Stem cell therapy for spinocerebellar ataxias: A narrative review :Rakesh Kumar Singh, Manish Bhartiya, Ayush Agarwal, Divya M Radhakrishnan, Roopa Rajan, Achal Kumar Srivastava, Annals of Movement Disorders

REVIEW ARTICLES
Year : 2023 | Volume : 6 | Issue : 1 | Page : 1--6

Stem cell therapy for spinocerebellar ataxias: A narrative review

Rakesh Kumar Singh¹, Manish Bhartiya², Ayush Agarwal¹, Divya M Radhakrishnan¹, Roopa Rajan¹, Achal Kumar Srivastava¹,
¹ Department of Neurology, All India Institute of Medical Sciences, New Delhi, India
² Army Hospital, Guwahati, Assam, India

Correspondence Address:
Achal Kumar Srivastava
Room no 60, Cardioneurosciences Centre, AIIMS, New Delhi
India

Abstract

Stem cells have proved to be the “wonder treatment” for various genetic diseases and holds great potential for the treatment of numerous, but presently incurable maladies. However, stem cells may not be the answer for all such diseases. With the rampant growth of clinics offering stem cell therapy for almost every incurable disease, it is prudent that the indications, ethical considerations, and potential side effects of this treatment are known to the physicians and patients. In this article, we have summarized the available evidence on stem cell therapy in spinocerebellar ataxias.

How to cite this article:
Singh RK, Bhartiya M, Agarwal A, Radhakrishnan DM, Rajan R, Srivastava AK. Stem cell therapy for spinocerebellar ataxias: A narrative review.Ann Mov Disord 2023;6:1-6

How to cite this URL:
Singh RK, Bhartiya M, Agarwal A, Radhakrishnan DM, Rajan R, Srivastava AK. Stem cell therapy for spinocerebellar ataxias: A narrative review. Ann Mov Disord [serial online] 2023 [cited 2023 May 28 ];6:1-6
Available from: https://www.aomd.in/text.asp?2023/6/1/1/375300

Full Text

Introduction

Ataxia is a Greek word that means “lack of order” and indicates a jerky/irregular movement or posture. These movements may result from the involvement of multiple structures along the neuraxis, such as sensory ataxia (caused by lesions of the peripheral nerves, dorsal root ganglion, or spinal cord) and cerebellar ataxia (caused by involvement of the cerebellum or spinocerebellar tracts).

There are multiple varied etiologies of cerebellar ataxia; they may be acquired (vascular, demyelinating, metabolic, space occupying lesions, or toxin/drug induced) or heredodegenerative. The treatment and prognosis depend on the etiology. The neurodegenerative ataxias progress over time, resulting in substantial morbidity.[1] Cerebellar symptoms are commonly accompanied by cortical symptoms, peripheral neuropathy, and autonomic dysfunction in this subset.

The main cause of adult neurodegenerative ataxias is spinocerebellar ataxia (SCA). They result from genetic mutations or repeats, resulting in abnormal aggregation, apoptosis, autophagy, calcium homeostasis, signaling alterations, excitotoxicity, mitochondrial dysfunction, oxidative stress, and alteration of proteosome degradation.[2] To date, there is no definitive treatment for spinocerebellar ataxias, and any available treatment is mainly symptomatic.[3] Various pharmacological agents such as riluzole, lithium, varencline, antioxidants (ibedinone, coenzyme Q, and Vit E), propranolol, amantadine, and pramipexole have been attempted without any remarkable symptomatic relief.[4],[5] A Cochrane review of 14 randomized trials investigated various pharmacological interventions for dysarthria in hereditary ataxias, including Friedreich’s, and found no substantial improvement with any drug.[5],[6] Physical rehabilitation is the only intervention that was found to result in marked clinical improvement.

Stem cells are derived from the word “stammzelle,” and they are unicellular ancestor organisms, from which all multicellular organisms have evolved. Their unique properties are their self-renewal capability and ability to differentiate into multiple cell types. As a consequence, they can provide de novo or replacement cells for many tissues.[7] Stem cell therapies (SCTs) can potentially regenerate or replace diseased cells; therefore, they can restore normal function.[7] They provide a hypothetical alternative to the presently unresolved problems and have been widely employed in various disorders with mixed results. While it has a definitive role in the management of multiple sclerosis, it is being explored in the management of stroke, amyotrophic lateral sclerosis, idiopathic Parkinson’s disease, and Alzheimer’s disease.[8],[9],[10],[11]

