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.

Fig. 1

Cell-mediated therapies. Multiple cell types can be employed as a source for cell-mediated therapies

Fig. 2

Derivation and application of iPSCs. Induced pluripotent stem cells can be derived through specific factor reprogramming of patients’ somatic cells. Pluripotent stem cells are then grown in culture and differentiated into cell types, such as neuronal cells, which are useful for the treatment of a particular disease. Derived neurons and other neural cell types can be investigated in vitro and used for disease modeling. Neural cells can also be genetically corrected in vitro and employed for therapeutic transplantation

Fig. 3

Rationale for minimally invasive protocols of administration. Features of both neural stem cells (green boxes) and ALS disease (red boxes) make the assessment of minimally invasive protocols of administration feasible