Novel Adipose Targeted Gene Therapy for Lipodystrophy

新型脂肪靶向基因疗法治疗脂肪营养不良

• 批准号: 10820263
• 负责人: Lei Cao
• 金额: $ 29.38万
• 依托单位: ZVELT THERAPEUTICS INC.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-15 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10820263
• 关键词: Adipose tissue; Adverse effects; Affect; Agreement; Animal Model; Animals; Australia; Biodistribution; Businesses; Canada; Cardiac; Clinical Research; Coupled; DNA cassette; Data; Degenerative Disorder; Diabetes Mellitus; Diagnosis; Disease; Dose; Engineering; Europe; Fatty acid glycerol esters; Genes; Harvest; Hyperglycemia; Hyperlipidemia; Injections; Insulin Resistance; Intraperitoneal Injections; Kidney; Legal patent; Leptin; Leptin deficiency; Licensing; Lipodystrophy; Liver; Mediating; Metabolic Diseases; Metabolic syndrome; Methods; Monitor; No-Observed-Adverse-Effect Level; Obese Mice; Obesity; Ohio; Patients; Phase; Publishing; Randomized; Recombinant adeno-associated virus (rAAV); Rodent Model; Safety; Serotyping; Small Business Technology Transfer Research; Specificity; Technology; Testing; Therapeutic; Tissues; Titrations; Toxic effect; Toxicology; Transgenes; Treatment Cost; Treatment Efficacy; Universities; Validation; adeno-associated viral vector; appropriate dose; clinical practice; cost; cost effective treatment; dosage; effective therapy; efficacy study; experience; experimental study; first-in-human; gene correction; gene therapy; immunogenicity; in vivo; innovation; intravenous injection; invention; metabolic phenotype; mouse model; novel; novel therapeutics; particle; pharmacokinetics and pharmacodynamics; pharmacologic; pre-clinical; preclinical study; product development; research and development; safety study; senior faculty; side effect; transduction efficiency; transgene expression; vector

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.

项目概要 脂肪营养不良包括一组异质性疾病，其特征是异常或 脂肪组织的退行性病变。这种罕见且经常被诊断不足的情况可能是 部分/局部或全身性，通常与胰岛素等代谢紊乱有关 抵抗力、糖尿病、高血糖、高血脂等严重病症。脂肪营养不良可以是 先天性或后天性的，通常会因肝脏、肾脏和心脏疾病而导致致命的后果 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。现在， 使用 Metreleptin 替代瘦素是脂肪营养不良的唯一治疗方法。然而，美曲普汀注射液 每天一次或两次的剂量平均每位患者每年花费 565,000 美元，并且可能有不利的一面 影响。 Zvelt Therapys 正在开发一种安全、高效且具有成本效益的治疗方法 脂肪营养不良。该疗法由重组腺相关病毒 (rAAV) 载体介导，该载体提供 持久的转基因表达和低免疫原性。通常，当提供 AAV 疗法时 从系统角度来看，绝大多数 AAV 被隔离在肝脏中，在靶组织中表达很少。 这种效应导致治疗窗口狭窄，因为全身 AAV 的剂量必须接近毒性水平才能达到 治疗益处。为了克服这些挑战，Zvelt 将使用新型工程 AAV 血清型 优先针对脂肪的 Rec2，加上双盒平台可最大限度地减少转基因 在肝脏中表达。 Zvelt Therapeutics 已经证明了 Rec2/Dual 的功效 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 的平台已被证明可以在目标中表达 脂肪组织，同时限制小鼠模型肝脏中的脱靶表达。在本次 STTR 第一阶段 项目中，我们将在相关脂肪营养不良小鼠中进行 Rec2-Leptin 的剂量探索和安全性分析 验证这一创新有效治疗脂肪营养不良的模型。 在第二阶段，我们将解决产品开发的关键技术问题以及安全性和有效性研究 更大的动物模型以获得支持 IND 申请的必要数据。这将为首创铺平道路 人体临床研究旨在收集有关脂肪营养不良治疗的安全性和有效性的证据。