Phase 1b Trial of stem cells in ALS

描述(由申请人提供)：本提案概述了将人脊髓来源干细胞(HSSCs)注射到ALS患者的颈髓中的1b期临床试验计划。这项试验是埃默里大学已经在进行的一项试验的后续，在该试验中，12名ALS患者被注射了相同的HSSCs到腰椎脊髓。为了使这一治疗方法更接近于临床试验，以确定它在改善疾病方面是否有效，我们提议测试HSSC注射到颈髓的安全性。颈髓中的运动神经元支配呼吸隔膜，呼吸隔膜的缺失通常是ALS患者死亡的原因。我们认为，对这些神经元的保护可能会通过保护呼吸功能来延长生命。这项安全性试验将采用逐步剂量递增的方法来确定可用于执行第二阶段和第三阶段疗效试验的长期目标的最大耐受剂量。有两个具体目标。在目标1中，我们建议按照1)细胞数/注射，2)脊髓注射次数，3)单侧或双侧注射的定义，按顺序递增给药剂量。该剂量递增计划旨在安全和高效地测试我们实现预定义目标治疗剂量的能力，该治疗剂量可用于 下一阶段的治疗效果测试。这项建议的目标2是检查几个探索性终点，这些终点可用于在未来的2期和3期试验中测试该疗法的疗效。这些指标包括呼吸功能、横隔膜功能、肌肉力量和肌肉的电特性(电阻抗肌图)。这项1b期试验的成功完成将允许对这一治疗ALS的高度创新方法进行测试。这一影响将扩大到ALS患者，因为这项新的试验将提供有关手术方法和安全性的数据，以及与脊髓损伤、多发性硬化症、脊髓性肌肉萎缩和其他神经疾病的细胞疗法高度相关的试验设计。

DESCRIPTION (provided by applicant): This proposal outlines a plan for a Phase 1b clinical trial for the injection of human spinal cord derived stem cells (HSSCs) into the cervical spinal cord of patients with ALS. This trial is a follow up to a trial already underway at Emory University, where 12 ALS patients have been injected with the same HSSCs into the lumbar spinal cord. In order to move this therapeutic approach closer to a clinical trial to determine if t is effective in ameliorating disease, we are proposing to test the safety of HSSC injection into the cervical spinal cord. Motor neurons in the cervical spinal cord innervate the respiratory diaphragm, the loss of which is typically the cause of death in ALS patients. We propose that the protection of these neurons is likely to prolong life by preserving respiratory function. This safety trial will employ progressive dose escalation to determine the maximum tolerated dose that can be used for the long term goal of performing Phase 2 and Phase 3 efficacy trials. There are two specific aims. In Aim 1 we propose to sequentially escalate the dose of delivery as defined by 1) the number of cells/injection, 2) the number of injections into the cord, and 3) either unilateral or bilateral injections. This dose escalation scheme is designed to safely and efficiently test our ability to achieve a pre-defined target therapeutic dose, which can be used in the next phase of testing therapeutic efficacy. Aim 2 of this proposal is to examine several exploratory endpoints that may be used to test the efficacy of this therapy in future Phase 2 and Phase 3 trials. These include measures of respiratory function, diaphragm function, muscle strength, and electrical characteristics of muscle (Electrical Impedance Myography). Successful completion of this Phase 1b trial will allow for testing of this highly innovative approach to the treatment of ALS. The impact will extend beyond patients with ALS since this novel trial will provide data on surgical approach and safety, as well as trial design that will be highly relevant to cellular therapeutics for spinal cord injury, multiple sclerosis, spinal muscular atrophies, as well as other neurological diseases.