Vascular Delivery of alpha-Sarcoglycan for LGMD2D

用于 LGMD2D 的 α-肌聚糖的血管输送

• 批准号: 8546147
• 负责人: Jerry Roy Mendell
• 金额: $ 49.63万
• 依托单位: RESEARCH INST NATIONWIDE CHILDREN'S HOSP
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-17 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8546147
• 关键词: Adhalin; Adverse effects; Applications Grants; Award; Biodistribution; Blood Circulation; Blood Pressure; Blood Vessels; Caring; Clinical; Clinical Trials; Containment; Dose; FDA approved; Foundations; Funding; Gene Delivery; Gene Expression; Gene Transfer; Genes; Human; Immune response; Infusion procedures; Institutional Review Boards; Intramuscular; Knee; Laboratories; Lead; Leg; Life; Ligature; Limb structure; Limb-Girdle Muscular Dystrophies; Lower Extremity; MM form creatine kinase; Methods; Muscle; Muscular Dystrophies; Outcome Measure; Patients; Pediatric Hospitals; Performance; Phase; Positioning Attribute; Preparation; Production; Qualifying; Quality of life; Research Institute; Safety; Site; Toxicology; Transgenes; Virus; cost; experience; femoral artery; gene therapy; improved; manufacturing facility; meetings; muscle strength; nonhuman primate; programs; promoter; quadriceps muscle; respiratory; vector

DESCRIPTION (provided by applicant): An intramuscular gene therapy trial in LGMD2D to replace the human alpha-sarcoglycan gene (hSGCA) delivered by rAAV1 under control of a muscle creatine kinase promoter was recently completed. Gene expression was observed for as long as 6 months. No adverse effects were encountered. That study provided the foundation and the impetus to move forward with a vascular delivery trial. In the laboratory we have established that rAAV.rh.74 can effectively deliver hSGCA to specific muscle groups through the femoral artery in the non-human primate. Delivery is achieved with the extremity isolated from the systemic circulation using a temporary ligature proximal to the site of infusion and a blood pressure cuff at the knee. Containment of virus to promote safety is an important consideration for the first vascular gene delivery trial in muscular dystrophy. The method is safe, effective and reproducible. We have presented these findings to the FDA (pre- IND meeting) and they were receptive to this approach. In addition we have obtained funding (MDA) for the toxicology-biodistribution study that is currently underway that will lead to an IND, permitting entrie to the clinical trial. Our Center holds two INDs for muscular dystrophy gene therapy and we have a devoted staff that is self sufficient and capable of preparing all of the necessary regulatory documents (IND, RAC, IRB) for the clinical trial. The current grant proposal is divided into two aims. Aim1 is the preparation of vector for the clinical trial (self-complementary rAAV.rh.74.tMCK.hSGCA). Nationwide Children's Hospital is uniquely positioned to make vector in a timely manner because a vector manufacturing facility has been established in the Center for Gene Therapy within the Children's Hospital Research Institute. Production of clinical grade vector can start immediately upon receiving funds awarded by this grant proposal. Aim 2 calls for the performance of a dose-escalation trial in LGMD2D patients. The Center for Gene Therapy at NCH is highly qualified and uniquely experienced in gene therapy trials. The proposed study will be a dose escalation trial of rAAV.rh.74.tMCK.hSGCA delivered through the femoral artery. Targeting the quadriceps muscle will provide a means for improving muscle strength and thereby prolong ambulation. Both limbs will be perfused within a single treatment episode, an approach approved by the FDA in our pre-IND meeting. Three patients will receive low dose vector (6x1011 vg/kg) and three others will receive the high dose (2x1012 vg/kg). The immune response to virus and transgene will be fully studied as we have done in prior gene therapy studies. The outcome measures proven to be satisfactory and used extensively in our clinical trials program will determine efficacy of this approach.

描述（由申请人提供）：LGMD2D中的肌内基因治疗试验替代了Raav1在控制肌肉肌酸激酶启动子的控制下由Raav1提供的人α-盐基因（HSGCA）。观察到基因表达长达6个月。没有遇到不利影响。该研究为进行血管递送试验提供了基础和动力。在实验室中，我们确定Raav.RH.74可以通过非人类灵长类动物的股动脉有效地将HSGCA传递给特定的肌肉群。通过从全身循环中分离出的肢体，使用临时连接到输注部位和膝盖上的血压袖带来实现递送。促进安全性的病毒遏制是肌营养不良症第一次血管基因输送试验的重要考虑因素。该方法是安全，有效且可再现的。我们已经将这些发现提交了FDA（前会议），他们接受了这种方法。此外，我们还获得了目前正在进行IND的毒理学生物分配研究的资金（MDA），从而允许进入临床试验。我们的中心拥有两个用于肌肉营养不良基因疗法的IND，我们有一个忠实的员工，他们足够足够，能够为临床试验准备所有必要的调节文件（IND，RAC，IRB）。当前的赠款提案分为两个目标。 AIM1是为临床试验的矢量制备（自我平衡raav.rh.74.tmck.hsgca）。全国儿童医院的独特位置可以及时制作媒介，因为在儿童医院研究所的基因治疗中心已经建立了媒介制造设施。临床级向量的生产可以在收到该赠款提案授予的资金后立即开始。 AIM 2要求在LGMD2D患者中进行剂量升级试验的性能。 NCH基因治疗中心在基因治疗试验中具有很高的资格和独特的经验。拟议的研究将是通过股动脉进行的raav.74.tmck.hsgca的剂量升级试验。靶向股四头肌的肌肉将提供一种改善肌肉力量并从而延长行动的手段。这两个肢体都将在单个治疗情节中灌注，这是FDA在我们的预定会议上批准的方法。三名患者将接受低剂量载体（6x1011 VG/kg），另外三名将接受高剂量（2x1012 VG/kg）。像我们在先前的基因治疗研究中所做的那样，将对病毒和转基因的免疫反应进行全面研究。事实证明，结果度量令人满意，并且在我们的临床试验计划中广泛使用将确定这种方法的功效。