Cell therapy in ALS: An update on preclinical and clinical studies

Abstract

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by the loss of motor neurons and neuromuscular impairment leading to complete paralysis, respiratory failure and premature death. The pathogenesis of the disease is multifactorial and noncell-autonomous involving the central and peripheral compartments of the neuromuscular axis and the skeletal muscle. Advanced clinical trials on specific ALS-related pathways have failed to significantly slow the disease. Therapy with stem cells from different sources has provided a promising strategy to protect the motor units exerting their effect through multiple mechanisms including neurotrophic support and excitotoxicity and neuroinflammation modulation, as evidenced from preclinical studies. Several phase I and II clinical trial of ALS patients have been developed showing positive effects in terms of safety and tolerability. However, the modest results on functional improvement in ALS patients suggest that only a coordinated effort between basic and clinical researchers could solve many problems, such as selecting the ideal stem cell source, identifying their mechanism of action and expected clinical outcomes. A promising approach may be stem cells selected or engineered to deliver optimal growth factor support at multiple sites along the neuromuscular pathway. This review covers recent advances in stem cell therapies in animal models of ALS, as well as detailing the human clinical trials that have been done and are currently undergoing development.

Keywords: Bone marrow stem cells; Clinical trials; Hematopoietic stem cells; Mesenchymal stem cells; Neural stem cells; SOD1G93A transgenic rodents; Umbilical cord blood stem cells.