Stem cell transplantation for amyotrophic lateral sclerosis: therapeutic potential and perspectives on clinical translation

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neurological disease characterized by degeneration of upper and lower motor neurons. There are currently no clinically impactful treatments for this disorder. Death occurs 3-5 years after diagnosis, usually due to respiratory failure. ALS pathogenesis seems to involve several pathological mechanisms (i.e., oxidative stress, inflammation, and loss of the glial neurotrophic support, glutamate toxicity) with different contributions from environmental and genetic factors. This multifaceted combination highlights the concept that an effective therapeutic approach should counteract simultaneously different aspects: stem cell therapies are able to maintain or rescue motor neuron function and modulate toxicity in the central nervous system (CNS) at the same time, eventually representing the most comprehensive therapeutic approach for ALS. To achieve an effective cell-mediated therapy suitable for clinical applications, several issues must be addressed, including the identification of the most performing cell source, a feasible administration protocol, and the definition of therapeutic mechanisms. The method of cell delivery represents a major issue in developing cell-mediated approaches since the cells, to be effective, need to be spread across the CNS, targeting both lower and upper motor neurons. On the other hand, there is the need to define a strategy that could provide a whole distribution without being too invasive or burdened by side effects. Here, we review the recent advances regarding the therapeutic potential of stem cells for ALS with a focus on the minimally invasive strategies that could facilitate an extensive translation to their clinical application.

Autophagy in motor neuron disease: Key pathogenetic mechanisms and therapeutic targets

“…Currently available ALS models do not entirely recapitulate the human pathology, thus raising the question whether screening therapeutic compounds in such models may prove beneficial in humans. In this regard, the advent of iPSC-based models may represent a valuable approach for future research (Faravelli et al, 2014).…”

From mice to mind: Strategies and progress in translating neuroregeneration

“…Interestingly, MSCs from one patient with a favorable response to autologous MSCs were tested in SOD1 mice and found to prolong survival more than MSCs from patients who had failed to improve, illustrating the potential of animal models to help evaluate clinical observations as trials progress . The reader is referred to other more comprehensive reviews for additional details regarding ongoing cell therapy trials for ALS (Antonic et al, 2013;Donnelly et al, 2012;Faravelli et al, 2014;Thomsen et al, 2014) …”

Amyotrophic Lateral Sclerosis - Cell Based Therapy and Novel Therapeutic Development

“…There have been ongoing human trials with MSC on ALS treatment with completed human trial data (human clinical trials data as time of review paper written, https://clinicaltrials.gov) [7, 8, 17]. In 2010, Mazzini et al reported phase 1 trial data with MSC transplant in ALS patients in Italy [18].…”

“…The neurotropic effects were effective enough to revive the ALS animals, which consisted mostly of SOD1 rodents. Current ongoing human trials will give better understanding of cord blood cells against ALS [17, http://clinicaltrials.org]. …”

“…Their ability to connect the central nervous system (CNS) with the peripheral nervous system (PNS) and their multi-potent stem cell properties make OEC an excellent candidate for ALS cell transplant. Successful preclinical studies with OEC cells have been shown in clinical tests [7, 17]. …”