Human embryonic stem cell-derived mesenchymal stromal cell therapy for lupus nephritis

 描述(由申请人提供)：高级细胞技术公司(ACT)是一家专注于再生医学和细胞治疗技术的开发和商业化的生物技术公司。它是目前唯一一家正在进行临床试验的公司 在美国和欧洲用于测试人类胚胎干细胞(HESC)衍生产品的安全性和有效性。ACT的临床重点涉及各种与眼睛相关的适应症以及涉及自身免疫、炎症和伤口愈合的非眼部疾病。这项SBIR一期应用的总体目标是扩展ACT的临床前干细胞技术平台，使用移植的hESC来源的间充质干细胞(MSCs)治疗系统性红斑狼疮(SLE)和狼疮性肾炎(LN)。系统性红斑狼疮是一种破坏性的系统性自身免疫性疾病，对疾病管理提出了重大挑战，目前尚无治愈方法。虽然轻到中度的系统性红斑狼疮患者在某种程度上可以通过目前的治疗方案在临床上得到控制，但仍有一部分SLE患者抵制所有形式的当前干预措施，并患有严重疾病。因此，迫切需要一种战略来处理 对于这一患者群体，特别是对于缓解缓慢且对当前治疗反应有限的LN而言。虽然MSCs可以从多种来源分离，但组织中自然产生的MSCs的稀缺性、体外扩增时免疫调节特性的丧失以及缺乏可靠的质量控制等问题导致了其体内有效性的报道不一致。ACT通过一种新颖而有效的方法克服了许多这些障碍，该方法使用hESCs作为MSCs的来源，以获得质量一致的无限量、可补充的早期传代MSCs。重要的是，ACT已经证明其hESC-MSCs在几种自身免疫性疾病模型中发挥治疗作用，包括延长狼疮倾向的NZB/W F1小鼠的存活。由于人类系统性红斑狼疮的遗传复杂性，在具有不同潜在遗传易感性的LN疾病模型中检验潜在的新疗法是当务之急。通过两个特定的目标，这里提出的研究将使用额外的经典小鼠模型MRL/LPR，以扩展使用NZB/W F1小鼠的先前的发现，并使基于hESC-MSC的SLE/LN方法的进一步发展合理化。目的1将确定ACT的hESC-MSCs用于降低狼疮倾向的MRL/LPR小鼠LN疾病严重程度的最小有效剂量和最大耐受量，并与人类脐带(Huc)来源的MSCs(在人类狼疮临床试验中显示出前景)的效果进行比较。AIM 2将确定hESC-MSC在AIM 1注射小鼠的组织/血清中的治疗活性的分子和细胞靶点，并将这些作用与Huc-MSCs进行比较。

 DESCRIPTION (provided by applicant): Advanced Cell Technology, Inc. (ACT) is a biotechnology company focused on the development and commercialization of regenerative medicine and cell therapy technology. It is currently the only company with ongoing clinical trials in the U.S. and Europe for testing the safety and efficacy of a human embryonic stem cell (hESC)-derived product. ACT's clinical focus involves a variety of eye-related indications as well as non-ocular disorders involving autoimmunity, inflammation, and wound-healing. The overall objective of this SBIR Phase I application is to extend ACT's preclinical stem cell technology platform for the treatment of systemic lupus erythematosus (SLE) and lupus nephritis (LN) using transplanted hESC-derived mesenchymal stromal cells (MSCs). SLE is a devastating systemic autoimmune disease that presents significant disease management challenges with no currently known cure. While patients with mild to moderate SLE are to some extent clinically manageable with current protocols, there remains a subset of SLE patients that resists all forms of current interventions and suffers severe disease. A critical need therefore exists for strategies that deal with this patient population, particularly for LN where remission is slow and response to current treatments limited. Although MSCs can be isolated from several sources, issues such as the scarcity of naturally occurring MSCs in tissues, loss of immunomodulatory properties upon in vitro expansion, and a lack of reliable quality control have led to inconsistencies in their reportd in vivo effectiveness. ACT has overcome many of these obstacles through a novel and efficient method that uses hESCs as a source for MSCs to derive unlimited, replenishable amounts of early-passage MSCs of consistent quality. Importantly, ACT has demonstrated that its hESC-MSCs exert therapeutic effects in several autoimmune disease models, including prolonged survival of lupus-prone NZB/W F1 mice. Due to the genetic complexity of human SLE, it is imperative to examine potential new therapeutics in LN disease models harboring different underlying genetic susceptibilities. Studies proposed here, through two Specific Aims, will employ an additional classic mouse model, MRL/lpr, to extend previous findings using NZB/W F1 mice and rationalize further development of a hESC-MSC-based approach for SLE/LN. Aim 1 will determine minimal effective and maximum tolerated doses of ACT's hESC-MSCs for reducing LN disease severity in lupus-prone MRL/lpr mice and compare the effects to those of human umbilical cord (hUC)-derived MSCs (which are showing promise in human clinical trials for lupus). Aim 2 will define the molecular and cellular targets of hESC-MSC therapeutic activity in tissues/sera from mice injected in Aim 1 and compare these effects to those of hUC-MSCs.