Stem cell types

Stem cells [Figure 1] can be derived from multiple sources. Embryonic stem cells are harvested from the blastocyst’s inner cell mass, and they can thereafter differentiate into any cell type.[12],[13] A common source is the umbilical cord. Neural stem cells (NSCs) are derived from the neuroectoderm of early embryos and are found in the nervous system.[7],[14] They have the ability to differentiate into any cell type of the central nervous system. The ability to differentiate is limited in adult NSCs compared to embryonic stem cells. Mesenchymal stem cells (MSCs) are harvested from adult connective tissues, e.g., bone marrow and adipose tissue. They are multipotent and have the ability to differentiation into multiple cell types. Induced pluripotent stem cells can be harvested from the somatic cells of patients after reprogramming them with specific factors.[15],[16] They have the ability to form all three germ layers.[14] The properties, sources, and limitations of different stem cell types that are being presently used to treat various disorders of the nervous system are summarized in [Table 1].{Figure 1} {Table 1}

Rationale for use in SCA

The main hypothesis driving the role of stem cells in ataxia is twofold: direct (the presumed replacement of degenerating neurons with healthy cells) and indirect (promoting neuroprotection and delaying neurodegeneration by the modification of specific neurotrophic growth factors, removal of toxins, and reduction of oxidative stress). We believe that once they are implanted into the body, these cells will migrate to the area of interest and restore the normal function by developing into specific neurons.[13],[15],[17] MSCs have been most commonly used in preclinical and animal studies in ataxia because they are allogenic, which makes them less immunogenic (they express only major histocompatibility complex I and not major histocompatibility complex II, CD40/CD80/CD86 costimulatory cell surface molecules). In addition, they secrete immune-regulatory cytokines; therefore, they suppress the activation and proliferation of lymphocytes and dendritic cells.[15] The objective of this review is to analyze the evidence regarding the use of SCTs in SCAs.

Review

We searched various databases such as PubMed, Medline, Scopus, Embase, and clinical trial registries for the studies using SCTs for SCA treatment. We reviewed clinical and preclinical studies using all types of stem cells.

Although there have been numerous studies and trials conducted using SCTs in various neurological diseases, very few studies have been conducted on cerebellar ataxias. The earliest animal studies established the potential of SCTs as a therapeutic option for degenerative ataxias, although the route and frequency of administration were nonstandardized.

A study found that intravenous injection of human MSCs not only led to improvements in motor function but it also delayed ataxic symptom onset (through Purkinje cell preservation) in a mouse model of SCA type 2. Mendonça et al.[18] transplanted NSCs harvested from neonatal mice into the cerebellums of adult mice with Machado–Joseph disease (SCA type 3), which resulted in an increase in neurotropic factors, reduction loss of neurons, and neuronal inflammation, with improvement in motor coordination. Nuryyev et al. studied the effect of transplantation of stem cells into ataxic mice and recorded the outcome in the form of motor activity and weekly weight. At the end of 60 days, they found remarkable improvement in the motor activity and weight gain compared to controls. Histological examination showed that the transplanted human NPCs revealed signs of migration and neuronal development in the previously degenerated Purkinje cerebellar cell layer.[19]

NSCs obtained from an adult mouse brain upon transplantation into ataxic SCA1 mice with marked Purkinje cell loss showed increased motor activity, molecular layer thickness recovery, and increased Purkinje cell survival. However, the histology did not reveal direct replacement of Purkinje cells, leading the authors to hypothesize that SCTs offered neuroprotection via direct contact with the surviving neurons.[20]

Jin et al. tested the efficacy of intrathecal and intravenous infusion of umbilical cord-derived MSCs in 16 SCA patients over 12 months. They found that motor improvement was maximal at 3–6 months after infusion, and no patient experienced any serious side effects during the study.[21]

Dongmei et al. studied the effect of intrathecal transplantation of human umbilical cord-derived MSCs in 24 patients, which included 14 SCA patients (remainder were MSA-c patients). All the patients were followed-up using the International Cooperative Ataxia Rating Scale (ICARS) and activities of daily living (ADL) scores. Although all patients showed improvement in the ICARS and ADL scores, the effect regressed back to baseline after approximately 10 months.[22]

Yang et al. studied the efficacy of intrathecal transplantation of mononuclear cells derived from human umbilical cord blood in 30 hereditary ataxia patients. The endpoint measures used were the Berg Balance Scale and Ig and T-cell serum markers (at baseline and post-treatment). The treatment resulted in the reduction of both signs and symptoms of the disease through these outcome parameters without any adverse events.[23]

Yun et al. studied the effect of SCT in 12 genetically proven SCA patients.[24] The intervention was weekly administration of intrathecal stem cells, for a total of 4 weeks with routine premedication steroids. The outcome measurement was improvement in pre- and post-transplant ICARS and ADL scores. Although there was a statistically significant improvement in these scores initially, the efficacy of this treatment could not be commented on due to the absence of a long-term follow-up.

