Amyotrophic lateral sclerosis (ALS) is a devastating incurable neurodegenerative disease that targets motor neurons (MNs) and their connections to muscle. The rate of decline in the number of MNs in ALS patients is very rapid compared with other neurodegenerative diseases. Putative mechanisms of toxicity targeting MNs include oxidative damage, accumulation of intracellular aggregates, mitochondrial dysfunction, defects in axonal transport, impairment of growth factor trophic support, altered glial function, aberrant RNA metabolism and glutamate excitotoxicity. Most cases of ALS are sporadic and are not associated with any known risk factors. The 5-10% of inherited ALS cases are termed familial ALS. Mutations in superoxide dismutase 1 (SOD1) are the mutations most commonly associated with familial ALS, and can be observed in 1–2% of all ALS patients.
ALS is characterized by the extensive degeneration of MNs of the spinal cord, brain stem and cerebral cortex. Therefore, the two major objectives of cell therapy for ALS are first, replacement of the lost motor neurons, and induction of neuroprotection of the still viable motor neurons. The main cell types that are being tested for cell therapy are mesenchymal (MSCs) and neural stem cells (NSCs) to promote neuroprotection, and to provide some degree of cell replacement. Embryonic stem cells (ESC) and induced pluripotent stem cells (iPSC)-derived motor neurons are being used to model the disease in-vitro, in order to study disease-related molecular mechanisms.
Neural stem cells (NSCs) are multipotent, self-renewable cells residing within the nervous system. They can be isolated from adult or fetal nervous system tissues, cultured in-vitro either as neurospheres or in a cell layer and can be further differentiated into mature neuronal cells. In the adult brain, NSCs are found at the subventricular zone (SVZ) of the lateral ventricles, and the subgranular zone of the hippocampal dentate gyrus. In addition, NSCs can also be found in the spinal cord and in the olfactory epithelium. NSC-based therapy for ALS aims to 1) replace dying neurons either by the injected cells or by mobilization of host NSCs, and to 2) promote neuroprotection by growth factor secretion. Upon spinal implantation, human NSCs were shown to protect endogenous motor neurons by secretion of glial-derived growth factor (GDNF), and brain-derived neurotrophic factor (BDNF) in the cerebral spinal fluid (CSF).
Mesenchymal stem cells (MSCs) can be easily isolated from different tissues of the body and cultured in-vitro. The ability to isolate them from the patient's own tissues, thereby circumventing risk of immune rejection, renders them ideal candidates for cell therapy. Their immunomodulatory capacities enable MSCs to rescue neurons and oligodendrocytes from apoptosis through the release of trophic, anti-apoptotic, and anti-inflammatory molecules, resulting in the induction of a neuroprotective effect. In addition, MSCs can promote the proliferation and maturation of local neural precursor cells, leading to their differentiation into mature neurons and oligodendrocytes Although there is some evidence that human MSCs can express neural markers such as Nestin and GFAP, their neuronal differentiation capacity is questionable. Therefore, their secretion of neurotrophic factors and immunomodulatory properties are more relevant for neuroprotective ALS therapy than for potential cell replacement.
Currently, several phase1/phase2 clinical trials using mesenchymal stem cells are being conducted. Modified MSCs, such as NurOwn™, which is comprised of neurotrophin-secreting cells, are being tested in phase 2 clinical trials and have shown promising therapeutic results.