Sporadic amyotrophic lateral sclerosis (ALS) is a fatal disease with unknown etiology, characterized by a progressive loss of motor neurons leading to paralysis and death typically within 3-5 years of onset. Recently, there has been remarkable progress in understanding inherited forms of ALS in which well defined mutations are known to cause the disease. Rodent models in which the superoxide dismutase-1 (SOD1) mutation is overexpressed recapitulate hallmark signs of ALS in patients. Early anatomical changes in mouse models of fALS are seen in the neuromuscular junctions (NMJs) and lower motor neurons, and selective reduction of toxic mutant SOD1 in the spinal cord and muscle of these models has beneficial effects. Therefore, much of ALS research has focused on spinal motor neuron and NMJ aspects of the disease. Here we show that, in the SOD1 G93A rat model of ALS, spinal motor neuron loss occurs presymptomatically and before degeneration of ventral root axons and denervation of NMJs. Although overt cell death of corticospinal motor neurons does not occur until disease endpoint, we wanted to establish whether the upper motor neuron might still play a critical role in disease progression. Surprisingly, the knockdown of mutant SOD1 in only the motor cortex of presymptomatic SOD1 G93A rats through targeted delivery of AAV9 -SOD1-shRNA resulted in a significant delay of disease onset, expansion of lifespan, enhanced survival of spinal motor neurons, and maintenance of NMJs. This datum suggests an early dysfunction and thus an important role of the upper motor neuron in this animal model of ALS and perhaps patients with the disease.

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder that is characterized by progressive degeneration of motor neurons in the cortex, brainstem and spinal cord. This leads to paralysis, respiratory insufficiency and death within an average of 3 to 5 years from disease onset. While the genetics of ALS are becoming more understood in familial cases, the mechanisms underlying disease pathology remain unclear and there are no effective treatment options. Without understanding what causes ALS it is difficult to design treatments. However, in recent years stem cell transplantation has emerged as a potential new therapy for ALS patients. While motor neuron replacement remains a focus of some studies trying to treat ALS with stem cells, there is more rationale for using stem cells as support cells for dying motor neurons as they are already connected to the muscle. This could be through reducing inflammation, releasing growth factors, and other potential less understood mechanisms. Prior to moving into patients, stringent pre-clinical studies are required that have at least some rationale and efficacy in animal models and good safety profiles. However, given our poor understanding of what causes ALS and whether stem cells may ameliorate symptoms, there should be a push to determine cell safety in pre-clinical models and then a quick translation to the clinic where patient trials will show if there is any efficacy. Here, we provide a critical review of current clinical trials using either mesenchymal or neural stem cells to treat ALS patients. Pre-clinical data leading to these trials, as well as those in development are also evaluated in terms of mechanisms of action, validity of conclusions and rationale for advancing stem cell treatment strategies for this devastating disorder.

Early dysfunction of cortical motor neurons may underlie the initiation of amyotrophic lateral sclerosis (ALS). As such, the cortex represents a critical area of ALS research and a promising therapeutic target. In the current study, human cortical-derived neural progenitor cells engineered to secrete glial cell line-derived neurotrophic factor (GDNF) were transplanted into the SOD1 G93A ALS rat cortex, where they migrated, matured into astrocytes, and released GDNF. This protected motor neurons, delayed disease pathology and extended survival of the animals. These same cells injected into the cortex of cynomolgus macaques survived and showed robust GDNF expression without adverse effects. Together this data suggests that introducing cortical astrocytes releasing GDNF represents a novel promising approach to treating ALS. STEM CELLS 2018;36:1122-1131 SIGNIFICANCE STATEMENTStudies suggest that upper motor neurons in the cortex are affected in amyotrophic lateral sclerosis (ALS) patients and in the SOD1 rat. As such, this study assessed the effects of transplanting neural progenitor cells secreting a powerful growth factor, glial cell line-derived neurotrophic factor (GDNF) (hNPC GDNF ) into the motor cortex of the SOD1 rat. For the first time, it is shown that the cells survived, matured into astrocytes, and released GDNF in the brain. Critically, these cells in the cortex were able to protect both upper and lower motor neurons, delay disease pathology and extend survival of the ALS rats. Furthermore, these cells injected into the cortex of cynomolgus macaques survived and showed robust GDNF expression without adverse effects, suggesting that this novel approach is a promising therapeutic strategy for the treatment of ALS patients.

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Therapeutic study, level IV.