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IPS cell-based therapy for Parkinson's disease: A Kyoto trial.

ABSTRACT: Following intensive efforts since their discovery little more than 10 years ago, cell replacement therapy using induced pluripotent stem (iPS) cells is now becoming reality. However, there remain several obstacles in the translation of basic research to clinical application, obstacles known as the "Valley of Death". With regards to regenerative medicine using iPS cells for Parkinson's disease, we have developed a method for the 1) efficient induction of dopaminergic neurons from human iPS cells and 2) sorting dopaminergic progenitor cells using a floor plate marker, CORIN. The grafted CORIN⁺ cells survived well and functioned as midbrain dopaminergic neurons in the Parkinson's disease model rats and monkeys, and showed minimal risk of tumor formation. Based on these results, we performed a pre-clinical study using a clinical-grade iPS cell line and finally started a clinical trial to treat Parkinson's disease patients in August 2018. Here, I discuss the key issues to crossing the Valley of Death: scientific rationale, pre-clinical study, and clinical trial.

SUBMITTER: Takahashi J

PROVIDER: S-EPMC7794047 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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iPS cell-based therapy for Parkinson's disease: A Kyoto trial.

Takahashi Jun J

Regenerative therapy 20200301

Following intensive efforts since their discovery little more than 10 years ago, cell replacement therapy using induced pluripotent stem (iPS) cells is now becoming reality. However, there remain several obstacles in the translation of basic research to clinical application, obstacles known as the "Valley of Death". With regards to regenerative medicine using iPS cells for Parkinson's disease, we have developed a method for the 1) efficient induction of dopaminergic neurons from human iPS cells ...[more]

PMID: 33490319

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Project description:While astrocytes, the most abundant cells found in the brain, have many diverse functions, their role in the lysosomal storage disorder Gaucher disease (GD) has not been explored. GD, resulting from the inherited deficiency of the enzyme glucocerebrosidase and subsequent accumulation of glucosylceramide and its acylated derivative glucosylsphingosine, has both non-neuronopathic (GD1) and neuronopathic forms (GD2 and 3). Furthermore, mutations in GBA1, the gene mutated in GD, are an important risk factor for Parkinson's disease (PD). To elucidate the role of astrocytes in the disease pathogenesis, we generated iAstrocytes from induced pluripotent stem cells made from fibroblasts taken from controls and patients with GD1, with and without PD. We also made iAstrocytes from an infant with GD2, the most severe and progressive form, manifesting in infancy. Gaucher iAstrocytes appropriately showed deficient glucocerebrosidase activity and levels and substrate accumulation. These cells exhibited varying degrees of astrogliosis, Glial Fibrillary Acidic Protein (GFAP) up-regulation and cellular proliferation, depending on the level of residual glucocerebrosidase activity. Glutamte uptake assays demonstrated that the cells were functionally active, although the glutamine transporter EEAT2 was upregulated and EEAT1 downregulated in the GD2 samples. GD2 iAstrocytes were morphologically different, with severe cytoskeletal hypertrophy, overlapping of astrocyte processes, pronounced up-regulation of GFAP and S100?, and significant astrocyte proliferation, recapitulating the neuropathology observed in patients with GD2. Although astrocytes do not express ?-synuclein, when the iAstrocytes were co-cultured with dopaminergic neurons generated from the same iPSC lines, excessive ?-synuclein released from neurons was endocytosed by astrocytes, translocating into lysosomes. Levels of aggregated ?-synuclein increased significantly when cells were treated with monomeric or fibrillar ?-synuclein. GD1-PD and GD2 iAstrocytes also exhibited impaired Cathepsin D activity, leading to further ?-synuclein accumulation. Cytokine and chemokine profiling of the iAstrocytes demonstrated an inflammatory response. Thus, in patients with GBA1-associated parkinsonism, astrocytes appear to play a role in ?-synuclein accumulation and processing, contributing to neuroinflammation.

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IPS cell-based therapy for Parkinson's disease: A Kyoto trial.

Publications

iPS cell-based therapy for Parkinson's disease: A Kyoto trial.

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