Transplantation of glial precursors: Astrocyte replacement in ALS

描述（由申请人提供）：肌萎缩性侧索硬化症（ALS）是一种运动神经元疾病，仅在美国就影响约30，000人，其特征在于上和下运动神经元的相对快速变性，通常在诊断后2-5年由于呼吸麻痹而死亡。神经前体细胞（NPC）的移植是用于治疗创伤性CNS损伤和神经变性（包括ALS）的有前景的治疗策略，因为其能够替代丢失或功能障碍的CNS细胞类型、提供神经保护和递送感兴趣的基因因子。先前在ALS治疗中的NPC移植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组织建立连接相关的问题。在ALS模型中的研究表明，细胞异常不仅限于运动神经元。鉴于这些观察结果，该提案旨在靶向替代非神经元细胞类型以获得可能的治疗益处。具体而言，将在移植到SOD 1G 93 A大鼠（ALS的啮齿动物模型）的脊髓中后评估胶质限制性前体（GRP）-分化限于星形胶质细胞和少突胶质细胞的谱系限制性NPC-的治疗潜力。将野生型GRP或经工程改造以过表达星形胶质细胞谷氨酸转运蛋白GL 1 T1的GRP移植到SOD 1G 93 A大鼠的颈脊髓的腹角中。在目标#1中，将检查移植细胞的命运，包括存活、迁移、分化和谷氨酸吸收。在目标#2中，将评估移植受体动物的许多表型和病理组织学指标，以确定移植细胞的治疗功效。在目标#3中，将测试移植的GRP特异性挽救横膈膜功能的能力。敷设总结：肌萎缩侧索硬化症（ALS或Lou Gehrig病）是一种破坏性的神经系统疾病，可导致瘫痪并最终因呼吸衰竭而死亡。移植来自中枢神经系统的干细胞是治疗脑和脊髓疾病（如ALS）的一种有前途的治疗策略，因为它们具有替代丢失或功能障碍的细胞类型的独特能力。本研究提出的工作与公共卫生具有重要的治疗相关性，因为它的目的是利用干细胞移植来取代导致ALS疾病进展的功能失调细胞类型，从而可能减缓或阻止疾病。

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.