PORTLAND, ORE. – Implantation of dopamine-producing cells to replace those lost in the substantia nigra has been seen as the cure for Parkinson’s disease, with many attempts in patients over the years. Along the way, a few successes have occurred, but in general, cell-based therapies have produced mixed results.
“When it works well, it works very well with fetal dopamine cells, but it does not always work well,” said Roger Barker, MBBS, PhD, of the department of clinical neurosciences at the University of Cambridge (England). In his lecture to a large, capacity crowd at the World Parkinson Congress, he reviewed the field going back more than three decades and drew “lessons learned” from the results of animal experiments and human trials.
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He said dopamine-producing cell therapy will never cure the disease, although it works well early in the disease “but creates problems later,” with off-target and nonphysiologic effects in other parts of the brain, such as overstimulation. One exception was the use of fetal dopamine cells in an animal model, showing that cells could survive long-term, connect and integrate into the brain, release dopamine, and restore behaviors to normal if cells from the same species were used at the right developmental stage of the animal and implanted where dopamine normally works, that is, in the striatum.
Other problems reported from human trials using embryonic dopamine neurons or fetal nigral transplants have been graft-induced dyskinesias, but without clinical benefit, as well as Lewy bodies in grafted neurons, suggesting host-to-graft disease propagation. However, in another report, a patient had a clinical benefit and showed extensive graft-derived dopaminergic innervation 24 years after transplantation, at which time the patient died.
Lessons learned over time
Dr. Barker explained that the variable results that have been achieved in various trials using different protocols and nonstandardized approaches over the years make it “extremely difficult to make any conclusions.” These variations included performing tests on different kinds of patients and using different doses of cells, delivery approaches, immunosuppression, primary endpoints of the trials, and levels of follow-up.
The age of the patient, disease stage, and graft technique emerged as key issues in data gathered from the trials, he said. The best chance of success occurred in younger patients with less advanced disease, when grafting occurred across the whole striatum evenly, and when contamination with 5-hydroxytryptamine (serotonin) neurons was avoided.
Going forward, trials in Parkinson’s disease are planned or underway using embryonic/fetal stem cells or adult stem cells. Such cells provide logistical advantages in that their differentiation can be controlled more easily and they are a defined product. Nigral dopaminergic cells can be produced from human embryonic stem cells that behave like human fetal ventral midbrain dopamine cells in vitro and in vivo in rats and show similar efficacy and potency.
The Center for iPS Cell Research and Application in Kyoto, Japan, will conduct a trial using induced pluripotent stem (iPS) cells beginning next year, the New York State Stem Cell Science Consortia (NYSTEM) will use human embryonic stem cells beginning in 2018, and around the same time the European Union’s NeuroStemCellRepair network will also use human embryonic stem cells. In addition, the European TRANSEURO trial, coordinated by Dr. Barker, is planning a single-arm, multicenter, dose-escalation trial for 2018/2019 using intracerebral neurotransplantation of dopaminergic neurons derived from human embryonic stem cells. Participating patients will be younger than 65 years with less than 10 years disease duration, no significant levodopa-induced dyskinesia, and no cognitive or psychiatric problems.
From these trials, scientists hope to eventually produce a human embryonic stem cell–derived dopaminergic cell product made under GMP (good manufacturing practice) conditions that can be tested for safety and efficacy and put into clinical trials, with an ultimate goal of production and commercialization.
Finally, Dr. Barker alerted physicians to published guidance from the International Society for Stem Cell Research that can help them critically evaluate any cell-based clinical trial that they may be asked to run. And for patients, large numbers of whom attended the conference, he advised avoiding any “trial” that would charge them to participate because legitimate research trials do not charge for experimental therapies.
Asked to comment on the field, Peter LeWitt, MD, director of the Parkinson’s Disease and Movement Disorders Program at Henry Ford Hospital, West Bloomfield, Mich., and professor of neurology at Wayne State University, Detroit, said, “The jury is out and is coming back on stem cells and its alternative, such as fetal tissue. It’s pointing to the bright future of restoring the brain and not just using drugs to mask symptoms.”