Zhuang-Yao Daniel Wei

Introduction. Parkinson’s Disease (PD) is the second most common neurodegenerative disorder and is characterized by degeneration of the substantia nigra pars compacta dopamine neurons (DN).^1,2 The loss of neurons gives rise to some of the PD symptoms: bradykinesia, tremors, and walking difficulties. The patient’s symptoms are treated with medications to supplement dopamine or reduce degradation; however, the loss of DNs is still permanent.³ Fortunately, research into stem cells has shown a way to generate dopamine neurons to be transplanted. Somatic cells can be taken from the patient and reprogrammed with episomal vectors into a human induced pluripotent stem cell (hiPSC). These stem cells can be differentiated into DNs and grafted back into the patient.^4-6 Methods. hiPSCs were generated from healthy humans and humans with PD using episomal vectors and differentiated into DNs following floorplate neuroembryological development. The neurons were confirmed to express appropriate midbrain markers. Monkeys were then treated with MPTP to induce PD and transplanted with DNs. The monkeys were studied with MRI and PET studies as well as neurological rating scale and spontaneous movement studies. The grafts were then evaluated postmortem.⁶ Results. Pre-transplantation, the neurons expressed appropriate midbrain markers: FOXA2, NURR1 and βIII tubulin. There was no difference between neurons derived from healthy humans and humans with PD. Post-transplantation, the monkeys had improvements in PD score and spontaneous movement. When compared to L-DOPA, the therapeutic effects were found to be comparable. PET studies showed increased dopamine synthesis and dopamine transporter 21 months post transplantation. Postmortem, the grafts continued to express appropriate midbrain markers: TH, GIRK2, and FOXA2, with outgrowth of the graft into the host putamen. There was no difference between grafts from healthy humans and humans with PD after two years.⁶ Conclusion. It is possible to derive DNs from healthy hiPSCs and PD hiPSCs. Monkey models showed improvement after transplantation, as well as survival of the graft after two years. The grafted DNs were shown to expand into the host brain as well. PD was once thought to be an untreatable disease, with only symptomatic treatment available to curb the symptoms. However, stem cells now provide a way for patients to regenerate their degenerated dopamine neurons, from their own somatic cells. A clinical trial is currently underway where hiPSC derived DNs are injected into multiple human patients, who have shown improvement. More trials are required to ensure the safety and efficaciousness of stem cell therapy for PD.⁵

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