Journal Article

Autologous transplant therapy alleviates motor and depressive behaviors in parkinsonian monkeys

Block, Walter F., Olsen, Miles, Bondarenko, Viktoriya, Vermilyea, Scott C., Holden, James E., Simmons, Heather, Schultz-Darken, Nancy, Christian, Bradley T., Zhang, Su-Chun, Barnhart, Todd E., Phillips, Sean, Brunner, Kevin, Zammit, Matthew, Lu, Jianfeng, Yao, Lin, Tao, Yunlong, Chen, Yuejun, Metzger, Jeanette M., Emborg, Marina E.

2021

Overview

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 PD 1 . 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. Rescue of motor and behavioral deficits in a primate model of Parkinson’s disease following autologous transplantation of iPSC-derived dopaminergic neural progenitors without immunosuppression.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/378/1689/1718 / 631/532/1360 / 631/532/2182 / 692/617/375/1718 / Animals / Autografts / Basal ganglia / Behavior / Behavior, Animal / Biomedical and Life Sciences / Biomedicine / Cancer Research / Central nervous system diseases / Clinical trials / Degeneration / Depression - complications / Dihydroxyphenylalanine / Dopamine / Dopamine - metabolism / Dopamine receptors / Fetal Tissue Transplantation / Fetuses / Immunosuppression / Induced Pluripotent Stem Cells - metabolism / Infectious Diseases / Inflammation - pathology / Letter / Levodopa / Linear Models / Macaca mulatta / Male / Mathematical models / Mesencephalon / Mesencephalon - transplantation / Metabolic Diseases / Mice / Model testing / Molecular Medicine / Monkeys / Monkeys & apes / Motor Activity / Movement disorders / Neural stem cells / Neurodegeneration / Neurodegenerative diseases / Neurons / Neurosciences / Parkinson Disease - complications / Parkinson Disease - physiopathology / Parkinson Disease - therapy / Parkinson's disease / Pathogenesis / PD-1 protein / Pluripotency / Positron emission / Positron emission tomography / Primates / Recovery / Robustness (mathematics) / Signs and symptoms / Stem cell transplantation / Stem cells / Tomography / Transplantation / Transplantation, Autologous / Transplantation, Homologous / Transplants & implants / Tyrosine 3-Monooxygenase - metabolism