Enhancing the Reparative Efficacy of Schwann Cells following Chronic SCI

增强慢性 SCI 后雪旺细胞的修复功效

• 批准号: 9313645
• 负责人: Damien D. Pearse
• 金额: --
• 依托单位: MIAMI VA HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9313645
• 关键词: Acids; Acute; Address; Adult; Affect; American; Anatomy; Authorization documentation; Autologous; Axon; Bacteria; Biochemical; Biology; Biopsy; Cell Survival; Cell Transplants; Cells; Cervical; Chest; Chronic; Clinical; Clinical Treatment; Clinical Trials; Collaborations; Data; Demyelinations; Development; Distal; Effectiveness; Engineering; Enzymes; Experimental Models; Foundations; Gene Delivery; Goals; Growth; Health; Health Care Costs; Human; In Vitro; Individual; Injection of therapeutic agent; Injury; Investigational New Drug Application; Lesion; Light; Measures; Modeling; Modification; Molecular; Motor; Natural regeneration; Neuraxis; Neuroglia; Neurons; Pathway interactions; Peripheral; Peripheral Nerves; Phase I Clinical Trials; Polysialic Acid; Procedures; Recovery; Recovery of Function; Research; Research Personnel; Schwann Cells; Sensory; Site; Spinal; Spinal cord injury; Supporting Cell; Technology; Therapeutic; Tissues; Treatment Efficacy; United States; United States Food and Drug Administration; Veterans; Viral Vector; War; Work; axon growth; axon regeneration; base; behavior test; cell motility; design; experimental study; functional outcomes; gene therapy; genetic approach; implantation; improved; in vivo; injury and repair; migration; myelination; novel therapeutics; permissiveness; prevent; public health relevance; repaired; social; success; translational approach; treatment strategy

DESCRIPTION Chronic spinal cord injury (SCI) affects more than 1.25 million people in the United States, with more than 11,000 new injuries sustained annually. Recovery is limited because severed axons of the adult mammalian central nervous system (CNS) are unable to regenerate. Of the multiple treatment strategies employed in experimental models for SCI repair, cellular grafting to bridge the injury site and provide a substrate for axonal re-growth has been a foundation for many of the promising acute, sub-acute and chronic therapies. Our work to date has focused on the utility of the Schwann cell (SC), a peripheral glial cell critical for peripheral nerve regeneratio and repair, to anatomically and functionally restore the injured spinal cord. SCs can facilitate anatomical repair and improvements in functional recovery in a number of experimental SCI models (complete and incomplete; cervical and thoracic; acute and chronic). Importantly, SCs could be obtained from a peripheral nerve biopsy from a SCI individual, purified and expanded to large numbers in culture for ensuing autologous implantation. It is because of these beneficial effects that The Miami Project recently submitted to The Food and Drug Administration an Investigational New Drug Application to request permission to undertake a Phase 1 clinical trial with autologous SCs for sub-acute human SCI repair. Despite this success, the fact remains that SC migration is very limited within the injured spinal cord, which is likely to significantly lessen their therapeutic efficacy. A lack of migration limits the ability of SCs to guide axons bot into and from the lesion as well as prevents SCs from reaching regions of distal demyelination so as to facilitate re-myelination repair. It therefore occurred to us that the ability of cell surace polysialylic acid (PSA) to facilitate cell migration during normal development might be exploited in the SC translational approach. We have recently shown in sub-acute SCI that SCs can readily migrate within the injured spinal cord when they have been genetically modified to express high levels of PSA, and that this SC modification leads to significantly greater axon regeneration and functional restitution following SCI. The next step in our work, as represented in this proposal, is to move closer to therapeutic relevance through the optimization and extension of the use of PSA in SCI, particularly to the treatment of chronic SCI. The research plan seeks to achieve that goal first by improvement in the practicality of the PSA-SC approach through the use of the purified polysialyltransferase (obtained from bacteria) to synthesize PSA directly on SCs and/or axons, thus avoiding the use of gene therapy in experimental paradigms of sub-acute and chronic SCI (Specific Aim 1). The proposal then seeks to understand the mechanism(s) by which PSA alters the migratory capacity of Schwann cells and improves the axon growth promoting ability of Schwann cells. (Specific Aim 2). As the ultimate goal of this work is to improve SCI repair in vivo, these studies will be evaluated not only in terms of the cel and tissue biology of our manipulations, but also the effect of those procedures on functional outcomes as measured in extensive behavioral testing. The proposed work will provide important data to allow us to expand the scope of our initial clinical trial with SCs from sub-acut to chronic SCI as well as provide readily translatable combinatory approaches that can putatively enhance the effectiveness of SCs clinically in both sub-acute and chronic SCI.

描述 在美国，慢性脊髓损伤(SCI)影响着超过125万人，每年有超过11,000人新受伤。恢复是有限的，因为成年哺乳动物中枢神经系统(CNS)的轴突无法再生。在脊髓损伤修复实验模型中采用的多种治疗策略中，细胞移植桥接损伤部位并为轴突再生长提供基质，已成为许多有前景的急性、亚急性和慢性治疗的基础。到目前为止，我们的工作主要集中在雪旺细胞(SC)的用途上，雪旺细胞是一种对周围神经再生和修复至关重要的外周神经胶质细胞，在解剖和功能上恢复受损的脊髓。SCS可以促进一些实验性脊髓损伤模型(完全性和不完全性；颈椎和胸椎；急性和慢性)的解剖修复和功能恢复的改善。重要的是，干细胞可以从脊髓损伤患者的周围神经活检中获得，纯化并在培养中大量扩增，用于随后的自体植入。正是由于这些有益的效果，迈阿密项目最近向食品和药物管理局提交了一份调查性新药申请，请求允许进行一项使用自体干细胞进行亚急性人类脊髓损伤修复的第一阶段临床试验。尽管取得了这样的成功，但事实仍然是，SC在受损脊髓内的迁移非常有限，这可能会显著降低它们的治疗效果。缺乏迁移限制了SCs引导轴突进入和离开病变的能力，并阻止SCs到达远端脱髓鞘区域，以促进重新髓鞘修复。因此，我们认为细胞表面多唾液酸(PSA)在正常发育过程中促进细胞迁移的能力可以在SC翻译方法中得到利用。我们最近在亚急性脊髓损伤中表明，当干细胞被基因修饰以表达高水平的PSA时，它们可以很容易地在损伤的脊髓内迁移，并且这种SC修饰导致了脊髓损伤后显著更大的轴突再生和功能恢复。我们工作的下一步，如本提案所示，是通过优化和推广PSA在脊髓损伤中的使用，特别是在慢性脊髓损伤的治疗中，更接近于治疗意义。该研究计划首先寻求通过改进PSA-SC方法的实用性来实现这一目标，方法是使用纯化的聚唾液酸基转移酶(从细菌中获得)直接在干细胞和/或轴突上合成PSA，从而避免在亚急性和慢性脊髓损伤的实验范例中使用基因疗法(具体目标1)。然后，该提案试图了解PSA改变雪旺细胞的迁移能力并提高雪旺细胞的轴突生长促进能力的机制(S)。(具体目标2)。由于这项工作的最终目标是改善在体脊髓损伤的修复，这些研究将不仅从我们的操作的细胞和组织生物学方面进行评估，而且还将根据广泛的行为测试来衡量这些操作对功能结果的影响。这项拟议的工作将提供重要的数据，使我们能够将SCs的初步临床试验范围从亚急性脊髓损伤扩大到慢性SCI，并提供易于翻译的组合方法，可以在临床上增强SCs在亚急性和慢性SCI中的有效性。