Kenneth Pettine

Mesenchymal Stem Cell Therapy for Parkinson’s Disease

Mesenchymal Stem Cell Therapy for Parkinson’s Disease

Written by: Dr. Kenneth Pettine (Retired)
Website: KennethPettine.com

Parkinson ‘s Disease is a progressive disorder of the nervous system that affects movement. It is characterized by a loss of dopaminergic neurons in the midbrain region known as the striatum. It develops gradually, sometimes starting with a slight tremor in just one hand. The disorder also commonly causes stiffness or slowing of movement.  In the early stages of Parkinson’s Disease,  a decrease in facial expressions may be noticed or the fact that arms don’t swing while walking. Speech may become soft or slurred. Parkinson’s Disease symptoms worsen as the condition progresses over time. Symptoms vary from person to person. Parkinson’s Disease usually begins at the age of 60 or older. Men are more likely to develop Parkinson’s Disease than women and there appears to be a hereditary component. Other symptoms may include difficulty in thinking processes, depression, emotional changes, swallowing problems, sleep disorders, and bladder difficulties.

There is no cure for Parkinson’s Disease. Medications can be utilized in an attempt to decrease your symptoms. The most common medication used to treat Parkinson’s is levodopa, a compound that is metabolized in the brain into dopamine. Levodopa can be combined with carbidopa to increase dopamine concentrations in the brain. These medications include Rytary and Sinemet. As Parkinson’s Disease progresses, the benefits from levodopa tend to decrease, and the medication can begin to cause involuntary spastic movements called dyskinesias . The FDA approved a dru called Duopa in 2015, which is levodopa, placed through a feeding tube directly into the small intestine.

Other drugs have been developed to mimic the dopamine effects in your brain. They generally are not as effective as levodopa, but these include Mirapex, Requip, Apokyn, and a skin patch medication called Meupro. All of these medications have side effects, such as hallucinations, compulsive behaviors and sleepiness. Other medications have been developed to prevent the breakdown of brain dopamine called MA0-8 inhibitors. Finally, medications, called Catechol-0- methyltransferase inhibitors have been developed to help prevent the breakdown of dopamine prolonging the effects of levodopa . The tremors associated with Parkinson’s Disease have been treated with anticholinergics. These medications have side effects including impaired memory, confusion, hallucinations , dry mouth, and impaired urination.

Surgical procedures to treat Parkinson’s include deep brain stimulation where electrodes are implanted in specific parts of the brain . These are connected to a generator implanted near the chest that sends electrical pulses to your brain and may reduce your symptoms of Parkinson’s Disease.

A healthy lifestyle can help treat Parkinson’s Disease. This includes exercise, healthy eating, and attempting to avoid falls. Other alternative medicine treatments that may help the symptoms of Parkinson ‘s Disease include the use of Coenzyme Q10, massage, acupuncture, Tai Chi, yoga, Alexander technique, meditation, music or art therapy and pet therapy.

The Use of Mesenchymal Stem Cells for Treatment of Parkinson’s Disease

I performed a literature review at the beginning of 2014 and was able to locate over 2,000 peer­ reviewed published papers concerning mesenchymal stem cells in just the last three years. The

MSC is by far the most studied adult stem cell in your body. The main focus of all this research has    been on MSC’s ability to influence biological function through its trophic mechanisms, including the secretion of cytokines which might serve both paracrine (cells communicating with adjacent cells) and endocrine (cells communicating long distances through the body) functions [11-14]. This shift away from just using MSCs in orthopedics and spine is the result of scientific observations that MSC therapy results in reduction of inflammation and apoptosis (cell death) in numerous disease models. These positive systemic effects from the MSCs occurred before they differentiated into osteoblasts,    chondroblasts, or fibroblasts. Thus, it has been discovered the MSC exerts these properties as a stem cell. This realization also resulted in a paradigm shift away from local injection of the MSCs into damaged tissue to systemic administration through IVs, which is less invasive and more convenient to the patient.

When I inject bone marrow concentrate into the IV, this can range in volume from a few millimeters up to 20mL of bone marrow concentrate. This material is put through a filter (Hemo-Nate® Syringe Infusion Set), which removes the cell aggregates and particulates (181lm or larger) prior to the slow infusion of the bone marrow concentrate. The mesenchymal stem cells travel through your venous system and the first filter they encounter is your lungs [15-18]. The MSCs trapped in pulmonary tissue eventually travel through capillaries into your arterial system and then travel throughout the body. Despite the MSCs temporary location in the pulmonary capillaries, numerous animal studies and some clinical trials have reported favorable outcomes following systemic infusion of MSCs. In a seminal paper by Lee, et al (12], a paracrine (cell signaling) factor was found to be released by MSCs in the pulmonary capillary bed. This factor promotes tissue regeneration through a systemic effect, similar to the action of a conventionally administered drug.

