In June, I attended the International Society for Stem Cell Research (ISSCR) Annual Meeting. After returning, I began a series of blogs related to information from the meeting and this series has continued several weeks. Today’s blog will focus on one of the talks given in the Therapies in the Clinic Plenary session, “Taking Stem Cell-Based Therapies to the Clinic in Parkinson’s Disease”, by Roger A. Barker, University of Cambridge. At ISSCR there were several talks on progressing therapies from research to the clinic and I thought Dr. Barker, did an excellent job demonstrating how imperative it is to examine work that has already been done in the area and to formulate future strategies based on these experiences.
What is Parkinson’s Disease?
Parkinson’s Disease is a neurodegenerative disease that develops due to the loss of the nigral dopaminergic neurons. These neurons produce dopamine, which is a chemical involved in transporting messages between different parts of the brain to ensure smooth, controlled muscle movement. When there is a lack of dopamine, due to loss of cells, there are visible nervous system symptoms. Symptoms often begin with a slight muscle tremor and eventually progress to more significant symptoms including, increased tremors, slowed movement, muscle stiffness, stooped posture, problems with balance, and speech impediments.
Parkinson’s disease afflicts 7-10 million people worldwide and an estimated 50,000 – 60,000 people in the US are diagnosed with Parkinson’s disease each year. There is currently no cure for Parkinson’s disease, but many patients do well on dopamine replacement medication. However, the efficacy of these medications can be reduced over time and there can be side effects.
Other Therapeutic Options
While the dopamine replacement medications work well initially, they still don’t represent a cure and the disease continues to progress. In an effort to provide a more lasting therapeutic option and perhaps even a possible cure, other treatment options have been explored.
In his talk, Dr. Barker described early animal studies, which indicated that tissue transplantation could be successful and laid the foundation for future human studies. From the animal models, researchers learned that the best behavioral recovery occurred when tissue from the same species was used and was transplanted at the right developmental age. It was also important to implant the tissue where dopamine works and not where the cells had been lost.
These insights led to open label studies in humans where fetal material was transplanted into patients. From these studies they established that graft survival and functional improvement could be achieved. These positive results, provided evidence that perhaps transplantation could lead to long term benefits for Parkinson’s patients.
As a result of the success found in early off-label studies, two randomized double-blind placebo controlled studies were initiated that also used fetal material transplantation. The two trials that came out in 2001 and 2003 had very different outcomes than the open label studies. The first, published in the New England Journal of Medicine, reported that by the end of year one the patients didn’t feel any better and 15% of patients developed dyskinesias as a side effect of the treatment. In the second study, published in the Annals of Neurology, there was no significant benefit across the treatment and control groups based on the standard rating scale and 54% of patients developed graft induced dyskinesias. However, these findings were inconsistent with what researchers were finding in the long-term follow up of the open label study patients. In these patients, researchers found treatment could provide lasting benefits.
A New Approach
Since it was effectively demonstrated that open label studies could be successful, researchers weren’t ready to give up on the idea of tissue transplantation for Parkinson’s disease. Dr. Barker and his colleagues developed a research consortium called TransEUro to look at innovative treatment options for Parkinson’s disease using fetal cells. Dr. Barker described why it was important for the consortium to examine the disappointing clinical trials to see if they could find how future studies could be better designed and how to move the field forward despite the disappointing results.
After careful study of all the results and new study planning, TransEUro has launched a series of clinical studies to further investigate the use of fetal cells in Parkinson’s disease. The first, located in Sweden, will include five patients with Parkinson’s disease who will receive brain cell transplants. Dr. Barker described that these studies have been designed with key differences from the failed studies in 2001 and 2003, including: recruiting younger patients, less advanced disease, tissue preparation optimization, and a three year primary end point.
One of my favorite aspects of the talk was when Dr. Barker walked through key questions to consider when thinking about the development of a stem Cell Therapy. Of course, he approached this from the perspective of treating Parkinson’s disease, but I think these are relevant and can be applied to many potential stem Cell Therapy applications.
Here is my summary of his questions and answers in the case of Parkinson’s disease:
- Do dopamine cell therapies work for Parkinson’s disease? Answer: Yes, but not in all cases, special attention needs to be paid to certain aspects of the study.
- Can stem cells be made into authentic nigral dopaminergic neurons safely? Answer: The cells must be an A9 nigral dopaminergic neuron and have to release dopamine. In addition there can be no safety concerns around the cells themselves, they must be from a stable source and GMP compliant. In patients the cells must be able to survive long-term after grafting with functional benefits in animal models.
- How can you test such therapies in patients? Answer: First you must create an A9 dopaminergic neuron from a stem cell source and test in a 6-OHDA lesion model. Then test in a small open label study to better understand how many cells to transplant, what type of patient is optimal and other important information necessary to optimize procedures. Finally a double-blind placebo/sham surgery trial could then be planned. It is important to remember how important planning is, as mistakes can set the field back a number of years.
- Are such therapies competitive? Answer: Yes, many therapies already work well, so any new therapy must be competitive and cost effective.
There are several groups who are working on developing a dopamine Cell Therapy from a stem cell source and these groups meet on a regular basis to share information and to discuss how to proceed with future clinical trials.
It is exciting to see that after a bit of a set back for the field, new studies are planned and that the studies have considered previous studies that worked and didn’t. It is also refreshing to see research groups working together to advance the field in an attempt to prevent study design errors with negative results that would reverse any progress made.
It would be nice if patients could have a Cell Therapy option, but as mentioned by Dr. Barker, in order to be successful, the stem Cell Therapy would have to be competitive with current medications, be cost-effective and have widespread applicability.
To learn more:
This is the fourth in a series of blogs covering ISSCR 2014. It was an excellent meeting and I highly recommend attending if you get the opportunity. Find out more about the ISSCR’s 2015 Annual Meeting in Stockholm, June 24-27 by visiting – ISSCR’s 2015 Annual Meeting