Successful Function of Autologous iPSC-Derived Dopamine Neurons following Transplantation in a Non-Human Primate Model of Parkinson’s Disease

Abstract

Summary Autologous transplantation of patient-specific iPSC-derived neurons is a potential clinical approach for treatment of neurological disease. Preclinical demonstration of long-term efficacy, feasibility and safety of iPSC-derived dopamine neurons in non human primate models will be an important step in clinical development of cell therapy. Here, we analyzed cynomolgus monkey (CM) iPSC-derived midbrain dopamine neurons for up to 2 years following autologous transplantation in a Parkinson's disease (PD) model. In one animal, with the most successful protocol, we found that unilateral engraftment of CM-iPSCs could provide a gradual onset of functional motor improvement contralateral to the side of dopamine neuron transplantation, and increased motor activity, without a need for immunosuppression. Post-mortem analyses demonstrated robust survival of midbrain-like dopaminergic neurons and extensive outgrowth into the transplanted putamen. Our proof of concept findings support further development of autologous iPSC-derived cell transplantation for treatment of PD.

Enhancement of Striatal Dopaminergic Function Following Autologous Neural Cell Ecosystems (ANCE) Transplantation in a Non-Human Primate Model of Parkinson’s Disease

“…Moreover, embryonic stem cell engraftment raises the issue of tumor formation due to uncontrolled cellular proliferation and ethical controversies [20,21]. Recently, the induced pluripotent stem cell approach showed positive outcomes in NHP MPTP model but these positive results still need to be confirmed [22].…”

Rhesus iPSC Safe Harbor Gene-Editing Platform for Stable Expression of Transgenes in Differentiated Cells of All Germ Layers

“…Nonhuman primate (NHP) induced pluripotent stem cells (iPSCs) have been valuable resources to model iPSC-based cell therapies in clinically relevant settings. [1][2][3][4] The close phylogenetic relationship of NHPs to humans, as well as their size, longevity, and the well-developed understanding of NHP physiology, makes these models very well suited to preclinical iPSC development. The ability to track derivation of tissues from iPSCs is necessary; thus, engineering NHP iPSCs to strongly and stably express reporter genes is desirable for monitoring of autologous or allogeneic transplanted cells in vivo.…”

Stem Cell Applications in Parkinson’s Disease

“…In another primate study, iPSC-derived dopaminergic neurons from cynomolgus monkey were transplanted into a PD monkey model. One monkey showed long-term survival for 2 years and behavioral improvement without any immunosuppression intervention [22]. Thus, autologous transplantation of stem cells may have beneficial clinical application.…”