MDS Position Paper - Use of Stem Cell Therapies for Parkinson's Disease

Lay Summary: Use of cell-based therapies for Parkinson’s disease

January 2021

The Scientific Issues Committee on behalf of the International Parkinson and Movement Disorder Society (MDS) has commissioned a brief review of the current place of cell-based therapies in Parkinson’s disease (PD) from recognized international experts. This review is intended to provide readers with a balanced view of the current state of cell therapies in PD.

The last several years have seen exciting advances in the development of potential new therapies for PD. Interest has focused in particular on cell-based therapies, including the use of stem cells. Theoretically, such cells could replace or repair those lost or damaged in the disease process, thereby improving symptoms. However, there are important limitations to such a strategy. These include identifying the disease stage that is most suited for this type of therapy, defining what type of nerve cells have the most appropriate properties, turning stem cells into nerve cells with normal physiological functions, ensuring that they do not grow uncontrollably and form tumors (a particular risk with stem cells), injecting them safely into the right place in the patient’s brain, making them connect to other remaining nerve cells and communicate with them without causing adverse effects. In addition, PD involves the loss of different types of cells and current efforts are mostly focused on replacing only the dopamine-producing nerve cells, which means that not all symptoms are like to improve following this type of cell therapy.

Several business enterprises world-wide offer ‘stem-cell therapies’ for many neurological diseases including PD by injection of ‘stem-cells’ into the veins, the spinal fluid or even the brain. The nature of these ‘stem-cells’ varies widely with respect to their origin and potential to become nerve cells. Some clinics claim that the stem cells do not need to develop into nerve cells, but instead release an undefined cocktail of factors that somehow is supposed to support the survival of remaining nerve cells or stimulate them to regrow new contacts in the brain. Information about the scientific laboratory studies that support the use of these types of approaches and the outcome of these treatments should be published in peer-reviewed medical and scientific journals. Unfortunately, in most of these cases the appropriate submission of techniques and results for independent scientific peer-review is missing. Regulatory approval for the procedure might not even be in place. Many of the claims of considerable benefit are unsubstantiated and do not address potentially very significant side effects. A concerning practice that has evolved is ‘stem-cell tourism’ in which patients will travel far distances and pay large sums of money to private clinics for these unproven cell therapies. 

The Society wishes to caution patients about some treatments that are carried out without appropriate supportive scientific research and are performed outside a recognized academic or clinical setting. The Society fully supports research into the area of cell-based therapies and recognizes that there potentially is much to be gained by research in this important area. However, until such treatments are proven to be safe and of benefit, and validated by data published in recognized scientific journals that objectively scrutinize their procedures, the Society encourages patients to participate only in cell therapy studies that are part of a research program affiliated with a recognized academic institution with rigorous oversight and approval by regulatory bodies.


 

Use of cell-based therapies for Parkinson's disease

Position paper of the International Parkinson and Movement Disorder Society

 

The present paper is an updated version of the previously released position paper of the Society, and was prepared by current members of the MDS-Scientific Issues Committee: Patrik Brundin, MD, PhD1, Lorraine V. Kalia, MD, PhD2, Abby L. Olsen, MD, PhD3, Ece Bayram, MD, PhD4, Han-Lin Chiang, MD5, Hideki Mochizuki, MD6, Serge Przedborski, MD, PhD7, Un Jung Kang, MD8 and Stella M. Papa, MD9

1 Van Andel Institute, Center for Neurodegenerative Science, Grand Rapids, Michigan, USA. 2 Morton and Gloria Shulman Movement Disorders Clinic and the Edmond J Safra Program in Parkinson's Disease, Toronto Western Hospital, Division of Neurology, Department of Medicine, University of Toronto, Toronto, ON, Canada. 3 Department of Neurology, Harvard Medical School, Brigham and Women’s Hospital, Boston, Massachusetts, USA. 4 Parkinson and Other Movement Disorders Center, Department of Neurosciences, University of California San Diego, La Jolla, California, USA. 5 Neurological Institute, Taipei Veterans General Hospital, Taipei, Taiwan. 6 Department of Neurology, Osaka, University Graduate School of Medicine, Osaka, Japan.  7 Departments of Neurology, Pathology & Cell Biology, and Neuroscience, Division and Movement Disorders and Center for Motor Neuron Biology and Diseases, Columbia University, New York, New York, USA. 8 Department of Neurology, New York University Grossman School of Medicine, New York, New York, USA. 9 Yerkes National Primate Research Center, Department of Neurology, Emory University School of Medicine, Atlanta, Georgia, USA.

