Mesenchymal Stem Cells As A Therapeutic Option For Patients With ALS

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease with poorly understood pathophysiology. Death of upper and lower motor neuron results in weakness and paralysis of skeletal muscles including respiratory musculature. Disease typically begins with muscle weakness and atrophy or progressive bulbar palsy and leads to respiratory distress and death about 5 years from the diagnosis. About 1-2 new cases per 100000 per year are diagnosed, about 10% is familial and connected with superoxide dismutase 1 (SOD1) mutation.


Background
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease with poorly understood pathophysiology. Death of upper and lower motor neuron results in weakness and paralysis of skeletal muscles including respiratory musculature. Disease typically begins with muscle weakness and atrophy or progressive bulbar palsy and leads to respiratory distress and death about 5 years from the diagnosis. About 1-2 new cases per 100000 per year are diagnosed, about 10% is familial and connected with superoxide dismutase 1 (SOD1) mutation.
Despite scientific development, there is no successful treatment for ALS, riluzol only prolongs survival for about 10-20% [1]. Stem cell treatment might be a disease-modifying strategy for ALS patients. Mesenchymal stem cells (MSC) have been defined by International Society for Cellular Therapy, they are known to be weakly or nonimmunogenic and thus applicable in an allogeneic setting [2]. Wharton's jelly-derived MSC (WJ-MSC) seem to be a preferable source because of easiness and safety of the harvesting procedure as well as a rich number of cells contained in the umbilical cord. WJ-MSC have high immunomodulatory capabilities as well as good proliferation and differentiation potential. Their characteristics close to embryo-derived stem cells but with lower risk of potential tumorigenesis [3].

Mechanism of action
The mechanism behind ALS are not entirely known. Studies on animal models have been undertaken to deepen understanding of the disease and explore potential mechanisms of treatment with MSC. The hypothesis include indirect effects such as the delivery of growth factors in situ, modulation of glial cells secretome, up-regulating regulatory T-cell activity. Preclinical studies showed that MSC express 12 neural genes and 11 transcription factors, and are able to differentiate into neural and glial cells in an appropriate media [4].
Sun et al.
[5] study on ALS animal model proved that MSC plays a role in neuroprotection of motor neurons, astrocytes, microglia, and modulates their response to apoptosis. Modulation of response to inflammation by down-regulating expression of TNFα and IL-6 and iNOS was observed as well. According to Uccelli et al.
[6] study, paracrine mechanisms are more probable than local production of growth factors since MSC intravenous infusion into mouse ALS model lead to amelioration of motor neuron function, slowdown of weight loss and survival improvement, despite low engraftment rates. The results of co-culture of MSC with peripheral blood mononuclear cells Abstract It has been postulated that mesenchymal stem cells could play a role in treatment of patients with amyotrophic lateral sclerosis. Variety of mechanism behind MSC action has been proposed including immunomodulation and delivery of trophic factors. The scientific rationale in preclinical studies is being proved along with first clinical uses.

Preclinical studies
It has been confirmed during ex vivo experiment that WJ-MSC maintain their immunomodulatory properties upon a long-term culture and preserve genetic stability through expansion up to 15 passages without chromosomal changes and malignant transformation both in vitro and after MSC injection into nude mice with follow-up of 4 weeks Another study administered autologous mesenchymal stem cells intravenously and intrathecally. Stem cells infused through lumbar puncture were committed to neuronal differentiation. Disease progression was observed in study and control group, however its dynamics was significantly slower in patients who received stem cell therapy [19].
Oh et al. [20] conducted an open label phase I clinical trial with intrathecal injections of autologous BM-MSC. Seven out of 8 patients received 2 doses with time interval of about 1 month. No serious adverse effects were noted within 12 months of follow-up. The course of the disease seemed to be slower after therapy in comparison to previous decline. A retrospective analysis of 57 ALS patients, including 20 controls and 37 patients treated with autologous bone marrow mononuclear cells, showed survival benefit of stem cell therapy [21]. Another approach was demonstrated by Deda et al. [22] and Blanquer et al. [23]. The first above-mentioned study delivered bone marrowderived hematopoietic progenitor cells were to 13 patients via total laminectomy and under general anesthesia [22]. The second one administered neurosurgically BM-MNC to patients with bulbar-onset ALS and noted slower disease progression [23].

Summary
Application of stem cells as an actual therapy for ALS patients is still in debate. It is a promising method, however current results are difficult to evaluate due to vast heterogeneity of patients and therapeutic schemes as well as lack of long-term follow-up. A growing number of clinical trials undertake this issue to assess answers about MSC efficacy