Tsai et al. established the safety of MSC transplantation in their open label study comprising six SCA3 patients.[25]

A recent meta-analysis and systemic review by Bhartiya et al.[26] on SCT for neurodegenerative cerebellar ataxias revealed no statistically significant improvement in the ataxia rating scale scores. Similarly, a meta-analysis by Appelt et al.[27] did not reveal any remarkable benefit of MSCs in SCAs. There was no difference noted with respect to the type of ataxia and gene mutation involved in response to the treatment. However, there were no remarkable adverse outcomes reported in any of these studies included in the systematic review.

Various clinical trials using SCTs in SCAs are summarized in [Table 2].{Table 2}

Issues and uncertainties of cell therapy for ataxia

SCTs for SCAs is still in its nascent stage, and many pertinent questions remain unanswered. The absence of randomized controlled trials portends all available evidence as weak. In addition, different studies used different stem cell types (MSCs used most commonly), varied routes of administration (intrathecal versus intravenous), and variable protocols for symptom analysis. There is no mention of the protocol used for induction and maintenance of immunosuppression post-transplantation in any of the studies.

Finally, the main issue with using stem cell therapy is the source and harvesting of cells. While neural progenitor cells are available, the use of umbilical cord cells have ethical controversies and is in its infancy in India. Although there are numerous regulations in place to monitor stem cell research in India, the bench to bedside journey is prone to several uncertainties,[28] including social and ethical considerations.

Conclusion

Although there is enough preclinical data on the role of stem cells in SCA treatment, there are many unanswered questions regarding the dose and duration of therapy and the type of stem cells to be used. In addition, most human studies were of poor design, nonuniform, had low patient numbers, and lacked long-term follow-up data. The routine use of stem cell therapy outside research settings is not recommended until robust data from randomized controlled trials is available.

Acknowledgement

None.

Author contribution

All authors contributed towards the idea, writing and editing of the manuscript.

Ethical compliance statement

All authors comply with the journal's publishing ethics and guidelines.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

