Second Thoughts on Out-of-Favor Parkinson’s Disease Treatment

Monday October 06, 2014

A Small Number of Patients With Fetal-Cell Transplants Are Thriving Two Decades Later

Shirley S. Wang

Wall Street Journal - Several patients with Parkinson’s disease who received brain-tissue transplants from fetuses in the early 1990s have needed little or no medicine to treat the disease ever since—an outcome virtually unheard of in the course of the disease, researchers have found.

The results are particularly striking because the treatment is controversial and has been questioned by some researchers in the field.

Bolstered by these promising cases, 14 European hospitals, research institutions and companies have launched a new, controversial trial on fetal-cell transplants, known as Transeuro. Funded with a $15 million grant by the European Union, surgeons in Cambridge, England, are expected to perform their first transplant on a trial participant by year’s end. It would be the first since the 1990s.

WHERE FETAL CELLS MIGHT HELP

A fetal-cell transplant is an experimental technique in which healthy cells from fetuses are implanted into people with disease. The treatment has been considered for potential use in the following conditions:

•   Parkinson’s disease

•   Alzheimer’s disease

•   Huntington’s disease

•   Multiple sclerosis

The debate primarily stems from two U.S. government-funded clinical trials that found such transplants didn’t significantly benefit the overall group of participants. There are also risks: Some patients developed involuntary movements that could be severe.

But some European researchers have challenged aspects of the U.S. trials for years. They argue that the scientific community prematurely dismissed the idea of fetal-cell transplants for Parkinson’s. The disease is a condition in which certain brain cells are damaged and die off, causing movement problems, tremors and other symptoms. It affects 6.3 million people world-wide, according to the European Parkinson's Disease Association.

The use of human fetuses in research has been a hotly debated topic, with moratoriums issued in the U.S. for federal funding of fetal tissue and stem-cell research at times over the past 40 years. Critics suggest that a demand for fetal tissue might encourage abortion. The U.S. federal government is now allowed to fund embryonic stem-cell research.

The idea of replenishing damaged cells with fresh, healthy ones to treat or even cure disease has been a scientific dream. But progress has been slow. The Transeuro trial will test whether cell therapy—in this case transplanted dopamine cells—may help Parkinson’s patients above and beyond current medications and brain-stimulation techniques.

In the trial, doctors take brain cells that make dopamine, a neurotransmitter depleted in Parkinson’s, and implant them into different areas of an adult brain through a small hole in the skull. The goal is for the cells to grow normally. The brain tissue—an amount smaller than the size of a walnut—is taken from fetuses that were aborted and would be otherwise discarded.

Scientists hope that as cell-therapy science continues to advance, the treatment will shift to using stem cells rather than fetal tissue. Stem cells provide a renewable source of cells and are more versatile, able to differentiate into any type of cell. Some types can exist in adults, but they need to be coaxed or programmed into nerve cells that produce dopamine.

If the Transeuro trial shows that patients gain improvements after the transplant with reduced side effects, “there’s a future for stem cells” with the disease, says Stanley Fahn, a neurology professor at Columbia University in New York who was the co-primary investigator on one of the two National Institutes of Health-funded transplant trials in the 1990s.

The current mainstay of treatment is a medication called levodopa, which boosts dopamine in the brain. Long-term, however, levodopa use tends to induce uncontrollable involuntary movements known as L-dopa-induced dyskinesia. It also only tends to work for part of the day.

Deep-brain stimulation, or DBS, which sends a small amount of electric current into a strategic nerve center that controls movement, appears to be a better option. Not all people, however, can or want to undergo DBS, and its effects can be modest.

Some experts have serious concerns about how useful the Transeuro results will be because it lacks a control group, which is typically a requirement in a high-quality clinical trial. That means participants and the researchers could be affected by bias, perhaps unconsciously, says C. Warren Olanow, a neuroscience professor at New York’s Icahn School of Medicine at Mount Sinai who led the other U.S. trial.

In addition, Parkinson’s research in the last decade or more has found that other cells, not just dopamine neurons, are involved in the disease. The transplant presumably wouldn’t improve symptoms caused by those other cells.

University of Cambridge neuroscience professor Roger Barker is coordinator of Transeuro. UNIVERSITY OF CAMBRIDGE

Roger Barker, the coordinator of Transeuro and a clinical neuroscience professor at University of Cambridge , acknowledges the concerns. Instead of having a control group, all participants will be matched with patients of similar disease severity and age and videotaped while wearing caps to hide any signs of the cell transplants. The videos will be assessed for changes in symptoms and behavior by independent raters who won’t know who received the transplant.

The transplant would likely only benefit a subset of people with Parkinson’s and wouldn’t necessarily improve all the symptoms associated with the disease, Dr. Barker says. He adds that the coming transplants will improve on the previous ones by implanting more dopamine cells relative to other types of cells, hopefully reducing side effects. This study also involves younger patients with less advanced disease who are likely to respond.

Doctors must use great caution with cell therapy. Once fetal tissue cells are implanted, they can’t be controlled or easily removed. In the past, some patients experienced involuntary movements that developed from the transplant, known as graft-induced dyskinesia. Further treatment can make it more mild but it can’t be easily reversed, and there are other potential secondary risks.

In the two U.S. trials, which consisted of 34 and 40 patients each, brain scans showed that the transplanted dopamine cells did survive. But it wasn’t clear whether the cells integrated into the brain circuits normally, Dr. Olanow says.

The transplant didn’t have any substantial effect in any patients over age 60, Dr. Fahn says of his study with Curt Freed, a medicine professor at the University of Colorado, Denver. In contrast, several of the younger cases did benefit and were able to come off or reduce their medication eventually.

Dr. Fahn still sees one participant in his clinical practice who continues to do well while taking a lowered dose of the medication, he says. The patient declined to comment.

Thomas Foltynie, a neurologist at University College London, also cares for two patients who received transplants as part of an 18-person trial in Sweden in the mid-1990s when they were at a moderate stage of disease and in their 40s. He and colleagues published a case report on them in January in the journal JAMA Neurology.

Before their transplants, both patients still responded to levodopa for periods and could function more or less normally when the drug was “on”. But during the “off” periods, they were disabled, experiencing tremors, slowness and even freezing in place, Dr. Foltynie says.

They responded so well to the transplants that months afterward, doctors took them off the drug. Both patients experienced the side effect of graft-induced dyskinesia, Dr. Foltynie says. (Researchers determined the side effects were due to the transplant, not the drugs.)

Now 15 and 18 years post-transplantation, both patients have non-motor symptoms of the disease, like cognitive impairment. Recently one was diagnosed with cancer, though Dr. Foltynie says this was thought to be unrelated to the transplant and Parkinson’s. Both declined to speak for health reasons, according to Dr. Foltynie.

There are many unanswered questions about cell therapy but for these two patients, “it’s hard to ignore the longevity of the benefit of the transplant,” Dr. Foltynie says.

http://online.wsj.com/articles/second-thoughts-on-out-of-favor-parkinsons-disease-treatment-1412615382