验室）（参见支持信）。该项目将促进这些应用中的每一个：在这里，我们建议通过优化其静脉注射并证明其安全性和有效性，开始将我们的药物转化为人体研究。优化静脉注射在我们的药物输送过程中，我们将比较当前最好的和最先进的 RNA 载体。 2007年，人们发现人体内外泌体通过血液等体液在细胞之间运输mRNA，2011年，自体外泌体被用于通过静脉注射输送核酸。注射。我们将测试自体外泌体作为静脉注射的载体。交付我们的药物。我们将使用最好的静脉注射。延长血管内皮细胞端粒的递送方法，以预防或治疗短端粒 mTERC 缺失小鼠高血压模型中的高血压。高血压是心力衰竭的主要危险因素，端粒短的小鼠同时表现出高血压和心力衰竭，而短端粒可以预测人类的这两种情况。在端粒较短的小鼠和人类中，高血压的一个关键致病机制是衰老内皮细胞产生过量的内皮素-1，我们（库克实验室）已经证明端粒延长可以防止内皮细胞衰老。因此，有强有力的证据支持这样的假设：我们的药物延长内皮细胞端粒将有助于预防或治疗高血压。我们还将通过量化短端粒高血压小鼠的免疫反应、肿瘤形成以及对寿命的影响来测试我们药物的安全性。如果成功，这项工作将启动我们和我们的合作者将我们的快速、安全的端粒延长疗法转化为临床，用于预防和治疗高血压和其他与年龄相关的疾病（参见支持信）。