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

 描述（由申请人提供）：杜氏肌营养不良症（DMD）是一种退行性肌肉疾病，由X连锁DMD基因突变引起，影响约1：3500至1：5200的活产男婴。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，导致12岁时失去记忆力，历史上20岁时死亡。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保健费用、职业和工作的机会成本以及对父母和兄弟姐妹的心理影响。我们的长期目标是开发rAAVrh74.MCK.GALGT2作为替代基因疗法，可以为受DMD影响的男孩提供显著的临床益处。我们在该项目中的目的是进行首次人体研究，证明肌肉注射后载体的安全性和表达，我们的中心假设是肌肉注射到趾短伸肌（EDB）肌肉后，CT抗原表达将在肌膜上广泛识别，并且不会观察到显著的炎症。该试验的基本原理是，在首次人体背景下肌内注射rAAVrh74.MCK.GALGT 2后的安全性的证明代表了靶向整个肢体的血管内基因转移研究的必要前提，其目的是防止amphetamine的损失，目前正处于计划阶段。我们的具体目标是1）进行rAAVrh74.MCK.GALGT 2肌内基因转移的首次人体安全性研究，和2）评估EDB肌肉中CT抗原表达的程度和影响。这些目标的预期结果将是首次在人类中证实GALGT 2从rAAVrh74.MCK.GALGT 2载体的表达，与我们在小鼠、狗和非人灵长类动物（NHP）中的临床前数据一致，并且类似地显示缺乏与我们的临床前结果一致的毒性。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的规划阶段，得到了小鼠和NHP中额外广泛的临床前工作的支持。这种血管输送预计将为患有DMD的男孩提供显著的临床意义的益处。

 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.