Introduction

The last decades have seen exciting advances in the development of potential new therapies for Parkinson’s disease (PD). There has been great interest in cell-based therapies, including the use of stem cells. Theoretically such cells could replace or repair those lost or damaged in the disease process, thereby improving function. However, there are important limitations to such strategies. These include reproducibly producing sufficient numbers of cells with the desired neuronal phenotype, safely transplanting them into the right location in the brain, and ensuring they have the capability to connect to other neurons with appropriate physiological interactions. PD involves the loss of different types of cells and compensatory plastic changes in additional neuronal populations and related brain circuits. Most of the current research focus is on replacing dopamine neurons by transplantation. Whether this can only be hoped to reduce motor symptoms, or also ameliorate some of the non-motor symptoms seen in PD, is still not clear. Furthermore, it is not clear if transplants will be equally effective at all disease stages, and it is not fully understood how the replaced cells can integrate functionally with the retuned brain, especially in advanced disease. While the brain is immunologically privileged transplantation site, immunosuppression is likely to increase transplant survival if the cells are not genetically identical to the graft recipient. However, the best type of and the necessary duration of such immunosuppressive treatments are unknowns. Potential side effects, including tumor formation, which is a particular risk with stem cells, are other concerns. Here, we briefly review the available data to provide readers with a balanced view of the current state of cell-based therapies in PD.

The Society wishes to inform patients that some treatments are carried out without appropriate supportive scientific research and are performed outside a recognized academic or clinical setting. The Society fully supports research into the area of cell-based therapies and recognizes that there is much to be done in this important area. However, until such treatments are proven to be of benefit and safe, and validated by data published in recognized scientific journals, it would encourage patients only to participate in cell therapy studies that are part of a research program in a recognized academic institution with rigorous oversight.

Scientific Background

The recent progress in stem cell technology and regenerative medicine has led to numerous attempts to use cell-based therapies to repair the brain in patients with neurodegenerative disease. Cell therapy involves the introduction of new functional cells to restore damaged tissue. In Parkinson’s disease (PD), one major use of cell therapy has been to transplant dopaminergic neurons to replace the function of those cells lost during the neurodegenerative process. Despite major advances in the field of regenerative medicine, several challenges to promote the use of stem cells for this type of therapy in PD remain. Not all protocols used to differentiate the stem cells give rise to true nigral dopaminergic neurons that are capable of effectively re-innervating the host striatum. Furthermore, most approaches to cell therapy overlook that the loss of dopaminergic innervation is widespread in the forebrain, and that also non-dopaminergic neurons degenerate. Other points that cell transplantation approaches typically do not address are that abnormalities of non-neuronal cells occur in PD, and that the introduction of new cells does not address the enigmatic underlying disease process. Thus, even if a successful replacement of dopaminergic neurons is achievable, such a cell therapy would not represent a ‘cure’ because it would not address the treatment of ‘dopamine-resistant’ motor features (e.g. freezing and postural instability) or common non-motor symptoms, such as dementia, hallucinations, olfactory loss, abnormal sleep, and dysautonomia, which have a significant impact on the quality of life of patients with PD. In addition, compensatory mechanisms that develop in multiple brain regions as a response to the progressive loss of dopaminergic neurons (1-3) and understanding how the transplanted cells interact with these brain plasticity changes is a major challenge. Finally, because current cell-based therapies do not address the continuous degenerative process, it is conceivable that the transplanted cells are also directly impacted by the underlying disease. Therefore, while it is technically possible to differentiate stem cells into neurons that have properties similar to dopaminergic neurons, goals and expectations of this cell therapy should be carefully considered in clinical application. In addition, there is a considerable number of studies aimed at optimizing different types of cell therapy currently underway. This includes transplanting fetal dopamine neurons, embryonic, mesenchymal and neural stem cells, and the use of reprogrammed fibroblasts and astrocytes.

