Stem Cells for Neonatal Hypoxic-Ischemic Brain Injury

描述：这一STTR第二阶段研发项目的具体目标是提供一种治疗新生儿缺氧缺血(HI)损伤及其相关结局的优化细胞治疗方案。作为资助的第一阶段STTR赠款的一部分，在HI损伤的大鼠幼鼠模型中进行的临床前研究表明，在HI损伤后一周静脉(IV)或脑内(IC)注射多潜能成体干细胞(MAPC)将受益。同基因和异基因MAPC在没有或存在免疫抑制的情况下显示出统计上显著的疗效，从而解决了将MAPC用作现成同种异体产品的关键临床问题。在收到FDA在B型IND前讨论后的反馈后，这项第二阶段的提案积极探讨了推进基于MAPC的治疗方法在新生儿HI损伤治疗中的应用所需的临床前问题。这项第二阶段的STTR提交有4个具体目标，这将完成IND提交所需的临床前报告包。目的1：确定在cGMP条件下处理的预期临床产品-人MAPC在新生大鼠缺氧缺血性脑损伤模型中表现出与同种异体大鼠MAPC相同的治疗行为和组织学益处。给药实验将包括：目标1.1：静脉注射剂量范围，以确定人类MAPC的最佳剂量；目标1.2：HI损伤后的最佳给药时机；以及目标1.3：多次静脉注射的益处。目的2：证明MAPC移植物在大鼠缺氧缺血性脑损伤模型中具有稳定和长期的治疗行为和组织学益处，即在新生大鼠具有安全成分的移植后6个月，使用Aim 1的优化条件(按照FDA的建议)。目的3：确定细胞疗法在轻、中、重度HI模型中的相对疗效收益。这些数据将有助于确定I期和II期临床开发的适当纳入标准和临床终点(根据与FDA的讨论)。目的：研究大鼠和人MAPC中干细胞的组织相容性、炎症反应和肿瘤/异位组织形成情况，以支持静脉注射MAPC在新生大鼠缺氧缺血性脑病模型中的安全性。这项STTR第二阶段研究的首要目标是在HI模型中提供MAPC移植的最佳方案，解决FDA法规标准内的可行性、安全性和有效性标准，从而实现这种基于细胞的治疗从实验室顺利转移到临床。

DESCRIPTION: The specific objective of this STTR Phase II research and development project is to provide an optimized cellular therapy regimen for treating hypoxic-ischemic (HI) injury and its related outcomes in neonates. Pre- clinical studies performed in a rat pup model of HI injury as part of the funded Phase I STTR grant, point to benefit when Multipotent Adult Progenitor Cells (MAPC), a pluripotent adult stem cell, are administered intravenously (IV) or intracerebrally (IC) one week post-HI injury. Syngeneic and allogeneic MAPC demonstrated statistically significant efficacy in the absence or presence of immunosuppression, thereby resolving key clinical issues for using MAPC as an off-the-shelf allogeneic product. After receiving feedback from the FDA following a Type B pre-IND discussion, this Phase II proposal aggressively pursues those preclinical issues required to advance the application of MAPC based therapy to treat HI injury in neonates. This Phase II STTR submission has 4 specific aims, which will complete the pre-clinical report package required for IND submission. Aim 1: Determine that the anticipated clinical product, human MAPC processed under cGMP conditions, exhibits therapeutic behavioral and histological benefit equivalent to those previously observed with allogeneic rat MAPC in the rat neonatal HI injury model. Dosing experiments will include: Aim 1.1: IV dose ranging to determine optimal dose of human MAPC; Aim 1.2: Optimal timing of delivery, post-HI injury; and Aim 1.3: Benefit of multiple IV dose administrations. Aim 2: Demonstrate stable and long-term therapeutic behavioral and histological benefits of MAPC grafts in the rat HI injury model, i.e., 6 months post-transplantation with safety component in both male and female neonatal rats, using optimized conditions from Aim 1 (as per FDA recommendation). Aim 3: Determine the relative efficacy benefit of cell therapy in minimal, moderate and severe HI injury models. These data will help determine the appropriate inclusion criteria and clinical endpoints for Phase I and Phase II clinical development (as per discussion with FDA). Aim 4: Characterize stem cell histocompatibility, inflammation and tumor/ectopic tissue formation in rat and human MAPC to support safety of IV MAPC in rat neonatal HI model. The overarching goal of this STTR Phase II study is to provide the optimal regimen of MAPC transplantation in an HI model that addresses the feasibility, safety and efficacy criteria within the standards of FDA regulations, thereby realizing a smooth translation of this cell based therapy from the laboratory to the clinic.