Long-Awaited, Global Trial of Fetal Cells for Parkinson’s

In two months, the first of many new Parkinson’s disease (PD) patients will receive a fetal cell transplant. The transplant will mark the end of a voluntary moratorium by many Western nations after complications arose a decade ago.

This, combined with news that embryonic stem (ES) cell PD therapies may also near prime-time, made Parkinson’s a big topic at the recent International Society for Stem Cell Research (ISSCR) meeting.

"Amazing success stories are coming out in the literature and starting to come toward the clinic," said Janet Rossant, outgoing ISSCR president.

The new multi-center, open-label, fetal cell TRANSEURO PD trial is enrolling 150 patients, Principle Investigator Roger Barker of the University of Cambridge told the ISSCR presser. It is sponsored by the European Union.

TRANSEURO will mimic, in key ways, specific earlier trials, Barker told Bioscience Technology via email. Those earlier trials have produced, over time, “quite remarkable sustained effects,” Memorial Sloan Kettering neurologist Lorenz Studer told the conference. TRANSEURO will try to avoid less successful tactics of other earlier trials.

 Voluntary Moratorium

A voluntary moratorium was placed, in many nations, on fetal cell transplants for PD in 2003, after the publication of mixed results from two double-blind, placebo-controlled clinical trials with fetal tissue cells. For 10 to 20 years prior, results were varied from small open label trials. But the general impression was one of success.

The placebo-controlled trials—the gold standard, in principle—shattered that image, finding too many patients may suffer from severe dyskinesias (robust shaking) post-treatment.

The point of the trials had been to replace dopamine neurons lost in PD with neural cells derived from fetal substantia nigra grafts and with this give them smoother motor control.

Worldwide, scientists and doctors stepped back to reassess.

 “Transformed Lives”

In recent years, there has been good news about those earlier trials.  It was reported in The Lancet last year trials from Saskachewan/Halifax, Canada and Lund, Sweden produced a number of patients doing well, years out. Younger, healthier patients were among those.

That review noted earlier variable results may have been partly due to grafts containing too many of the wrong cell types, in too many stages, or transplanted in a way that produced dopamine “hot spots."

This January, a JAMA Neurology paper found that two Lund patients (from the UK, grafted in Lund, followed in the UK) receiving grafts 15 and 18 years ago were doing stunningly well. They were no longer on medication. Said a JAMA perspectives piece: “Among the cohort of 18 patients in the Lund study…there were substantial differences in short-term motor outcomes between patients, and long-term follow-up data could be obtained on only a few.”

But in two patients, said the primary paper: “Motor improvements gained gradually over the first postoperative years were sustained up to 18 years post-transplantation, while both patients have discontinued, and remained free of any, pharmacological dopaminergic therapy…Dopaminergic cell transplantation can offer very long-term symptomatic relief.”

The perspectives piece, by Northwestern University neurologists Dimitri Krainc and Danny Bega, called this “important and unexpected.”

Agreed Barker: “If you follow these patients over time—remember these are cell-based therapies, not drugs, so they work after years not weeks—you can see dramatic results....We have in that study two patients transplanted 20 odd years ago who have almost no features of Parkinson’s today. They are on no medications. The transplants have transformed their lives. Thirty years into their illness, they have a motor-score less what they presented to neurologists in the late 1980s. So when it works, it works extremely well. It just doesn’t work consistently.”

TRANSEURO will mimic the Lund trial in key ways, Barker told Bioscience. The cells will be prepped “essentially the way they were in Lund.” They will be “early differentiated dopamine cells, derived from primary fetal brain without manipulation. (And) the technique for delivery ensures they are evenly distributed across the striatum.”

The idea behind early differentiated cells: they are mature enough to have stopped proliferating; immature enough to be sensitive to new niches. They have not yet grown axons. Transplanted with axons, “they die,” said Barker via email.

Ivar Mendez, the doctor behind the other trial hailed in The Lancet (the Saskachewan/Halifax trial), notes that a June 2014 Cell Reports study shows that all five of the patients who died in his trial-- of causes unrelated to Parkinson's--saw their new cells last to the end, up to 14 years. The new neurons were healthy, with normal mitochondria and robust expression of dopamine transporters. "This is very relevant to the TRANSEURO trial," he told Bioscience in an email.

 ES Cells: the Future?

Going forward, TRANSEURO will work with the G (“global”) Force. Comprised of transplantation experts in Japan, Europe, and North America, G Force will establish standards to avoid variability. The group met for the first time in May.

But, Barker told the ISSCR: “Human ES cells are the likely future source” for transplants, noting Studer makes neurons from ES cells “that really look like substantia nigra dopamine cells.”

ES cells come from spare in vitro fertilization (IVF) clinic embryos which IVF couples store. They are the earliest cells, proliferative and pliable, able to create all body cells. A few ES cells from an IVF clinic creates endless quantities of neurons. Fetal tissue cells of the age used for standard grafts transplants, by contrast, are weeks along, more differentiated, set in their ways, less proliferative. Fetal grafts are seen as more controversial than ES cells, coming from abortion clinics.

(Another, intermediate option is highly purified, dissociated fetal progenitor cells, which like ES cells can generate endless neurons. NeuralStem and Stem Cells Inc. conduct FDA-approved trials with those cells for other disorders.)

When Studer reached the ISSCR podium, he confirmed his human ES cells may be in trial by “early 2017.”

Studer said for years he could relieve PD symptoms in mice with dopamine neurons made from mouse ES cells. But human neurons wouldn’t engraft. Then in 2011, his team discovered, by changing differentiation techniques, they could “rather quickly” create human dopamine neurons that “survived long-term, and caused functional recovery in mouse, rat, and primate models.” After a month in primates, his team saw “quite promising outgrowth into rhesus monkey brain.”

“Magic” Cell Numbers

Studer’s team also found they could easily scale-up production of ES-derived cells to the “magic” PD transplant number of “100,000 surviving dopamine neurons per patient.” His team independently found the best maturation stage for transplant is “young neuron.”

Studer said ES cells enable transplant of purer concentrations of dopamine neurons than fetal grafts. This may matter. Fetal grafts can contain serotonergic neurons that may prompt dyskinesias. The team minimizes contamination by directing cells to a dopamine fate, checking for dopamine markers. Types of dopamine cells are sorted by behavior, as they mimic developmental behavior.

Many primate studies confirm long-term survival and engraftment, Studer said. “Once in the brain, it is quite remarkable how closely those cells mimic the normal developmental structure of a dopamine neuron.” They integrate well. Viewing MRI’s of dopamine neurons from fetal and ES cells, “pathologists could not distinguish the morphology.” He adds enzymes maximizing axon growth. “We have the right cells, and the right number for translation,” he said.

Like Studer, Barker plans, with Lund, to move on to trials with human ES cells.

Two more notable transplant trials planned involve the first use of induced pluripotent stem (iPS) cells for PD. One, helmed by Jun Takahashi of the Center for iPS Cell Research and Application, may launch in two years. The University of Saskatchewan’s Ivar Mendez plans another.

TRANSEURO centers: University College London; Imperial College London; Cardiff University; Lund University Hospital; University Medical Center Freiburg; and Assistance Publique-Hôpitaux de Paris.