Transplantation of fetal dopaminergic neurons

Initial encouraging results from small, non-randomized studies on transplants of fetal dopamine neurons demonstrated that successful re-innervation of the striatum could result in an improvement of motor function in patients with PD (4-6). However, when transplantation of embryonic dopamine neurons was performed in larger, randomized, sham-surgery controlled studies, no significant or only modest clinical benefits in patients with PD (aged 60 years or younger) were initially observed. Longer follow up studies were more encouraging (7, 8), especially in patients in whom preoperatively the dopaminergic denervation was restricted to the dorsal parts of the striatum (9).

The implanted dopamine neurons survive, which has been demonstrated by both post-mortem studies and functional PET studies in many patients (10, 11). However, recent studies have demonstrated accumulation of alpha-synuclein aggregates, that display the characteristics of Lewy pathology, in a small portion of these surviving neurons. Animal studies have demonstrated that alpha-synuclein can transfer between host and transplanted cells (12-16), indicating that in humans the implanted cells might acquire the same pathological processes that occur in PD. What this means for graft function is unknown, given that good long-term graft effects have been seen (17) and the number of cells displaying such pathology is small (8).

The development of off-medication dyskinesias (18, 19) in some patients who underwent transplantation of fetal nigral dopamine neurons has been of concern. The underlying mechanism of these so called ‘graft induced dyskinesias’ (GIDs) is not fully understood. Mechanisms that are suggested to contribute are the prior priming of the striatum with L-DOPA that leads to dyskinetic responses to the graft-derived dopamine (20), the inclusion of serotonin neurons in the grafted tissue (21) and heterogeneous distribution of graft-derived innervation across the host striatum (8, 22, 23).  The European TRANSNEURO study, which is currently still being evaluated, was designed to improve our understanding of the potential benefits and limitations of fetal cell transplantation therapy (24).

Other Cell-based therapies

Alternative sources of dopamine neurons for transplantation have been explored for over two decades. Currently, there are many global collaborations aiming to bring cell-based therapy for PD to clinical use. An example of such collaboration is G-FORCE PD (http://www.gforce-pd.com) (25). Some of the stem cell sources do not share the ethical concerns associated with the use of fetal tissue. When the source of cells allows for them to be dramatically expanded in number prior to the surgery, the obvious advantage would be to provide greater numbers of transplantable dopamine neurons. Differentiation of dopaminergic neurons from embryonic stem cells, mesenchymal stem cells or reprogrammed somatic cells, particularly fibroblasts, have all been explored. These different sources of cells are briefly discussed below.

Mesenchymal stem cells

Mesenchymal stem cells (MSC) are multipotent stem cells that can be isolated from bone marrow, adipose tissue, and umbilical cord blood. Transplantation of bone marrow-derived MSCs that purportedly differentiated into dopaminergic neurons has been reported to improve motor function in rodent models of PD, with no evidence of tumor formation (26). However, the validation that these cells can fully differentiate into dopamine neurons has not met the highest of current standards for rigor and reproducibility, and the ability of MSCs to differentiate into dopamine neurons remains unproven. Separate from their regenerative capacity, MSCs release a wide array of soluble factors.  Thus, based on their potential trophic and anti-inflammatory effects, MSCs have been explored as cell therapies for patients with atypical parkinsonism--Multiple System Atrophy (27) and Progressive Supranuclear Palsy (28). It is important to acknowledge that because of unproven differentiation, more experimental studies are needed before these cells can be considered for clinical use in PD, and therefore, there are no current clinical programs with transplantation of MSCs that rest on a firm scientific foundation.

Embryonic stem cells

Embryonic stem cells (ESCs) are pluripotent and thus can be differentiated into any type of cell in the body, including dopamine neurons. Initially, protocols for doing this were relatively inefficient, although this has changed with protocols that have been refined over the past decade (29). Successful transplantation of dopamine neurons differentiated from human ESCs has been performed in rodent models, with evidence both of functional recovery and graft survival presented by many groups (29-33). Problems using this approach include the risk of tumorigenesis, e.g. the development of teratomas that contain cells from all germ layers, or the continued proliferation of partially differentiated neural precursors included in the graft preparation (32, 34). The most recent approaches avoid continued cell proliferation and tumor formation, and lead to the generation of dopamine neurons that resemble true substantia nigra dopamine neurons. There are industry sponsored programs that aim to take these dopamine neurons derived from human ESCs into clinical trials. The current focus is on scaling up production of cells, ensuring batch to batch reproducibility and meeting the regulatory standards of GMP (Good Manufacturing Process).

