Safe, Rapid Telomere Extension to Prevent and Treat Hypertension

描述(申请人提供)：我们最近展示了一种新的、独特的端粒延伸药物：编码端粒酶的核苷修饰的mRNA。我们的信使核糖核酸药物将端粒延长6天，大约相当于人类正常衰老15年后端粒平均缩短的量，而且我们的药物是暂时的，在几天内就会被翻转。独一无二的是，这种方法有可能实现安全的端粒延长疗法，因为它延长端粒的速度如此之快，以至于治疗可能非常短暂(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不变。我们的药物不与基因组整合，是非免疫原性的，因为它含有最近发现包含成熟哺乳动物mRNA的相同修饰的核苷，并且可以编码各种形式的端粒酶，这种端粒酶可以避免翻译后调节，使端粒即使在慢周期的细胞群体中也能延长，例如一些祖细胞。我们和我们的合作者正在将我们的药物应用于几种由短端粒介导的与年龄相关的疾病：高血压和心力衰竭(库克和BLAU实验室)、免疫衰老(Weyand实验室)和血管性痴呆(Yesavage实验室)(见支持信)。这些应用中的每一个都将得到这个项目的促进：在这里，我们建议通过优化静脉给药并展示其安全性和有效性来启动我们的药物向人体研究的转化。优化静脉滴注。在我们的药物交付方面，我们将比较目前最好的RNA载体和尖端的RNA载体。2007年，人们发现在人体内，外切体通过包括血液在内的体液在细胞间转运mRNA，2011年，自体外切体被用来通过静脉注射运送核酸。注射。我们将测试自体外切体作为静脉注射载体的作用。把我们的药送到。我们会用最好的静脉注射。在短端粒mTERC缺失的高血压小鼠模型中延长血管内皮细胞端粒以预防或治疗高血压的递送方法。高血压是心力衰竭的主要风险因素，端粒较短的小鼠同时表现出高血压和心力衰竭，而端粒较短的小鼠在人类中可以预测这两种情况。在端粒较短的小鼠和人类中，导致高血压的一个关键机制是衰老的内皮细胞过度产生内皮素-1，我们(库克实验室)已经证明端粒延伸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，即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、肿瘤形成和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的快速、安全的端粒延长疗法，由我们和我们的合作者将其转化为预防和治疗高血压和其他与年龄相关的疾病的诊所(请参阅支持信)。

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).