This past June Cell Culture Dish attended the International Society for Stem Cell Research (ISSCR) Annual Meeting in San Francisco and over the next several weeks we will be sharing information that we gathered. One topic that I was happy to see covered was an update on the clinical progress of a Cell Therapy for Parkinson’s Disease. When I attended ISSCR in 2014, I had listened to an interesting talk by Dr. Roger Barker, John Van Geest Centre for Brain Repair and Department of Neurology, University of Cambridge, titled “Taking Stem Cell-Based Therapies to the Clinic in Parkinson’s Disease”. I followed up the talk with a blog titled, “Cell Therapy for Parkinson’s Disease – Considerations for the Future,” that discussed the status of Cell Therapy opportunities at that time.

I was pleased to see at this year’s ISSCR that Dr. Barker was giving another talk titled, “Where Are We Clinically with Cell Based Therapies for Parkinson’s Disease in 2016.” I was excited to see how this area had progressed over the past two years.

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 more than 5 million people worldwide and an estimated 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. Deep brain stimulation is another therapeutic option, but it carries the risk of infections, it is costly and requires follow-up surgeries. Surprisingly today’s best Parkinson’s disease drug was discovered in 1967.

Cell Therapy for Parkinson’s Disease Background

In his 2014 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. These studies will are scheduled to conclude in 2020, with a paper in 2021. Dr. Barker said that these trials take a long time to get to the end point of a study because the cells have to survive, integrate, connect and at the same time the patients have to learn to use these cells again in order to see improved motor performance.

Dr. Barker then went on in the talk to discuss why he feels stem cells are the future therapy for this disease over fetal cell transplants. He posed a number of questions and then gave his response to each. A summary of his questions and responses are listed below:

Why stem cells?

• It is easier to obtain enough material for transplant
• Ethical considerations less contentious
• Logistical advantages
• Controlled differentiation is easier
• Defined product

Which stem cells would you use?

There are two types to consider for clinic – iPS cells and human embryonic stem cells.

There are still a number of questions in using iPS cells a couple of which are demonstrating that it is safe and that they are economically viable as a therapeutic option.

Human ES cells have an advantage in that protocols have already been developed to make “authentic” nigral DA cells that behave like human fetal neurons in vitro and in vivo with similar efficacy/potency. See Grealish, et. al. paper, “Human ESC-Derived Dopamine Neurons Show Similar Preclinical Efficacy and Potency to Fetal Neurons when Grafted in a Rat Model of Parkinson’s Disease.”

Dr. Baker’s conclusions were that cell therapies for Parkinson’s Disease have a rational basis around dopamine cell replacement.

• Fetal VM trials have produced mixed results and there is a new trial ongoing.
• Stem cell therapies are about to enter the clinic, but it is easy for this to be derailed by trials that lack scientific rigor.
• Ultimately will these therapies be competitive in the treatment of PD? Yes if they can produce a major sustained benefit with minimal or manageable side effects. Also they must be cost-effective over 10 years especially when compared with current medications.

A Cell Therapy for Parkinson’s Disease – estimated to enter clinical trials in 2017

After Dr. Barker’s talk, I was able to attend at talk presented by Dr. Stefan Irion, MD, Memorial Sloan Kettering Cancer Center. In his talk, “A Cell Therapy for Parkinson’s Disease,” Dr. Irion described a proposed stem Cell Therapy that is targeting clinical trial initiation in late 2017.

He began his talk with a discuss of whether a new therapy is needed for Parkinson’s Disease and highlighted the benefits of a stem cell based therapy.

Benefits of a stem cell based regenerative therapy could replace function of damaged tissue:

• Proof of principle studies using fetal material show that the therapy works
• The therapy reverses symptoms of pd in animal models
• Cell-cell interactions may add additional benefits, beyond supplying dopamine such as synaptic connectivity
• Would provide a long term benefit, projected to be longer than 10 years as a one time surgery.

He then described how his group at Memorial Sloan Kettering Cancer Center (MSKCC), with funding from New York State, developed a novel stem Cell Therapy for PD that replaces lost dopamine cells. In May 2016 they had a pre-IND meeting with FDA and plan to file their IND by 2017. They are estimating that they will enter the clinic in late 2017. Today they have nearly 600 doses of a potential therapy manufactured and stored for future use. The therapy was manufactured under GMP conditions in MSKCCs Cell Therapy and cell engineering facility.

Manufacturing, testing and QC of an mDA Cell Therapy Product

Dr. Irion went on to describe their process for manufacturing mid brain dopamine neurons from human pluripotent stem cells. They start with bank of human embryonic stem cells, which then expand for 3-5 passages (9-15 days). Then they conduct mDA differentiation (16 days). Last they vial and cryopreserve the cells. Extensive testing is also conducted with initial testing consisting of viability and cell characterization (6 weeks), followed by nine months of cell characterization, safety and tumorigenicity testing.

Clinical trial plans

The plan is to enroll 10 patients exhibiting moderate to severe PD with a 1 year follow up for safety.

Summary

It is exciting to see that after a couple of years, there are some cell therapies for Parkinson’s Disease clinical trials planned for the near term. I am sure that there are many patients who are looking forward to Cell Therapy options, however there is still a long way to go before an approved Cell Therapy for Parkinson’s disease is available. I hope we can continue to see progress and positive results in the planned clinical trials. In addition, as Dr. Barker pointed out, in addition to being efficacious, the stem Cell Therapy would have to be competitive with current medications, be cost-effective and have widespread availability in order to successfully compete with current medications. There are also other groups moving toward clinical trials with their therapies as well, though I have only covered these talks from ISSCR in this blog.

To learn more:

GForce is a consortium of different research groups working on Parkinson’s Disease. The groups are from Europe, Japan and America and their goal is to work together and advice each other on progress and outcomes.

www.gforce-pd.com

ISSCR Series

This is one in a series of blogs covering ISSCR 2016. Find out more about the ISSCR’s 2017 Annual Meeting in Boston, June 14-17 by visiting – ISSCR’s 2017 Annual Meeting

ISSCR Series Blogs

Ten Years of Induced Pluripotent Stem Cells: A Look Back