I would encourage you to read a recent paper published by Glen, et al, in the World Journal of Stem Cells [18]. The title of the article is “Mesenchymal Stem Cells: emerging mechanisms of immunomodulation and therapy.” The following is a direct quote “Currently, much research  centers on the immunomodulatory aspects of MSCs, especially in reducing inflammation and suppressing immune cell function. Emerging research suggests a multi-functional quality of MSC immunomodulation.” This review paper discusses how MSCs modulate the body’s immune responses, which result in either immunosuppression or immunostimulation. The discovery of the immunosuppressive functions of MSCs has ushered in a plethora of research studying autoimmune diseases such as multiple sclerosis, autoimmune diabetes, and rheumatoid arthritis. Katata and Dezawa recently published a review article titled, “Parkinson’s Disease and Mesenchymal Stem Cells: potential for cell-based therapy” [19]. This paper focuses mainly on the potential of  the mesenchymal stem cell as a therapeutic biologic treatment in Parkinson’s disease. The following is a direct quote from this paper “MSCs are a great therapeutic cell source because they are easily accessible and can be given to patients without posing serious ethical or technical problems. They have trophic effects for protecting damaged tissues as well as differentiation ability to generate a broad spectrum of cells, including dopamine neurons, which contribute to the replenishment of lost cells in Parkinson’s disease.”

The shift from local administration of MSC based treatments to systemic, or body wide administration has greatly expanded the potential of this natural regenerative medicine approach to treating diseases. As more targeted treatments are developed in disease-specific models, it is likely that MSC therapies could replace the litany of harsh side effects from immunosuppressive and immunomodulatory drugs for autoimmune diseases, as well as a number of other drugs/treatments for other diseases that can cause side effects that may be worse than the disease itself. For example, long-term levodopa use in Parkinson’s disease loses efficacy over time, requires careful monitoring, and can cause significant motor dyskinesias or involuntary motions [5].

All this research as well as my early experience indicates that IV stem cells may help with a number of conditions. I have treated a small number of patients with Parkinson’s, Multiple Sclerosis, Fibromyalgia, Rheumatoid Arthritis, and even elevated liver enzymes from alcohol use who are reporting favorable results with no adverse events. These cases were not part of a formal study, but because the patients were so satisfied with the treatment, we are currently planning and implementing clinical studies to objectively assess the benefits of IV bone marrow concentrate infusion. The primary goal of this research is to provide our patients with the most cutting edge treatments in both orthopedics and general medicine.

Mesenchymal stem cells (MSCs) are attracted by cytokines to areas of inflammation. When an MSC arrives in areas of bodily damage they have been shown to actively participate in tissue repair. MSCs have the ability to suppress immune responses and have repeatedly shown efficacy in treating various autoimmune diseases. The proven ability of MSCs to regenerate damaged tissue combined with their capacity to regulate immune and inflammatory responses, gives a strong rationale for using MSCs as a new treatment option in autoimmune diseases [15-17].

The following is a review of current literature discussing the use of various stem cells in an attempt to treat Parkinson’s Disease.

The first paper is a literature review by Glavaski-Joksimovic entitled “Mesenchymal Stem Cell and neurodegeneration in Parkinson’s  Disease” [2]. The authors in this review report many animal studies have verified that bone marrow derived mesenchymal stem cells have the capacity to protect and regenerate damaged dopamine neurons [20, 21]. Recent studies suggest that a number of mechanisms are involved in the regenerative effects of mesenchymal stem cells. [20,22-26]. MSCs have been reported to secrete an array of growth factors and cytokines including nerve growth factor, glial cell line derived neurotrophic factor, fibroblast growth factor 2 and 8, hepatocyte growth factor, vascular endothelial growth factor, neuronotrophic factor and neurotrophin-3 [21,27-29]. The authors conclude there are numerous reasons for optimism concerning the use of MSCs for neuro repair and protection in Parkinson’s Disease.

The main body of evidence on the effects of mesenchymal stem cells in the animal models of Parkinson’s Disease suggest that mesenchymal stem cells act through paracrine mechanisms (cells communicating with adjacent cells). MSCs release various chemicals and proteins including neurotrophic, anti­ inflammatory, immunomodulatory, anti-apoptic (programmed cell death preventing) and angiogenic factors to positively affect cells and promote recovery of compromised dopamine neurons [30-32].

Although the mesenchymal stem cell approach is early in the clinical pipeline, the findings to date suggest this as a “Promising, novel approach to the treatment of Parkinson’s disease.”

