Transplantation of glial precursors: Astrocyte replacement in ALS

描述(申请人提供)：肌萎缩侧索硬化症(ALS)是一种运动神经元疾病，仅在美国就有大约30,000人受到影响，其特征是上下运动神经元相对较快的退化，通常发生在确诊后2-5年内因呼吸瘫痪而死亡。神经前体细胞移植是治疗包括肌萎缩侧索硬化症在内的外伤性中枢神经系统损伤和神经退行性变的一种很有前途的治疗策略，因为它能够替代丢失或功能障碍的中枢神经系统细胞类型，提供神经保护，并传递感兴趣的基因因子。以前鼻咽癌移植治疗ALS的研究主要集中在运动神经元替代上；然而，这是一个具有挑战性的策略，因为与运动神经元分化以及与宿主神经元和肌肉系统建立连接相关的问题。对ALS模型的研究表明，细胞异常并不局限于运动神经元。考虑到这些观察结果，这项建议旨在以非神经细胞类型的替代为目标，以获得可能的治疗益处。具体地说，胶质限制前体(GRPs)-谱系限制的NPC，其分化仅限于星形胶质细胞和少突胶质细胞-的治疗潜力将在移植到ALS啮齿动物模型SOD1G93A大鼠的脊髓后进行评估。野生型GRPs或GRPs将被移植到SOD1G93A大鼠的颈髓腹角。在目标1中，将检查移植细胞的命运，包括存活、迁移、分化和谷氨酸摄取。在AIM#2中，将评估移植受体动物的一些表型和病理组织学措施，以确定移植细胞的治疗效果。在目标#3中，将测试移植的GRP特异性挽救横隔膜功能的能力。摘要：肌萎缩侧索硬化症(ALS或Lou Gehrig病)是一种毁灭性的神经系统疾病，会导致瘫痪，最终因呼吸衰竭而死亡。中枢神经系统来源的干细胞移植是治疗ALS等脑和脊髓疾病的一种很有前途的治疗策略，因为它们具有替代丢失或功能失调的细胞类型的独特能力。这项研究中提出的工作对公共卫生具有很大的治疗意义，因为它旨在利用干细胞移植来取代导致ALS疾病进展的功能障碍细胞类型，潜在地减缓或阻止疾病。

DESCRIPTION (provided by applicant): Amyotrophic lateral sclerosis (ALS), a motor neuron disorder that affects approximately 30,000 individuals in the U.S. alone, is characterized by relatively rapid degeneration of upper and lower motor neurons, with death normally occurring 2-5 years following diagnosis due to respiratory paralysis. Transplantation of neural precursor cells (NPCs) is a promising therapeutic strategy for treatment of traumatic CNS injury and neurodegeneration, including ALS, because of the ability to replace lost or dysfunctional CNS cell types, provide neuroprotection, and deliver gene factors of interest. Previous NPC transplantation studies in ALS therapy have focused mostly on motor neuron replacement; however, this is a challenging strategy because of problems associated with motor neuron differentiation and establishment of connections with host neurons and musculature. Studies in ALS models have suggested that cellular abnormalities are not limited to motor neurons. Given these observations, this proposal aims to target the replacement of non-neuronal cell types for possible therapeutic benefits. Specifically, the therapeutic potential of Glial-Restricted Precursors (GRPs) - lineage-restricted NPCs whose differentiation is restricted to astrocytes and oligodendrocytes - will be assessed following transplantation into the spinal cord of SOD1G93A rats, a rodent model of ALS. Wild-type GRPs or GRPs engineered to over-express the astroglial glutamate transporter, GL1T1, will be transplanted into the ventral horn of the cervical spinal cord of SOD1G93A rats. In Aim #1, fate of transplanted cells will be examined, including survival, migration, differentiation, and glutamate uptake. In Aim #2, transplant recipient animals will be assessed for a number of phenotypic and pathohistologic measures to determine therapeutic efficacy of transplanted cells. In Aim #3, the ability of transplanted GRPs to specifically rescue diaphragm function will be tested. Lay summary: Amyotrophic lateral sclerosis (ALS or Lou Gehrig's Disease) is a devastating nervous system disorder that results in paralysis and ultimately death due to respiratory failure. Transplantation of stem cells derived from the central nervous system is a promising therapeutic strategy for treatment of brain and spinal cord disorders such as ALS because of their unique ability to replace lost or dysfunctional cell types. The work proposed in this study is of great therapeutic relevance to public health because it aims to utilize transplantation of stem cells to replace dysfunctional cells types that contribute to disease progression in ALS, potentially slowing or halting disease.