Human Dopamine Grafts in Alpha-Synuclein Models of Parkinson Disease

帕金森病α-突触核蛋白模型中的人多巴胺移植物

• 批准号: 10736403
• 负责人: VIVIANE TABAR
• 金额: $ 68.98万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10736403
• 关键词: Ablation; Animal Model; Animals; Anti-Inflammatory Agents; Astrocytes; Behavior; Behavioral; Bilateral; Brain; Brain region; CSF1R gene; Candidate Disease Gene; Cell Lineage; Cells; Clinic; Clinical Trials; Collaborations; Complex; Corpus striatum structure; DNA; Data; Deposition; Derivation procedure; Deterioration; Development; Disease; Disease Progression; Disease model; Dopamine Agonists; Environment; Exhibits; Experimental Designs; Gene Expression Alteration; Gene Modified; Generations; Genes; Graft Survival; Histologic; Human; Human Engineering; Immunologic Deficiency Syndromes; Inflammation; Injections; Lewy Bodies; Longevity; Longitudinal Studies; Maps; Methods; Microglia; Midbrain structure; Modeling; Motor; Mus; Mutation; Natural regeneration; Nature; Nerve Degeneration; Neurodegenerative Disorders; Neuroglia; Neuronal Dysfunction; Neurons; Parkinson Disease; Pathogenesis; Pathogenicity; Patients; Persons; Phase I Clinical Trials; Phenotype; Population; Proteins; Regenerative Medicine; Research; Resistance; Resistance development; Role; SNCA gene; Safety; Signal Transduction; Substantia nigra structure; Techniques; Technology; Testing; Therapeutic; Time; Toxic effect; alpha synuclein; base editing; brain cell; cellular engineering; clinical lot; combinatorial; dopamine graft; dopaminergic neuron; glial activation; graft function; human embryonic stem cell; immunoregulation; in vivo; inhibitor; mitochondrial dysfunction; monomer; motor symptom; mouse model; mouse synuclein alpha; mutant; neuroinflammation; neuron loss; neuronal survival; neuropathology; neuroprotection; neurotoxic; neurotoxicity; neurotransmission; novel; pars compacta; pre-formed fibril; predictive modeling; prion-like; regeneration potential; restoration; stem cells; synucleinopathy; tool; transcriptomics; transmission process

ABSTRACT Parkinson's disease (PD) is one of the most common neurodegenerative disorders. It is characterized by the progressive loss of dopamine neurons in the substantia nigra (SN) pars compacta, and their projections onto striatal neurons and the accumulation of α-Synuclein aggregates often into Lewy bodies. The pathogenesis of PD is not fully elucidated but there is vast evidence supporting complex loops of neuroinflammatory cascades, mitochondrial dysfunction, degenerating neurons, sustained microglial activation and other pathophysiological mechanisms that together amplify a relentless progression towards neuronal loss in the nigra and beyond. α- Synuclein (α-S) aggregates are implicated either directly in serving as a template that is transmitted transneuronally and seeding further aggregation, and/or in amplifying the neuroinflammatory loop, leading in both cases to neuronal dysfunction and death. To date, there are no therapeutic options that lead to the regeneration of lost neurons or to the restoration of circuitry. Our group has pioneered the derivation of functional dopamine neurons from human embryonic stem cells (hES) and we have just completed a Phase 1 clinical trial for the bilateral intrastriatal grafting of these cells. There is much excitement about the restorative potential of stem cell derived neurons in PD, but there remain multiple challenges. Here we propose to study the impact of microenvironmental alterations in the brain in the context of 2 different mouse models: the 3K mouse model which expresses a triple mutant form of α-synuclein based on the human E46K mutation, and exhibits histological hallmarks of PD as well as progressive motor and other behavioral abnormalities; the second model consists of the intrastriatal injection of preformed α-synuclein fibrils (PFF) which spread transneuronally through the brain to form pathogenic α-synuclein inclusions, leading to loss of DA neurons and behavioral deterioration. These models are predicated on two different hypotheses and will serve as great tools to study inflammation and its impact on behavior. In addition, we will graft the mice with the same hES cell derived dopamine neurons used in the clinical trial to analyze the impact of the microenvironment on the neurons' survival and phenotype, as well as on their ability to rescue behavior. We will capture grafted cells as well as host microglia and astrocytes at key timepoints during the in vivo lifespan of the grafts to establish dynamic maps of cell lineages, maturation, microglial and astrocytic phenotypes and potentially activation of neurotoxic signals. In the last aim, we will engineer the human ES cells to delete the SNCA gene encoding α-synuclein in an attempt at increasing the resistance of the grafts to neurotoxicity and potentially the transmission of pathogenic α- synuclein. Data obtained in this proposal will serve to further enhance our understanding of neuro-inflammation in different PD microenvironments and could result in enhanced strategies for cell grafting including the use of gene edited cells that are resistant to neuroinflammation.

摘要