Reprogrammed somatic cells

The 2012 Nobel prize for Physiology and Medicine recognized John Gurdon and Shinya Yamanaka for discovering that adult mature cells can be reprogrammed to ‘rediscover’ their regenerative properties. Currently, this is achieved by increasing the expression of genes that force the cell to become pluripotent and regain its original “stem-cell” properties. Originally this was done through the overexpression of four transcription factors (Oct4, Sox2, Klf4 and Myc), which can re-program differentiated cells (e.g., fibroblasts, peripheral blood mononuclear cells) to become pluripotent and display features of ESCs (35). These cells are referred to as ‘induced pluripotent stem cells’ or iPSCs. iPSCs can be differentiated into dopamine neurons for transplantation into patients. Thus, this approach avoids the use of fetal neurons or ESCs, and if the cells are derived from the patient, i.e. autologous iPSCs, they would have no risk of immunological rejection. Experimental studies of iPSCs transplantation into animal models of PD have shown functional recovery (36). While dopamine neurons can now be generated from iPSCs, these cells still carry the risk of tumor formation similar to ESCs. However, there are several protocols for elimination of tumor-forming cells currently under study.  

In an open label trial in Japan, three patients have received transplantation of 2.4 million dopaminergic progenitors, derived from iPSCs, per side into putamen with no complications reported so far and four other patients are in line to be treated to test the safety and efficacy of this cell-based therapy (Clinical Trail : R000038278) (37). These iPSCs were taken from a stem cell bank and partially matched with the hosts for histocompatibility antigens.

Additionally, a recent case report describes positive effects of grafted midbrain dopaminergic progenitor cells in one PD patient, which were differentiated from autologous iPSCs generated from the patient fibroblasts (38).  The grafted cell preparation was reported to be free of undifferentiated iPSCs. In addition to the small size and possibly placebo effect, it is important to emphasize that this type of uncontrolled studies of individual cases lack scientific rigor, and therefore, no conclusion can be drawn from their outcomes (39, 40).  An approach that has been explored in the laboratory, but that has not reached clinical development yet, is the direct conversion of adult cells to dopaminergic neurons. Using an approach that involves overexpression of specific transcription factors (NURR1, LMX1a, FOXA2), fibroblasts can be converted directly into dopamine neurons without entering a pluripotent state (41-43). However, the overall yield of dopamine neurons remains low and functional improvement following grafting in animal models of disease has still not been demonstrated (44). Progress in developing reprogramming strategies to control the expression of transcription factors consistently in starting cells is expected to improve the yield of induced dopamine neurons. In addition, a better understanding of the molecular underpinnings of cell reprogramming can contribute to refine the current methodologies. Very recently, the notion that astrocytes can be converted into dopamine neurons in situ in the brain has become an innovative research area, which might be developed into clinical programs during the coming decade. Notably, astrocytes that were converted in situ into to dopamine neurons with a nigral phenotype were just shown to successfully make functional connections and rescue motor impairment in a mouse model of PD (45), suggesting that this might be a promising future for cell therapy.

Publicly offered cell-based clinical therapies 

There are several organizations worldwide offering patients stem cell therapy. These are frequently intravenous or intrathecal administration of MSC-containing cell preparations of varying purity to treat a number of different neurological conditions at a substantial cost to patients. Adipose tissue-derived MSCs have become the most exploited because of ease of cell harvesting through relatively minor procedures, such as liposuction (46). There is little scientific information available about the outcome of these therapies including very limited safety data (47). In a case series, data from 17 patients with parkinsonism who underwent these procedures were collected retrospectively (48). The patients received intrathecal application of autologous unsorted bone marrow cells, which was safe and well tolerated, but there was no benefit after a median observation period of 10 months. Thus, intrathecal application of autologous bone marrow cells in such uncontrolled conditions is not a recommended approach. 

Conclusion

Cell-based therapies should demonstrate efficacy and safety particularly lacking adverse immune reactions, tumor formation or dyskinesias. There have been great advances in the research of stem-cell therapy, especially for PD, and clinical trials are ongoing. However, for the time being there is still not enough evidence to support the widespread use of cell-based therapies for PD outside of carefully controlled clinical trials.  We are hopeful for the future progress of such therapies based on extensive translational studies in proper animal models, and international clinical approaches with properly designed trials.

Disclosures related to this work
PB is a paid consultant for Fujifilm-Cellular Dynamics Inc.

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