Development of optimized adeno-associated viral capsids for muscle gene therapy

开发用于肌肉基因治疗的优化腺相关病毒衣壳

• 批准号: 10758732
• 负责人: Buel Rodgers
• 金额: $ 14.02万
• 依托单位: AAVOGEN, INC.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-02 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10758732
• 关键词: Adult; Age; Agreement; Award; Binding; Businesses; Capsid; Chronic; Clinical; Clinical Trials; Codon Nucleotides; Collaborations; Complementary DNA; Cytokeratin-8 Staining Method; Development; Diagnosis; Directed Molecular Evolution; Disease; Dose; Dose Limiting; Drug or chemical Tissue Distribution; Drug usage; Duchenne muscular dystrophy; Effectiveness; Engineering; Epitopes; Generations; Goals; Heparin; Hepatotoxicity; Immune response; Impairment; In Vitro; Inclusion Body Myositis; Integrin Binding; Intellectual Property; Legal patent; Licensing; Limb-Girdle Muscular Dystrophies; Link; Liver; Methods; Muscle; Muscle function; Muscular Atrophy; Myopathy; Neuromuscular Diseases; Patients; Penetrance; Pharmaceutical Preparations; Program Development; Property; Public Health; Quality of life; Recombinants; Risk; Safety; Serotyping; Sialic Acids; Skeletal Muscle; Smad7 protein; Specificity; Spinal Muscular Atrophy; Striated Muscles; Sulfate; Testing; Tissues; Toxic effect; Treatment Cost; Tropism; Viral; Virus Receptors; Wasting Syndrome; adeno-associated viral vector; animal breeding; comparative efficacy; drug development; drug efficacy; gene therapy; high risk; imaging approach; improved; in vivo; innovation; liver function; manufacture; manufacturing cost; medication safety; muscle form; neuromuscular; novel; older patient; pre-clinical; prevent; programs; promoter; rational design; receptor binding; success; therapeutic development; therapeutic gene; trait; vector

PROJECT SUMMARY. Gene therapeutics offer hope to many patients with rare muscle and neuromuscular diseases. Despite some early successes, several serious off-target safety concerns have compromised their development due to hepatic toxicities and related immune responses to the adeno-associated viral (AAV) vectors. The generation of novel capsids with superior muscle specificity could, therefore, revolutionize the muscle gene therapy space by avoiding the off-target effects that compromise drug efficacy and safety. Our objective is to engineer novel AAV capsids with muscle tropism that exceeds the current “muscle tropic” serotypes (e.g. AAV6, AAV8, AAV9, AAVrh74 & MyoAAVs) as none is actually “muscle-specific”. Indeed, all of these serotypes can transduce other tissues, especially the liver, which is functionally linked to the noted clinical toxicities. In fact, the liver functions as a sink for these vectors, limiting muscle transduction and elevating the minimally effective dose. We hypothesize that de-targeting the liver while simultaneously enhancing muscle tropism is key to improving muscle gene therapy safety and efficacy. Other groups have sought to enhance muscle tropism using directed evolution. This high throughput method artificially selects capsids with improved muscle tropism, but cannot also de-target the liver. By contrast, we will use a rational design approach to simultaneously target known epitopes for liver de-targeting, enhanced AAV-receptor binding and improved muscle targeting. These include those for improved sialic acid/AAV-receptor binding, impaired liver targeting/heparin sulfate binding, improved integrin binding and capsids with combined properties. We will also use AAV6 as liver- and muscle-targeting epitopes are known for this serotype, but not for the other serotypes. Milestone 1 will develop liver de-targeted/muscle targeted AAV6 capsids using well-established in vivo and in vitro imaging approaches. Milestone 2 will demonstrate functional efficacy by comparing a Smad7 muscle gene therapeutic featuring a wild-type AAV6 (AVGN7) to one with a novel optimized AAV6 capsid. These studies are understandably high risk yet their significance is disproportionately much higher as they will create a liver de- targeted capsid with improved muscle tropism and as a result, vastly superior safety and efficacy profiles. This would substantially innovate the muscle gene therapy space primarily by reducing a manufacturing burden that limits drug use to younger or fewer patients and thus, reducing the overall treatment costs while expanding the number of potential patient therapies.

项目摘要。基因疗法为许多稀有肌肉和神经肌肉的患者提供了希望 疾病。尽管取得了一些早期的成功，但一些严重的脱离目标安全问题却损害了他们的 由于肝毒性和对腺相关病毒相关的免疫反应引起的发育（AAV） 向量。因此 肌肉基因治疗空间通过避免损害药物效率和安全性的脱靶作用。我们的 目的是用肌肉向肌肉主义的新颖AAV Capsids来设计超过当前“肌肉热带”的肌肉 血清型（例如AAV6，AAV8，AAV9，AAVRH74和MYOAAVS）实际上没有“特定于肌肉”。确实，所有人 这些血清型可以翻译其他组织，尤其是肝脏，在功能上与著名的临床有关 战术。实际上，肝脏充当这些向量的下水道，限制了肌肉转导并提升 最小有效剂量。我们假设这种肝脏同时增强肌肉的靶向 向摩主义是提高肌肉基因治疗安全性和效率的关键。其他团体已经促进 使用定向进化的肌肉向向朝向。这种高通量方法人为地选择了带有改进的衣壳 肌肉向性欲，但也不能脱离肝脏。相比之下，我们将使用合理的设计方法来 类似的靶向已知肝脏脱靶表位，增强的AAV受体结合并改善 肌肉靶向。其中包括用于改善唾液酸/AAV受体结合的那些肝脏受损 靶向/硫酸肝素结合，改善了具有合并性能的结合结合和衣壳。我们也会 将AAV6用作肝和肌肉靶向表位以这种血清型而闻名，但对于其他血清型而不是。 里程碑1将使用良好的体内和In中的肝脏靶向AAV6衣壳的靶向AAV6衣壳。 体外成像方法。里程碑2将通过比较SMAD7肌肉基因来证明功能效率 具有野生型AAV6（AVGN7）的治疗性，具有新颖的AAV6 CAPSID。这些研究是 可以理解的高风险可以理解，但它们的意义不成比例地高得多，因为它们会产生肝脏 具有改善肌肉的肌肉状态，并因此，安全性和效率概况极高。这 通过减少制造业燃烧，将基本创新肌肉基因治疗空间 将药物用于年轻患者或更少的患者，从而降低了整体治疗成本，同时扩大了 潜在的患者疗法数量。