First-in-Human rAAVrh74.MCK.GALGT2 DMD Clinical Trial

 描述(申请人提供)：Duchenne肌营养不良症(DMD)是一种退行性肌肉疾病，由X连锁DMD基因突变引起，影响大约1：3500至1：5200的活男婴。DMD基因突变导致肌纤维中肌营养不良蛋白的缺失，导致肌纤维坏死、肌内膜纤维化和脂肪替代。这是一种毁灭性的疾病，会导致12岁时失去行走能力，历史上会导致20岁时死亡。这对家庭的心理和社会经济影响是巨大的；这些影响包括但不限于医疗成本、事业和工作的机会成本，以及父母和兄弟姐妹的心理损失。我们的长期目标是开发一种rAAVRH74.MCK.GALGT2作为替代基因疗法，能够为受DMD影响的男孩提供显著的临床益处。我们在这个项目中的目标是进行首例人体研究，证明肌肉注射后载体的安全性和表达，我们的中心假设是，在肌肉注射到趾短伸肌(EDB)后，CT抗原的表达将在肌膜上广泛识别，并且不会出现明显的炎症。这项试验的基本原理是，首次在人类环境下肌肉注射rAAVRh74.MCK.GALGT2后证明其安全性，这是针对整个肢体的血管内基因转移研究的必要先驱，目的是防止丧失行走能力，目前正处于规划阶段。我们的具体目标是：1)开展首次肌肉内基因转移rAAVrh74、MCK.GALGT2的人体安全性研究；2)评估CT抗原在EDB肌肉中表达的程度和影响。这些目标的预期结果将是证实GALGT2从rAAVrh74.MCK.GALGT2载体中首次在人类中表达，这与我们在小鼠、狗和非人类灵长类动物(NHP)的临床前数据一致，并类似地显示与我们的临床前结果一致的无毒性。我们工作的直接影响将是提供来自人类的初步数据，支持我们预期的人类血管递送研究；这些研究正处于积极规划阶段，并得到在小鼠和NHP上额外的广泛临床前工作的支持。这种血管分娩有望为患有DMD的男孩带来显著的临床意义。

 DESCRIPTION (provided by applicant): Duchenne muscular dystrophy (DMD) is a degenerative muscle disorder that affects approximately 1:3500 to 1:5200 live male births caused by mutations in the X-linked DMD gene. DMD gene mutations result in absence of the dystrophin protein in muscle fibers, leading to myofiber necrosis, endomysial fibrosis, and fat replacement. It is a devastating disorder, leading to loss of ambulation by age 12, and historically to death by age 20. The psychological and socioeconomic effects on families are enormous; these include but are not limited to the costs of medical care, opportunity costs for career and work, and the psychological toll taken on parents and siblings. Our long-term goal is to develop a rAAVrh74.MCK.GALGT2 as a surrogate gene therapy that can provide significant clinical benefit to boys affected by DMD. Our objective in this project is to perform first-in-huma studies demonstrating the safety and expression of the vector following intramuscular injection, and our central hypothesis is that following intramuscular injection into the extensor digitorum brevis (EDB) muscle, CT antigen expression will be widely identifiable at the sarcolemmal membrane, and no significant inflammation will be seen. The rationale for this trial is that the demonstration of the safety of rAAVrh74.MCK.GALGT2 following intramuscular injection in the first-in-human context represents a necessary precursor to intravascular gene transfer studies targeting whole limbs, with the goal of preventing loss of ambulation, that are now in the planning stages. Our specific aims are to 1) perform a first-in-human safety study of intramuscular gene transfer of rAAVrh74.MCK.GALGT2, and 2) assess the degree of and the effects of CT antigen expression in EDB muscles. The expected outcome of these aims will be to confirm the expression of GALGT2 from the rAAVrh74.MCK.GALGT2 vector for the first time in humans, consistent with our preclinical data in mice, dogs, and non-human-primates (NHPs), and similarly to show a lack of toxicity consistent with our preclinical results. The immediate impact of our work will be to provide preliminary data from humans that support our anticipated vascular delivery studies in humans; these are in the active planning stage, supported by additional extensive preclinical work in mice and in NHPs. Such vascular delivery would be expected to deliver significant clinically meaningful benefit to boys with DMD.