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Long Term Success Brings Autologous iPSC-Derivatives Closer to the Clinic



Review of “Successful Function of Autologous iPSC-Derived Dopamine Neurons following Transplantation in a Non-Human Primate Model of Parkinson's Disease” from Cell Stem Cell by Stuart P. Atkinson.

Using patient-specific human induced pluripotent stem cell (hiPSCs)-derived cells as a cell replacement therapy moves closer and closer to widespread clinical application with each passing day. Several studies have reported on the successful autologous transplantation of iPSC-derived dopamine neurons in the short term [1-3], and now, in order to demonstrate preclinical long-term efficacy, feasibility, and safety of iPSC-derivatives, the group of Ole Isacson (Harvard) has assessed the transplantation of autologous iPSC-derived dopamine neurons in a non-human primate model of Parkinson’s disease (PD). Their encouraging findings, reported recently in Cell Stem Cell, further support the further development of iPSC-derived cell replacement therapy [4]. 

The researchers assessed three cynomolgus monkeys (CMs) treated with systemic low-dose 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to induce a stable bilateral parkinsonian syndrome, followed by the autologous transplantation of CM-iPSC-derived neural cells into one side of the brain (putamen) without immunosuppression. In one animal (MF25-04), the group saw a 188% increase in daylight activity at two years, accompanied by a significant increase in upper limb function in one arm (contralateral to the graft) alongside a significant reduction in parkinsonian signs. Dopamine neuron-specific imaging found signals indicative of functional dopaminergic neurons on the side of the brain which received iPSC-derived cells at two years, and post-mortem examination found good evidence of robust re-innervation of the transplanted putamen from the engrafted CM-iPSC-derived dopaminergic neurons. Dopamine neuron enumeration in both the successful CM and the two animals with no functional improvements found that a higher level of surviving transplanted dopaminergic neurons with a far more extensive dopaminergic re-innervation in the putamen correlated to success. Further labelling studies confirmed the presence of high levels of midbrain-like dopamine neurons in the MF25-04 CM which demonstrated mature synapses, and also the presence of serotonergic neurons and striatal medium spiny GABAergic neurons. Importantly, the group found no sign of an immune or inflammatory response in the graft site, no graft overgrowth, and no tumor formation.

This study suggests for the first time that this autologous transplantation strategy is viable in the long-term, although requires the survival of large amounts of cells to lead to functional improvements. Strategies to improve cell survival or strategies to boost the amount of transplantable cells available will both improve further transplantation efforts and towards any potential future clinical trials.


  1. Emborg ME, Liu Y, Xi J, et al. Induced pluripotent stem cell-derived neural cells survive and mature in the nonhuman primate brain. Cell reports 2013;3:646-650.
  2. Morizane A, Doi D, Kikuchi T, et al. Direct comparison of autologous and allogeneic transplantation of iPSC-derived neural cells in the brain of a non-human primate. Stem Cell Reports 2013;1:283-292.
  3. Sundberg M, Bogetofte H, Lawson T, et al. Improved cell therapy protocols for Parkinson's disease based on differentiation efficiency and safety of hESC-, hiPSC-, and non-human primate iPSC-derived dopaminergic neurons. Stem Cells 2013;31:1548-1562.
  4. Hallett PJ, Deleidi M, Astradsson A, et al. Successful Function of Autologous iPSC-Derived Dopamine Neurons following Transplantation in a Non-Human Primate Model of Parkinson's Disease. Cell Stem Cell 2015;16:269-274.