Novel Adipose Targeted Gene Therapy for Lipodystrophy

项目总结 脂肪营养不良包括一组不同种类的疾病，其特征是异常或 脂肪组织的退化情况。这种罕见且经常被低估的情况可能是 局部/局部性的或全身性的，通常与胰岛素等代谢紊乱有关 抵抗力、糖尿病、高血糖、高脂血症等严重情况。脂肪营养不良可以是 先天的或后天的，通常会导致肝、肾和心脏的致命后果 并发症。所有形式的脂肪营养不良都有严重的胰岛素抵抗和非常低的瘦素水平。目前， 使用美托列汀替代瘦素是治疗脂肪营养不良的唯一方法。然而，美托列汀注射剂 每天服用一次或两次，平均每位患者/年的费用为565,000美元，并且可能有不良反应 效果。Zvelt Treateutics正在开发一种安全、有效和成本效益高的治疗方法 脂肪营养不良的症状。这种治疗是由重组腺相关病毒(RAAV)载体介导的，该载体提供 转基因表达时间长，免疫原性低。通常，当AAV疗法交付时 从系统上看，绝大多数AAVs滞留在肝脏中，在靶组织中几乎没有表达。 这种效应导致治疗窗口狭窄，因为全身性AAV必须接近中毒水平才能达到 治疗方面的好处。为了克服这些挑战，Zvelt将使用一种新的工程AAV血清型 优先针对脂肪的Rec2，结合最大限度减少转基因的双盒平台 在肝脏中的表达。Zvelt Treateutics已经证实了Rec2/Dual的疗效 含有瘦素基因(Rec2-Leptin)的盒式载体用于纠正瘦素缺乏、肥胖和 小鼠模型中的代谢综合征。Zvelt的平台已经展示了在有针对性的表达 在小鼠模型中，限制脂肪组织在肝脏中的非靶向表达。在本STTR第一阶段中 项目中，我们将在相关脂肪营养不良小鼠中进行Rec2-Leptin的剂量发现和安全性分析 模型，以验证这一创新，以有效治疗脂肪营养不良。 在第二阶段，我们将处理产品开发的关键技术方面，以及安全和功效研究 更大的动物模型，以获得支持IND应用的必要数据。这将为第一个进入- 人类临床研究，收集治疗脂肪营养不良的安全性和有效性的证据。

PROJECT SUMMARY Lipodystrophy includes a heterogeneous group of disorders that are characterized by abnormal or degenerative conditions of the adipose tissue. This rare and often underdiagnosed condition can be partial/localized or generalized and is generally associated with metabolic disorders such as insulin resistance, diabetes, hyperglycemia, hyperlipidemia, and other severe conditions. Lipodystrophy can be congenital or acquired and can often lead to deadly consequences due to liver, kidney, and cardiac complications. All forms of lipodystrophy have severe insulin resistance and very low leptin levels. Currently, leptin replacement using Metreleptin is the only treatment of lipodystrophy. However, Metreleptin injections at a dose of once or twice a day cost an average of $565,000 per patient/year and can have adverse side effects. Zvelt therapeutics is developing a safe, efficient, and cost-effective therapy for the treatment of lipodystrophy. This therapy is mediated by recombinant adeno-associated virus (rAAV) vectors that offer long-lasting transgenic expression and low immunogenicity. Typically, when AAV therapies are delivered systemically, the vast majority of AAVs are sequestered in the liver, with little expression in target tissues. This effect causes a narrow therapeutic window, as systemic AAV must be dosed near toxic levels to attain therapeutic benefits. To overcome these challenges, Zvelt will use a novel engineered AAV serotype Rec2 that preferentially targets fat, coupled with a dual cassette platform that minimizes transgene expression in the liver. Zvelt Therapeutics has already established the proof of efficacy of the Rec2/Dual Cassette vector containing the leptin gene (Rec2-leptin) for correcting leptin deficiency, obesity, and metabolic syndromes in mouse models. Zvelt’s platform has been demonstrated to express in the targeted adipose tissue while restricting off-target expression in the liver in the mouse model. In this STTR Phase I project, we will perform dose-finding and safety analyses of Rec2-Leptin in relevant lipodystrophy mouse models towards validation of this innovation for the effective treatment of lipodystrophy. In Phase II, we will address key technical aspects of product development and safety and efficacy studies in larger animal models to obtain essential data to support IND application. This will pave the way for a first-in- human clinical study to collect evidence on the safety and efficacy of the treatment for lipodystrophy.