Cell Transplant Trials for Parkinson’s Coming
There was an audible gasp at the New York Stem Cell Foundation (NYSCF) conference recently when neurosurgeon Ivar Mendez showed a video of a Parkinson’s patient before and after a transplant of fetal cells. The patient was affectless, and could barely move before the graft. Eight years later, he was animated and moving briskly.
“The patient walks at normal velocity, and there is no indication of Parkinson’s,” Mendez said.
“Very exciting,” said the moderator, NYSCF Research institute neurologist Zach Hall.
Mendez, who is Chairman of the Department of Surgery at the University of Saskatchewan, saw all ten of his patients improve that way. None regressed, he said, interviewed after his talk. In upcoming months he will publish results (updating his earlier published data showing robust cell engraftment in five patients dying of unrelated causes over 20 years.) Meanwhile, he and Harvard University neuroscientist Ole Isacson are gearing up to start preliminary plans for a new Parkinson's trial with even-better cells, immature A9 neurons made from embryonic-like cells created from patients' own cells: induced pluripotent stem cells (IPSCs).
They will not be the first, however. Transeuro, led by University of Cambridge neurologist Roger Barker, has already enrolled many patients for an upcoming multi-site fetal cell European trial, which registered with the NIH this July. The Transeuro grafts will be made of “early differentiated dopamine cells,” says Barker. “We are at the stage of making the last preparations.” About 150 patients will ultimately be enrolled at six European sites.
Both trials will be improved versions of most of the fetal cell trials launched in the 1990’s. Cells will be “evenly distributed across the striatum” in the Transeuro trial, for example, says Barker. The same is true of Mendez and Isacson's, although both the substantia nigra and the striatum will be covered, just as they were in their preliminary ten-patient trial, says Mendez.
The earliest open label trials of the early 1990’s—launched in Lund, Switzerland, England, Spain, the US, Mexico among others—led to two randomized controlled NIH funded trials in Denver and Tampa, which reported on their results in the early 2000’s. All told, the result was “highly variable” clinical efficacy, say Isacson and Mendez. There were many reports of dyskinesias (uncontrolled shaking). But Isacson and Mendez say they learned much from those trials, their own trial, and Isacson's ensuing extensive pre-clinical work with embryonic stem cells and iPSCs, some of which appeared in a poster at the NYSCF conference. A "very encouraging" update is expected to be published next year, says Isacson.
“When we compare our grafts to those in the Colorado and Tampa trials, for example, we see less inflammation in the brain,” Mendez says. One reason: their grafts were more diffuse, as Transeuro's will be. And since the new grafts to be offered by Mendez and Isacson will be made from patients' own cells, there may be no damaging immunosuppressives. Finally: "the exact right cells can be chosen when creating them from IPSCs. I am optimistic that we have the surgical technology now to safely deliver the appropriate cells to the appropriate areas of the human brain,” says Mendez.
The idea behind all immature neural cell grafts is that immature dopamine neurons might hook up in the brains of—and replace degenerated dopamine neurons in—Parkinson’s patients. Cells in these grafts are generally more differentiated, or mature, than stem cells, although there can be lingering stem cells.
Many believe variability of earlier trials was due in part to a lack of standardization across trials and countries. For instance, some trials placed the cells in the putamen, others in the caudate nucleus. There were vast differences in the ages and numbers of cell grafts.
Some conclusions were tentatively drawn. In an analysis appearing in The Lancet this year on the two NIH funded trials, and three of the open label studies, it was noted that younger patients, and less advanced patients, may respond better.
In that article, two theories were advanced regarding dyskinesia cause. One theory was that there were clumps of cells, or “hot spots,” that pumped out too much dopamine. The other was that too-mature neurons were included in the mix, neurons too differentiated to respond sensitively to new environments.
“In the two NIH-sponsored studies –Colorado and Tampa—there were side effects, runaway dyskinesias,” Mendez says. “It is critical that, unlike those trials, we used cell suspensions, not solid tissues which can be immunogenic (arousing inflammation). We also distributed our cells in a more uniform manner, whereas they were localized, creating “hot spots.” Thirdly, we implanted our cells into the substantia nigra and the striatum both (so critical areas need not wait for axon growth to reach them). Finally, we cultured our cells in (healing) neurotrophic factors that helped them grow.”
For years, Mendez followed his patients, and compared them to others receiving Deep Brain Stimulation (DBS). At first, both groups improved at similar rates. But at six years or so, DBS patients began declining. Mendez’s patients continued improving, he says.
Collaborators in the Transeuro group are: University College, London, Imperial College London, Cardiff University, Lund University Hospital, University Medical Center Freiburg, Assistance Publique - Hôpitaux de Paris.
The above Lancet article includes a chart showing that the trial of Mendez and Isacson, and the trial on which Transeruo is based (Lund), fared best among all the best-known of the open access trials, and the NIH trials. "The field is coming back," concludes Isacson.