Stem cells for amyotrophic lateral sclerosis modeling and therapy: myth or fact?

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease whose pathophysiology is poorly understood. Aiming to better understand the cause of motor neuron death, the use of experimental cell-based models increased significantly over the past years. In this scenario, much knowledge has been generated from the study of motor neurons derived from embryonic stem cells and induced pluripotent stem cells. These methods, however, have advantages and disadvantages, which must be balanced on experimental design. Preclinical studies provide valuable information, making it possible to combine diverse methods to build an expanded knowledge of ALS pathophysiology. In addition to using stem cells as experimental models for understanding disease mechanism, these cells had been quoted for therapy in ALS. Despite ethical issues involved in its use, cell therapy with neural stem cells stands out. A phase I clinical trial was recently completed and a phase II is on its way, attesting the method's safety. In another approach, mesenchymal stromal cells capable of releasing neuroregulatory and anti-inflammatory factors have also been listed as candidates for cell therapy for ALS, and have been admitted as safe in a phase I trial. Despite recent advances, application of stem cells as an actual therapy for ALS patients is still in debate. Here, we discuss how stem cells have been useful in modeling ALS and address critical topics concerning their therapeutic use, such as administration protocols, injection site, cell type to be administered, type of transplantation (autologous vs. allogeneic) among other issues with particular implications for ALS therapy.

Coatti GC ，Beccari MS ，Olávio TR ，Mitne-Neto M ，Okamoto OK ，Zatz M ... -  《-》

Reverse engineering human neurodegenerative disease using pluripotent stem cell technology.

With the technology of reprogramming somatic cells by introducing defined transcription factors that enables the generation of "induced pluripotent stem cells (iPSCs)" with pluripotency comparable to that of embryonic stem cells (ESCs), it has become possible to use this technology to produce various cells and tissues that have been difficult to obtain from living bodies. This advancement is bringing forth rapid progress in iPSC-based disease modeling, drug screening, and regenerative medicine. More and more studies have demonstrated that phenotypes of adult-onset neurodegenerative disorders could be rather faithfully recapitulated in iPSC-derived neural cell cultures. Moreover, despite the adult-onset nature of the diseases, pathogenic phenotypes and cellular abnormalities often exist in early developmental stages, providing new "windows of opportunity" for understanding mechanisms underlying neurodegenerative disorders and for discovering new medicines. The cell reprogramming technology enables a reverse engineering approach for modeling the cellular degenerative phenotypes of a wide range of human disorders. An excellent example is the study of the human neurodegenerative disease amyotrophic lateral sclerosis (ALS) using iPSCs. ALS is a progressive neurodegenerative disease characterized by the loss of upper and lower motor neurons (MNs), culminating in muscle wasting and death from respiratory failure. The iPSC approach provides innovative cell culture platforms to serve as ALS patient-derived model systems. Researchers have converted iPSCs derived from ALS patients into MNs and various types of glial cells, all of which are involved in ALS, to study the disease. The iPSC technology could be used to determine the role of specific genetic factors to track down what's wrong in the neurodegenerative disease process in the "disease-in-a-dish" model. Meanwhile, parallel experiments of targeting the same specific genes in human ESCs could also be performed to control and to complement the iPSC-based approach for ALS disease modeling studies. Much knowledge has been generated from the study of both ALS iPSCs and ESCs. As these methods have advantages and disadvantages that should be balanced on experimental design in order for them to complement one another, combining the diverse methods would help build an expanded knowledge of ALS pathophysiology. The goals are to reverse engineer the human disease using ESCs and iPSCs, generate lineage reporter lines and in vitro disease models, target disease related genes, in order to better understand the molecular and cellular mechanisms of differentiation regulation along neural (neuronal versus glial) lineages, to unravel the pathogenesis of the neurodegenerative disease, and to provide appropriate cell sources for replacement therapy. This article is part of a Special Issue entitled SI: PSC and the brain.

Liu Y ，Deng W 《-》

Cellular and molecular approaches to motor neuron therapy in amyotrophic lateral sclerosis and spinal muscular atrophy.

Amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA) are progressive fatal neurodegenerative diseases. They differ in their disease development but have in common a loss of motor neuron as they progress. Research is ongoing to further understand the origin of these diseases but this common thread of motor neuron loss has provided a target for the development of therapies for both ALS and SMA. It is the linked fields of gene and cell therapy that are providing some of the most interesting therapeutic possibilities.

O'Connor DM ，Boulis NM 《-》

Stem cell therapy in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder of upper and lower motor neurons, characterized by progressive muscular atrophy and weakness which culminates in death within 2-5 years. Despite various hypotheses about the responsible mechanisms, the etiology of ALS remains incompletely understood. However, it has been recently postulated that stem cell therapy could potentially target several mechanisms responsible for the etiology of ALS and other nervous system disorders, and could be regarded as one of the most promising therapeutic strategies for ALS treatment. We present a brief review of different methods of stem cell therapy in ALS patients and discuss the results with different cell types and routes of administration.

Meamar R ，Nasr-Esfahani MH ，Mousavi SA ，Basiri K ... -  《-》

Safety and Clinical Effects of Mesenchymal Stem Cells Secreting Neurotrophic Factor Transplantation in Patients With Amyotrophic Lateral Sclerosis: Results of Phase 1/2 and 2a Clinical Trials.

Petrou P ，Gothelf Y ，Argov Z ，Gotkine M ，Levy YS ，Kassis I ，Vaknin-Dembinsky A ，Ben-Hur T ，Offen D ，Abramsky O ，Melamed E ，Karussis D ... -  《-》