References

1	Ashizawa T, Xia G Ataxia. Contin Lifelong Learn Neurol 2016;22:1208-26.
2	Matilla-Dueñas A, Sánchez I, Corral-Juan M, Dávalos A, Alvarez R, Latorre P Cellular and molecular pathways triggering neurodegeneration in the spinocerebellar ataxias. Cerebellum Lond Engl 2010;9:148-66.
3	Sclnow Biotechnology Co., Ltd. A Clinical Research on the Safety/Efficacy of Umbilical Cord Mesenchymal Stem Cells Therapy for Patients with Spinocerebellar Ataxia. clinicaltrials.gov; 2020. Report No.: NCT03378414.
4	Kearney M, Orrell RW, Fahey M, Brassington R, Pandolfo M Pharmacological treatments for Friedreich ataxia. Cochrane Database Syst Rev 2016;2016:CD007791.
5	Vogel AP, Folker J, Poole ML Treatment for speech disorder in Friedreich ataxia and other hereditary ataxia syndromes. Cochrane Database Syst Rev 2014:CD008953. doi: 10.1002/14651858.CD008953.pub2.
6	Koller WC Pharmacologic trials in the treatment of cerebellar tremor. Arch Neurol 1984;41:280-1.
7	Barker RA, Jain M, Armstrong RJE, Caldwell MA Stem cells and neurological disease. J Neurol Neurosurg Psychiatry 2003;74:553-7.
8	Burt RK, Balabanov R, Burman J, Sharrack B, Snowden JA, Oliveira MC, et al. Effect of nonmyeloablative hematopoietic stem cell transplantation vs continued disease-modifying therapy on disease progression in patients with relapsing-remitting multiple sclerosis: A randomized clinical trial. JAMA 2019 15;321:165-74.
9	Aharonowiz M, Einstein O, Fainstein N, Lassmann H, Reubinoff B, Ben-Hur T Neuroprotective effect of transplanted human embryonic stem cell-derived neural precursors in an animal model of multiple sclerosis. PLoS One 2008;3:e3145. doi: 10.1371/journal.pone.0003145.
10	Duncan T, Valenzuela M Alzheimer’s disease, dementia, and stem cell therapy. Stem Cell Res Ther 2017;8:111.
11	Zeng L, Chan LL, Lim EC, Tan EK Stem cell replacement therapies in Parkinson’s disease. Ann Acad Med Singap 2019;48:112-4.
12	Barker RA Stem cells and neurological disease. J Neurol Neurosurg Psychiatry 2003;74:553-7.
13	Ben-Hur T Immunomodulation by neural stem cells. J Neurol Sci 2008;265:102-4.
14	Lukovic D, Moreno-Manzano V, Rodriguez-Jimenez FJ, Vilches A, Sykova E, Jendelova P, et al. hiPSC disease modeling of rare hereditary cerebellar ataxias: Opportunities and future challenges. Neuroscientist 2017;23:554-66.
15	Baksh D, Song L, Tuan RS Adult mesenchymal stem cells: Characterization, differentiation, and application in cell and gene therapy. J Cell Mol Med 2004;8:301-16.
16	Aliaghaei A, Boroujeni ME, Ahmadi H, Bayat AH, Tavirani MR, Abdollahifar MA, et al. Dental pulp stem cell transplantation ameliorates motor function and prevents cerebellar atrophy in rat model of cerebellar ataxia. Cell Tissue Res 2019;376: 179-87.
17	Chang YK, Chen MH, Chiang YH, Chen YF, Ma WH, Tseng CY, et al. Mesenchymal stem cell transplantation ameliorates motor function deterioration of spinocerebellar ataxia by rescuing cerebellar Purkinje cells. J Biomed Sci 2011;18:54.
18	Mendonça LS, Nóbrega C, Hirai H, Kaspar BK, Pereira de Almeida L Transplantation of cerebellar neural stem cells improves motor coordination and neuropathology in Machado-Joseph disease mice. Brain 2015;138:320-35.
19	Nuryyev RL, Uhlendorf TL, Tierney W, Zatikyan S, Kopyov O, Kopyov A, et al. Transplantation of human neural progenitor cells reveals structural and functional improvements in the spastic Han-Wistar rat model of ataxia. Cell Transplant 2017;26:1811-21.
20	Chintawar S, Hourez R, Ravella A, Gall D, Orduz D, Rai M, et al. Grafting neural precursor cells promotes functional recovery in an SCA1 mouse model. J Neurosci 2009;29:13126-35.
21	Jin JL, Liu Z, Lu ZJ, Guan DN, Wang C, Chen ZB, et al. Safety and efficacy of umbilical cord mesenchymal stem cell therapy in hereditary spinocerebellar ataxia. Curr Neurovasc Res 2013;10: 11-20.
22	Dongmei H, Jing L, Mei X, Ling Z, Hongmin Y, Zhidong W, et al. Clinical analysis of the treatment of spinocerebellar ataxia and multiple system atrophy-cerebellar type with umbilical cord mesenchymal stromal cells. Cytotherapy 2011;13:913-7.
23	Yang WZ, Zhang Y, Wu F, Zhang M, Cho S, Li CZ, et al. Human umbilical cord blood-derived mononuclear cell transplantation: Case series of 30 subjects with hereditary ataxia. J Transl Med 2011;9:65.
24	Yun Q, Zheng W, Hingshe L, Peng X, Wenyi C, Yanguang L, et al. Transplantation of umbilical cord mesenchymal stem cells for treatment of autosomal dominant spinocerebellar ataxia in 12 cases. Chinese J Tissue Eng Res 2012;53:2652-2655.
25	Tsai YA, Liu RS, Lirng JF, Yang BH, Chang CH, Wang YC, et al. Treatment of spinocerebellar ataxia with mesenchymal stem cells: A phase I/IIa clinical study. Cell Transplant 2017; 26:503-12.
26	Bhartiya M, Kumar A, Singh RK, Radhakrishnan DM, Rajan R, Srivastava AK Mesenchymal stem cell therapy in the treatment of neurodegenerative cerebellar ataxias: A systematic review and meta-analysis. Cerebellum 2022. doi: 10.1007/s12311-022-01403-6.
27	Appelt PA, Comella K, de Souza LAPS, Luvizutto GJ Effect of stem cell treatment on functional recovery of spinocerebellar ataxia: Systematic review and meta-analysis. Cerebellum Ataxias 2021;8:8.
28	Tiwari SS, Raman S Governing stem cell therapy in India: Regulatory vacuum or jurisdictional ambiguity? New Genet Soc 2014;33:413-33.