Stem cell technology for the study and treatment of motor neuron diseases

Abstract

Amyotrophic lateral sclerosis and spinal muscular atrophy are devastating neurodegenerative diseases that lead to the specific loss of motor neurons. Recently, stem cell technologies have been developed for the investigation and treatment of both diseases. Here we discuss the different stem cells currently being studied for mechanistic discovery and therapeutic development, including embryonic, adult and induced pluripotent stem cells. We also present supporting evidence for the utilization of stem cell technology in the treatment of amyotrophic lateral sclerosis and spinal muscular atrophy, and describe key issues that must be considered for the transition of stem cell therapies for motor neuron diseases from bench to bedside. Finally, we discuss the first-in-human Phase I trial currently underway examining the safety and feasibility of intraspinal stem cell injections in amyotrophic lateral sclerosis patients as a foundation for translating stem cell therapies for various neurological diseases.

Conflict of interest statement

Financial & competing interests disclosure

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Figures

Figure 1. Derivation of stem cells for the study of neurological disease and therapeutic development

Embryonic stem cells are derived from the blastocyst inner cell mass and have an unrestricted ability to differentiate into cells from all three germ layers. Neural progenitors and neural stem cells are derived from fetal or adult tissue, respectively, and give rise to neural lineages. Mesenchymal stem cells are derived from bone marrow, but must differentiate across lineages to produce neural cells for autologous therapies. Fibroblasts are utilized for the derivation of induced pluripotent stem cells, which may be utilized for the generation of new models of neurological disease.

Figure 2. Clinical trial design examining intraspinal transplantation of human spinal cord stem cells in amyotrophic lateral sclerosis patients

(A) Amyotrophic lateral sclerosis (ALS) patients will receive unilateral or bilateral human spinal cord stem cell injections in the lumbar or cervical enlargements of the spinal cord (arrows). (B) Proposed mechanism of neuroprotection conferred by grafted cells in ALS patients. As motor neurons normally residing in the spinal cord of ALS patients start to degenerate, injected human spinal cord stem cells are hypothesized to integrate into the spinal cord to provide a source of cellular support, maintain a healthy microenvironment within the spinal cord, and provide neurotrophic support to the remaining motor neurons. (C) The trial will follow a ‘risk escalation’ paradigm, which reflects the gradual increase in risk between the different cohorts. ALS patients are divided into groups A–E based on ambulatory ability, number of injections (unilateral vs bilateral), and injection location (lumbar [L] vs cervical [C]).