LAUSR

Parkinson’s disease (PD), the second most common neurodegenerative disorder after Alzheimer’s disease, is one of the most disabling and therapeutically challenging conditions. Although pharmacological therapy and deep brain stimulation often provide adequate symptomatic relief of most motor and some nonmotor symptoms, there is currently no effective disease-modifying treatment. Replacement of lost dopaminergic neurons with cells derived from adrenal medulla, fetal midbrain tissues, and other sources has been studied for decades as a potential therapeutic approach. However, largely as a result of scientific and ethical barriers, these approaches have not translated into practical therapies for PD. Advances in cell biology have recently led to the development of induced pluripotent stem cells (iPSCs), which have been increasingly investigated as a potential source of dopamine neurons. Autologous, patient-sourced iPSCs have potential advantages over embryonic stem cell or allogenic IPSC approaches as they could eliminate the need for immunosuppressive drugs (Fig. 1). In a recent single case report in the New England Journal of Medicine, Schweitzer and colleagues describe a 69-year-old man with a 10-year history of slowly progressive PD, complicated by mild levodoparelated motor fluctuations (less than 1 hour of off time per day) and no dyskinesia. He was implanted with a total of 4 million cells into each putamen 6 months apart at 2 different institutions. The implants were patient-derived midbrain dopaminergic progenitor cells, differentiated in vitro from autologous iPSCs. The iPSCs were generated from skin biopsy fibroblasts from the patient himself. The final product was, according to the authors, free of serotonergic neurons. This may be important as many experts believe that serotonergic neurons might be responsible, in part, for graft-induced dyskinesia, previously reported in patients undergoing PD cell replacement therapy. There are several troublesome concerns about this report. First, the patient had a relatively moderate disease, uncomplicated by levodopa-related dyskinesia, suggesting that a higher dose of levodopa may have meaningfully improved his motor symptoms without the need for invasive, experimental, therapy. Second, the procedure should not have been performed without an assessment of baseline motor function during the off period (without levodopa for at least 12 hours) prior to the initial implantation, and the patient should have been withdrawn from the protocol prior to surgery for “declining to cease medications.” Third, there was only a modest decline (24%) in his Movement Disorder Society Unified Parkinson’s Disease Rating Scale Part III score (from 43 to 33, on medication change), his levodopa-equivalent dose decreased only 6% (from 904 to 847 mg), and a serial fluorine-18-Ldihydroxyphenylalanine positron emission tomography–computed tomography showed only a modest increase in the fluorine-18-L-dihydroxyphenylalanine uptake in the posterior putamen region bilaterally. Fourth, finally, the lack of a control raises the question of a “placebo effect,” common especially in transplant therapies and potentially explaining the mild benefits. There are also several critically important scientific issues that warrant serious discussion. First, the findings from the N-of-1 uncontrolled study did not provide “a proof of principle.” Second, although the authors stated that “no detectable remaining undifferentiated iPSCs” were present in the final product, a higher standard should be employed. The authors should more directly address the possibility of tumorigenesis or neural overgrowth, which remains the major concern with other stem cell therapies. Might there still be a need for the © 2020 International Parkinson and Movement Disorder Society