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

基本信息

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
项目类别：
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

项目摘要

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。基因疗法为许多罕见肌肉和神经肌肉患者带来了希望。尽管取得了一些早期的成功，但一些严重的脱靶安全问题已经影响了它们。由于肝毒性和对腺相关病毒 (AAV) 的相关免疫反应而导致的发展因此，具有卓越肌肉特异性的新型衣壳的产生可能会彻底改变通过避免损害药物功效和安全性的脱靶效应，肌肉基因治疗空间得以实现。目标是设计新型 AAV 衣壳，其肌肉趋向性超过目前的“肌肉趋向性” 血清型（例如 AAV6、AAV8、AAV9、AAVrh74 和 MyoAAV）实际上都不是“肌肉特异性”的。这些血清型可以转导其他组织，尤其是肝脏，其与著名的临床功能相关事实上，肝脏充当这些载体的接收器，限制肌肉转导并提高毒性。我们以最低有效剂量对抗肝脏，同时增强肌肉。向性是提高肌肉基因治疗安全性和有效性的关键。这种高通量方法利用定向进化来人工选择具有改进的衣壳。肌肉向性，但也不能取消肝脏的目标。相比之下，我们将使用合理的设计方法来实现。同时靶向已知表位，实现肝脏脱靶、增强 AAV 受体结合并改善这些包括改善唾液酸/AAV 受体结合、受损肝脏等。靶向/硫酸肝素结合、改进的整合素结合和具有组合特性的衣壳。使用 AAV6 作为该血清型已知的肝脏和肌肉靶向表位，但其他血清型则不知道。里程碑 1 将利用成熟的体内和体外实验开发肝脏去靶向/肌肉靶向 AAV6 衣壳 Milestone 2 将通过比较 Smad7 肌肉基因来证明功能功效。这些研究将野生型 AAV6 (AVGN7) 与新型优化 AAV6 衣壳相结合。可以理解的是，它们的风险很高，但它们的重要性要高得多，因为它们会造成肝损伤。具有改善的肌肉向性的靶向衣壳，因此具有极其优越的安全性和功效。主要通过减少制造负担来大幅创新肌肉基因治疗领域将药物的使用限制在更年轻或更少的患者身上，从而降低总体治疗成本，同时扩大治疗范围潜在患者治疗的数量。