The next article is entitled “The Secretome of Mesenchymal Stem Cells: Potential Implications For Neuro Regeneration by Paul et.al [33]. This review article indicates over the course of the last decade, around 40 studies involving mesenchymal stem cells for the treatment of Parkinson’ s Disease have been published. The mechanisms responsible for a significant functional improvement in these animal studies with mesenchymal stem cells are still under debate.  Some authors claim mesenchymal stem cells differentiate into neuronal progenitor cells and even dopamine-producing cells [34-41].  Other authors suggest

secretion of neurotrophic and/or neuroprotective factors and/or the immunomodulatory actions of mesenchymal stem cells are responsible for the positive effects in treating Parkinson’s Disease [42-53]. Other authors believe a joint mechanism is responsible [54-64].  They state even though the mechanism leading to functional improvement remains unclear, experimental data suggests that the use of mesenchymal stem cells in treating Parkinson’s Disease warrant s further investigation.

Beginning approximately one year ago, I began systemically infusing the MSCs from bone marrow concentrate intravenously (IV) to utilize the amazing functions of the MSC throughout the body. This is a quote from an NIH manuscript [65). “Imagine a simple intravenous cell therapy that can restore function to damaged or diseased tissue, avoid host rejection and reduce inflammation throughout the body without the use of immunosuppressive drugs. Such a breakthrough would revolutionize medicine. Fortunately, pending regulatory approval, this approach might not be far off. Specifically, cell therapy utilizing adult MSCs, multipotent cells with the capacity to promote angiogenesis, differentiate to produce multiple types of connective tissue, and down-regulate an inflammatory process, is the focus of a multitude of clinical studies currently underway. MSCs are being explored to regenerate damaged tissue and treat inflammation resulting from:

cardiovascular disease and myocardial infarction (MI), brain and spinal cord injuries, stroke, diabetes, cartilage and bone injury, Crohn’s disease, and graft versus host disease. In this article we highlight the recent paradigm shift which has occurred in therapeutic use of MSC based on their immunomodulatory properties as opposed to their ability to differentiate into osteoblasts, chrondoblasts, or fibroblasts.”

The procedure to place mesenchymal stem cells into peripheral vein is as follows:

To begin the procedure, an IV will be started, typically in the arm. Antibiotics are placed into the IV and a small dose of IV versed (like Valium) is given for relaxation. The patient has transported a short distance to the procedure room to lie on a table similar to a massage table. The patient is placed on their abdomen and additional medication is given consisting of more IV versed and fentanyl (narcotic). At this point, most people are asleep or extremely relaxed. The versed also gives the patient amnesia for a brief time that the medication is in their bloodstream. Once the patient is completely relaxed or asleep, the skin area around the posterior iliac wing (hip) is sterilized with betadine and draped sterilely. The skin is anesthetized with buffered 1%xylocaine. Utilizing fluoroscopic control, a Jamshidi needle is placed into the patient’s posterior iliac wing. At this point, anywhere from 60 to 120 mL of bone marrow is carefully extracted. This entire procedure is performed with the patient asleep or highly relaxed and having amnesia. At this point,

the patient is placed in a wheelchair and transported back to a comfortable lounge chair to sleep or be highly relaxed for approximately one-half hour. During this time the bone marrow aspirate is placed in a centrifuge for approximately 15 minutes. This separates the bone marrow aspirate into various cell layers with red blood cells being at the bottom of the tube and plasma at the top. A small layer in the middle contains all of the nucleated cells including the mesenchymal stem cells. This layer is extracted and placed through a Hemo-Nate® Syringe Infusion Set. This filter removes all of the aggregates and particulates that are 18 m (Micrometers) or larger. The mesenchymal stem cell layer is placed into your IV at a rate of approximately 1mL per minute. The mesenchymal stem cells then travel to the capillary bed of the patient’s lungs where they remain for a few hours and then travel throughout the body. The mesenchymal stem cells are attracted to areas of inflammation in the body. They also release various growth factors and communicate to other cells to modulate the immune system. The IV is removed and the patient is transported home with a driver. Usually, people are sore from the removal of bone marrow for approximately 24 hours and may feel relaxed or sleepy for several hours following the procedure.

CONCLUSION :

Parkinson’s Disease can result in a chronic debilitating condition, impacting all aspects of the patient’s life. This condition has no current cure. All of the treatments utilized for Parkinson’s disease are simply to control the symptoms and not cure the underlying problem. Most experts agree this condition is an autoimmune disorder.  Extensive research has shown the safety and efficacy of utilizing adult mesenchymal stem cells to treat various autoimmune disorders including Parkinson’s disease, Multiple Sclerosis, Crohn’s disease, Fibromyalgia and other autoimmune disorders. I have treated a small number of patients with multi-year histories of debilitating multiple sclerosis. This therapy involves the utilization of bone marrow concentrate, which is then placed through a filter to remove cell aggregates and particulates prior to the slow IV infusion of the bone marrow concentrate. I am unaware of any adverse effects from this therapy. I would encourage you to research further the potential of utilizing this therapy to potentially control and in the future possibly cure Parkinson’s Disease.

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