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Researching mesenchymal stem cell therapy in MSA

Author Mary Views Posted at 2016/03/31

The MSA Coalition (Published on July 6, 2015 )

An Interview with Dr. Wolfgang Singer
In contrast to the polarizing controversies surrounding the medical use of embryonic stem cells, mesenchymal stem cells (those stem cells found in adult bone marrow and fat tissue) are free of ethical concerns. Mesenchymal stem cell research has evolved into a rapidly developing area of medical science with the potential to treat a wide range of diseases and health conditions. For patients with MSA and other neurodegenerative diseases stem cell therapy holds particular promise.
A preliminary study of stem cell therapy for MSA, currently being conducted by the Mayo Clinic, may help pave the way for further research. The phase I clinical trial primarily seeks to determine the safety and ideal dose range of stem cell therapy for treating MSA patients. In a recent interview with the MSA Coalition, Dr. Wolfgang Singer, Mayo Clinic Assistant Professor of Neurology and Co-Principal Investigator for the study, shared some news on the study’s progress and findings to date as well as possible future directions for research based upon the outcomes of the present study.
Who is Eligible?
A set of strict inclusion/exclusion criteria is in place to ensure that candidates have well-established MSA yet are at a stage in which the disease is still evolving so that levels of disease progress can be monitored, explains Dr. Singer. Enrollment includes both MSA-P and MSA-C patients. To help with the selection process, researchers are using autonomic testing, including a whole-body thermoregulatory sweat test. This procedure is performed at Mayo Clinic in Rochester, MN and only a few other facilities around the country. For that reason, researchers are recruiting only active Mayo Clinic patients for this study. As of August, 17 out of a total of 24 patients were enrolled, with the remainder of enrollment expected to be completed by the end of the year.
What Types of Procedures Are Involved?
Participants receive one or two stem cell injections into the cerebrospinal fluid at the level of the lumbar spine. The cells can circulate freely in the cerebrospinal fluid which surrounds spinal cord and brain. This method of administration is relatively safe, simple and, importantly, circumvents the blood-brain barrier, a protective filter that prevents foreign or potentially dangerous substances in the bloodstream from gaining access to the brain.
After each injection patients remain in the hospital for 2 days. To gauge progress the team conducts close follow-up for 4 weeks following each injection. Thereafter, telephone interviews occur at 3 and 9 months and neurological evaluations at 6 and 12 months. MRI scans are performed at baseline, 3 weeks and one year. Samples of cerebrospinal fluid are evaluated at several intervals during the study period to help the researchers determine how the stem cells affect their surroundings.
To shed light on the dose-response relationship and thereby determine the dose range that yields the greatest benefit with the fewest side effects, the study includes 3 dose levels. Each participant receives one of the 3 dose levels for the duration of the study.
What Types of Stem Cells Are Used?
Participants receive injections of mesenchymal stem cells derived from their own adipose tissue. These stem cells, which belong to a category of stem cells known as mesenchymal stem cells, or MSCs, are found in adults and located in various tissues throughout the body.
Adipose stem cells were chosen for this study for three important reasons, notes Dr. Singer. Since they are the patients’ own cells they are free of the ethical considerations that surround the use of embryonic stem cells. These and other MSCs also pose less risk for rejection by the immune system. Additionally, adipose cells are easier to obtain than bone marrow cells – another widely-used source of MSCs – and similar enough to bone marrow stem cells that there is not an advantage of using one over the other.
What Are the Potential Benefits of Mesenchymal Stem Cell Therapy in MSA?
Though the current approach cannot get stem cells to mature into neurons capable of replacing damaged brain cells, MSCs offer a range of potential benefits that may help surviving neurons and slow or possibly halt disease progression, most importantly, they provide a source of growth factors. Those factors (GDNF; BDNF) have been shown to be deficient in the brains of MSA patients and such deficiency is thought to be important in the development of neuronal death. MSCs are loaded with growth factors and target sick neurons in MSA. The hope is that replacing deficient GDNF and BDNF might prevent sick cells from dying.
In a small number of trials on MSA patients MSCs have been found to slow disease progression and improve patients’ ability to carry out basic tasks, such as walking and writing.
What Does the Study Show So Far?
Dr. Singer reports that the first of three dose-level groups has completed the treatments and 12-month follow-up and that early indications are encouraging. Among this group, which received the lowest dose level, no serious adverse events have occurred, indicating a good potential safety profile. Additionally, about half of this first group has experienced slower disease progression than expected. These patients show similar walking, talking and activities of daily living scores as at the start of the study. For the other half of the treatment group disease progress has continued at a rate about equal to what would be expected without treatment. In general, participants receiving stem cell therapy at earlier stages of disease have tended to fare better than those receiving stem cell therapy at later stages, notes Dr. Singer.
What’s Next?
Depending upon the final outcome of the current study, a placebo-controlled trial may be pursued to more accurately gauge the effectiveness of stem cell therapy for MSA. The research team has approached the FDA for permission to continue treatments at 6-month intervals for current study participants who have obtained benefits and have expressed interest in continuing.
When asked what he regards as the main barriers to progress in stem cell research for MSA, Dr. Singer points out that this type of research requires high-quality stem cell laboratories which are only available at selected institutions. Another concerning barrier is that many patients are not receiving the correct diagnosis until they reach a relatively late disease stage. He is convinced that improving the current ability to diagnose MSA early would result in improved outcomes of stem cell and other potentially disease-modifying treatments. The Mayo team is addressing this problem by utilizing data and markers obtained as part of their stem cell trial to develop new biomarkers for MSA. He also points to funding, citing that up until earlier this year the study was funded solely by the Mayo Clinic and generous donations. Since then, they have received dedicated support from Cure MSA, especially for the extension study. More recently the FDA has agreed to fund the very expensive MSC production process.
What Can Patients Do Now?
At this time, while stem cell therapy remains in the future and available treatments may manage symptoms but do not slow the course of the disease Dr. Singer recommends that MSA patients adopt and maintain a physical therapy and exercise program. He adds that movement therapy is currently the only proven effective treatment for neurodegenerative diseases such as MSA. Indeed, studies have shown that exercise can help MSA patients maintain muscle mass and balance. Exercise may provide similar neurotrophic (nerve growth-promoting), neuroprotective and anti-inflammatory benefits to those medical science seeks to provide through stem cell therapy.  However, Dr. Singer cautions, exercise must be carried out under the close supervision of a health professional trained in neurodegenerative conditions and aware of potential complications, including worsening of hypotension, in some patients.
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