LAUSR

We appreciate the opportunity to respond to the Viewpoint by Drs. Jankovic, Okun, and Kordower referencing our recent publication in the New England Journal of Medicine on the use of autologous skin cells, reprogrammed via induced pluripotent stem cell (iPSC) technology as dopaminergic precursors, for cell replacement in a patient with idiopathic Parkinson’s disease. The humanized mouse model was a test not of efficacy, but of the hypothesis that the autologously derived transplant would not be rejected in the absence of immunosuppression. We have previously published both the scientific rationale for our approach and an extensive genetic and cell biological characterization of the cell line used, including whole-genome sequencing and screening for oncogenic mutations, a detailed cell differentiation protocol, and rigorous animal safety (including tumorigenesis screening) and efficacy testing prior to transplantation, the latter coauthored by Dr. Kordower. This preclinical publication characterizing the cell line used in our New England Journal of Medicine article has been independently cited for its transparency and rigor by experts in cell therapy. Given the first-in-human nature of this treatment, the cell product chosen for transplantation was prepared in an established Good Manufacturing Practices (GMP) facility (Dana Farber/Harvard) with detailed safety release criteria and was conservative both in the number and maturity of the cells transplanted. The goal of the case report was to show feasibility, not to definitively test efficacy. Moreover, we explicitly addressed the importance of considering the placebo effect, noting that perceived clinical benefit should be interpreted with caution, given lack of blinding, no control arm, and limited 2-year follow-up. We proposed that this would be best evaluated in a randomized, controlled trial. As the most accepted noninvasive means of assessing graft viability, the observed increase in F-DOPA PET was readily detectable, particularly in the posterior putamen at the transplantation sites (Fig. 1). US Food and Drug Administration (FDA) Expanded Access is expressly intended for patients with “a serious disease or condition,” not just those that are immediately lifethreatening (https://www.fda.gov/news-events/public-healthfocus/expanded-access). The authors speculated that other FDA-approved treatments, which had been extensively discussed with the patient, may have been preferable. However, the patient’s disability had not been adequately relieved by oral medications, and DBS had been discussed repeatedly but not pursued by the patient. The authors raise important questions about the ethics of patient-supported research, complexities of stem cell research and public expectations. We share their concerns about stem cell tourism and are careful to distinguish our work from it. These issues were addressed proactively throughout the approval process, including extensive review by the FDA and two independent institutional review boards. We have further benefited from presenting our work at GForce-PD, an international meeting of leading experts in cell therapy for Parkinson’s disease that include Dr. Kordower in the years prior to publication and have appreciated the vigorous discussion about the scientific, technical, and ethical aspects of various approaches to cell therapy for Parkinson’s disease. We agree with the authors that “iPSCs, when rigorously studied scientifically and clinically, hold promise for future research.” We look forward to ongoing efforts to bring a new therapeutic approach to Parkinson’s disease.