Stem Cell Therapy Shows Early Promise in Parkinson’s Disease

Stem cell-derived dopamine cell transplantation appears to be a feasible approach to replacing dopamine-producing neurons lost in Parkinson’s disease (PD), although its long-term clinical benefit and safety remain uncertain.In a small phase 1/2 open-label study involving eight patients, transplanted human embryonic stem cell-derived dopamine progenitor cells survived in the brains of some patients with PD and did not lead to tumor formation or abnormal tissue growth. Seven patients remained clinically stable over 12 months, and six substantially reduced their dopaminergic medication.“The possibility of replacing dopamine neurons that are lost in Parkinson’s disease has been a long-standing goal in the field,” Malin Parmar, PhD, professor of cellular neuroscience at Lund University in Lund, Sweden and lead of the STEM-PD program, said in a statement.“The findings represent an important milestone for regenerative medicine approaches in Parkinson’s disease and support continued clinical development of stem cell-based therapies,” Parmar added.The study was published online on July 9 in Nature Medicine.Replacing Lost NeuronsPD is characterized by the progressive loss of neurons that produce dopamine. Current treatments such as levodopa alleviate symptoms but often become less reliable as the disease progresses and can cause complications including dyskinesia. Cell-based therapies aim to restore dopaminergic function by replacing the neurons lost to the disease.As previously reported by Medscape Medical News, two research groups found that dopamine-producing cells derived from embryonic or induced pluripotent stem cells could be transplanted into patients with PD, with imaging evidence of graft survival and preliminary indications of motor benefit.Parmar and colleagues evaluated STEM-PD, a cryopreserved, off-the-shelf dopaminergic progenitor product derived from human pluripotent stem cells. The cells are intended to mature into dopamine-producing neurons after being implanted bilaterally into the putamen.Eight adults (median age, 63 years) who had PD for a median of 14.5 years received the transplanted cell product at two different doses — a lower dose of approximately 3.5 million cells per putamen or a higher dose of about 7.1 million cells per putamen.Because the cells came from a donor cell line, participants received tacrolimus, azathioprine, corticosteroids, and induction therapy to prevent immune rejection. Immunosuppression continued for 12 months and was tapered off over the following 3 months.Safety Tempered by Fatal InfectionSeven patients completed the 12-month follow-up. One patient in the higher-dose group died 10 weeks after transplantation from disseminated pulmonary aspergillosis while receiving triple immunosuppression. Investigators considered the infection related to immunosuppressive treatment and unlikely to be related to the transplanted cells.Two other serious adverse events, involving transient worsening of parkinsonian symptoms and visual hallucinations, resolved.No serious adverse events were attributed to the transplanted cells or delivery device. Serial MRI showed no evidence of tumors or abnormal tissue growth, and no graft-induced dyskinesias were observed.“The surgery and cell product were generally well tolerated,” the investigators wrote, but the fatal infection underscores that immunosuppression accompanying allogeneic cell transplantation “can come with a risk of opportunistic infections.”Early Clinical SignalsDopamine PET imaging provided early evidence of graft survival at 6 and 12 months. The signal was generally greater in the higher-dose group, but dopamine activity was not restored to normal levels.Six of the seven surviving participants substantially reduced their dopaminergic medication. Levodopa-equivalent daily dose fell by approximately 16% in the lower-dose group and 28% in the higher-dose group. Patients receiving the higher dose also reported an increase in daily “on” time without troublesome dyskinesia and a reduction in “off” time.The researchers said the medication reductions should be interpreted cautiously because trial investigators were permitted to adjust therapy according to clinical need, and the reductions were not consistently accompanied by better off-medication motor scores. The study was open-label, single-arm, and included only eight participants, limiting conclusions about efficacy, they noted.Follow-up of the seven trial participants will continue through 3 years to assess longer-term safety, graft maturation, reinnervation, and possible clinical benefit. In addition, a larger phase 2 study is planned.Meaningful Progress, Cautious Optimism“This study is another important step forward for stem cell therapy in Parkinson’s disease. It strengthens the growing evidence that replacing lost dopamine-producing cells is scientifically feasible and can be performed safely in carefully selected patients,” said Michael Okun, MD, medical advisor of the Parkinson’s Foundation.Okun said one of the most important advances in this trial is the use of an “off-the-shelf” stem cell product. That means the cells are manufactured in advance, carefully evaluated, frozen, and ready when a patient needs them.“For persons with disease, ‘off-the-shelf’ means greater potential accessibility. If these therapies ultimately prove effective, they could be delivered to many more people without the months of waiting required to manufacture personalized cells,” Okun told Medscape Medical News.He noted that one of the biggest lessons from the study is that many of the serious risks came from the immunosuppressive medications required to protect donor cells, rather than from the transplanted cells themselves. “The challenge now is not simply getting new dopamine cells into the brain. It is learning how to maximize their survival, integration, long-term function, and safety,” Okun said.He added that several independent early-stage clinical trials of stem cell therapy for PD are now pointing in the same direction. “That growing consistency gives us increasing confidence that stem cell replacement deserves continued careful investigation,” he said.Still, he urged families to view the results with “cautious optimism,” noting that the treatments remain experimental and require longer follow-up to determine who benefits and for how long.Still, Okun urged patients and families to view the findings with “cautious optimism,” emphasizing that the therapy remains experimental and will require longer follow-up to determine who benefits and for how long.“Stem cell therapy has moved beyond the laboratory and into carefully conducted human clinical trials. That represents meaningful progress, but it does not represent a cure,” he said.The study was conducted in collaboration with Novo Nordisk A/S. Cellular Intelligence recently acquired the STEM-PD program and will lead its next phase of clinical development, including a planned phase 2 trial. The STEM-PD cells and their continued development hold IND clearance with FDA fast track designation. Disclosures for the authors are available with the original study publication. Okun reported being the author of The Parkinson’s Plan.