期刊
NATURE MEDICINE
卷 27, 期 4, 页码 -出版社
NATURE PORTFOLIO
DOI: 10.1038/s41591-021-01257-1
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资金
- National Institutes of Health-National Institute of Neurological Disorders and Stroke [NS076352, NS096282, NS086604]
- Eunice Kennedy Shriver National Institute of Child Health and Human Development [U54 HD090256, P51OD011106]
- National Medical Research Council of Singapore [MOH-000212, MOH-000207]
- Dr. Ralph & Marian Falk Medical Research Trust
- University of Wisconsin-Madison Office of Vice Chancellor for Research and Graduate Education
- Cellular and Molecular Pathology Graduate Program
- Neuroscience Training Program
- Departments of Radiology and Medical Physics at the University of Wisconsin-Madison
The degeneration of dopamine neurons in the midbrain is the underlying cause of Parkinson's disease. While fetal mesencephalic tissue transplantation can improve motor symptoms, the outcomes vary due to undefined and unstandardized donor tissues. Induced pluripotent stem cells offer a potential autologous transplantation therapy for PD, but its efficacy remains uncertain, especially in primates.
Degeneration of dopamine (DA) neurons in the midbrain underlies the pathogenesis of Parkinson's disease (PD). Supplement of DA via L-DOPA alleviates motor symptoms but does not prevent the progressive loss of DA neurons. A large body of experimental studies, including those in nonhuman primates, demonstrates that transplantation of fetal mesencephalic tissues improves motor symptoms in animals, which culminated in open-label and double-blinded clinical trials of fetal tissue transplantation for PD1. Unfortunately, the outcomes are mixed, primarily due to the undefined and unstandardized donor tissues(1,2). Generation of induced pluripotent stem cells enables standardized and autologous transplantation therapy for PD. However, its efficacy, especially in primates, remains unclear. Here we show that over a 2-year period without immunosuppression, PD monkeys receiving autologous, but not allogenic, transplantation exhibited recovery from motor and depressive signs. These behavioral improvements were accompanied by robust grafts with extensive DA neuron axon growth as well as strong DA activity in positron emission tomography (PET). Mathematical modeling reveals correlations between the number of surviving DA neurons with PET signal intensity and behavior recovery regardless autologous or allogeneic transplant, suggesting a predictive power of PET and motor behaviors for surviving DA neuron number.
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