Stimulated by the 2012 Nobel Prize in Physiology or Medicine awarded for Shinya Yamanaka and Sir John Gurdon, there is an increasing interest in the induced pluripotent stem （iPS） cells and ...reprograming technologies in medical science. While iPS cells are expected to open a new era providing enormous opportunities in biomedical sciences in terms of cell therapies and regenerative medicine, safety-related concerns for iPS cell-based cell therapy should be resolved prior to the clinical application of iPS cells. In this review, the pre-clinieal investigations of cell therapy for spinal cord injury （SCI） using neural stem/progenitor cells derived from iPS cells, and their safety issues in vivo, are outlined. We also wish to discuss the strategy for the first human trails of iPS cell-based cell therapy for SCI patients.
Biological systems can respond to a wide range of static magnetic fields (SMF). Some of these responses seem to be mediated partly through free radical reactions. For example, in magnetic sense and ...navigation using the geomagnetic field, one of the most promising mechanisms for explaining magnetic compass is "a radical pair mechanism". Biological free radicals are most commonly oxygen or nitrogen based with an unpaired electron, leading to the terms "reactive oxygen species (ROS)" or "reactive nitrogen species (RNS)". When applying SMF to medical treatment, coupling SMF exposure with possible chemotherapy of cancers is a novel fascinating area that SMF could enhance agent-induced ROS production against tumors. In addition, one of the potent mechanisms of SMF effects on hemodynamics and blood pressure has sometimes been linked to nitric oxide pathway. However, health and environmental concerns have been raised because the SMF effects on oxidative stress leading to genetic mutation and apoptosis/necrosis have been found. It seems to take place from free radical generation.
Numerous basic research studies have suggested the potential efficacy of neural precursor cell (NPC) transplantation in spinal cord injury (SCI). However, in most such studies, the origin of the ...cells used was mainly fetal tissue or embryonic stem cells, both of which carry potential ethical concerns with respect to clinical use. The development of induced pluripotent stem cells (iPSCs) opened a new path toward regenerative medicine for SCI. iPSCs can be generated from somatic cells by induction of transcription factors, and induced to differentiate into NPCs with characteristics of cells of the central nervous system. The beneficial effect of iPSC‐derived NPC transplantation has been reported from our group and others working in rodent and non‐human primate models. These promising results facilitate the application of iPSCs for clinical applications in SCI patients. However, iPSCs also have issues, such as genetic/epigenetic abnormalities and tumorigenesis because of the artificial induction method, that must be addressed prior to clinical use. The selection of somatic cells, generation of integration‐free iPSCs, and characterization of differentiated NPCs with thorough quality management are all needed to address these potential risks. To enhance the efficacy of the transplanted iPSC‐NPCs, especially at chronic phase of SCI, administration of a chondroitinase or semaphorin3A inhibitor represents a potentially important means of promoting axonal regeneration through the lesion site. The combined use of rehabilitation with such cell therapy approaches is also important, as repetitive training enhances neurite outgrowth of transplanted cells and strengthens neural circuits at central pattern generators. Our group has already evaluated clinical grade iPSC‐derived NPCs, and we look forward to initiating clinical testing as the next step toward determining whether this approach is safe and effective for clinical use.
This article is part of the mini review series “60th Anniversary of the Japanese Society for Neurochemistry”.
Since the development of induced pluripotent stem cells (iPSCs), we have demonstrated the efficacy of iPSC‐derived neural precursor cells (NPCs) in animal models of spinal cord injury (SCI), and challenged safety issues such as tumorigenicity. Moreover, we have advocated importance of combinatory therapy to enhance regeneration in SCI, especially at chronic phase. We are developing and characterizing clinical grade iPSC‐derived NPCs, and the application for SCI patients will start shortly.
This article is part of the mini review series “60th Anniversary of the Japanese Society for Neurochemistry”.
New trends in cellular therapy Okano, Hideyuki; Sipp, Doug
Development (Cambridge),
09/2020, Volume:
147, Issue:
18
Journal Article
Peer reviewed
Open access
Regenerative therapies, including both gene and cellular therapies, aim to induce regeneration of cells, tissues and organs and restore their functions. In this short Spotlight, we summarize the ...latest advances in cellular therapies using pluripotent stem cells (PSCs), highlighting the current status of clinical trials using induced (i)PSC-derived cells. We also discuss the different cellular products that might be used in clinical studies, and consider safety issues and other challenges in iPSC-based cell therapy.
Recent studies have revealed that decline in cellular nicotinamide adenine dinucleotide (NAD+) levels causes aging-related disorders and therapeutic approaches increasing cellular NAD+ prevent these ...disorders in animal models. The administration of nicotinamide mononucleotide (NMN) has been shown to mitigate aging-related dysfunctions. However, the safety of NMN in humans have remained unclear. We, therefore, conducted a clinical trial to investigate the safety of single NMN administration in 10 healthy men. A single-arm non-randomized intervention was conducted by single oral administration of 100, 250, and 500 mg NMN. Clinical findings and parameters, and the pharmacokinetics of NMN metabolites were investigated for 5 h after each intervention. Ophthalmic examination and sleep quality assessment were also conducted before and after the intervention. The single oral administrations of NMN did not cause any significant clinical symptoms or changes in heart rate, blood pressure, oxygen saturation, and body temperature. Laboratory analysis results did not show significant changes, except for increases in serum bilirubin levels and decreases in serum creatinine, chloride, and blood glucose levels within the normal ranges, independent of the dose of NMN. Results of ophthalmic examination and sleep quality score showed no differences before and after the intervention. Plasma concentrations of N-methyl-2-pyridone-5-carboxamide and N-methyl-4-pyridone-5-carboxamide were significantly increased dose-dependently by NMN administration. The single oral administration of NMN was safe and effectively metabolized in healthy men without causing any significant deleterious effects. Thus, the oral administration of NMN was found to be feasible, implicating a potential therapeutic strategy to mitigate aging-related disorders in humans.
•Recent gene manipulation technology enables generation of GM non-human primates.•Transgenic non-human primates modeling human diseases have been generated.•Genome editing technology has enabled ...creation of knockout non-human primates.
Although mice have been the most frequently used experimental animals in many research fields due to well-established gene manipulation techniques, recent evidence has revealed that rodent models do not always recapitulate pathophysiology of human neurological and psychiatric diseases due to the differences between humans and rodents. The recent developments in gene manipulation of non-human primate have been attracting much attention in the biomedical research field, because non-human primates have more applicable brain structure and function than rodents. In this review, we summarize recent progress on genetically-modified non-human primates including transgenic and knockout animals using genome editing technology.
Bioluminescence is a natural light source based on luciferase catalysis of its substrate luciferin. We performed directed evolution on firefly luciferase using a red-shifted and highly deliverable ...luciferin analog to establish AkaBLI, an all-engineered bioluminescence in vivo imaging system. AkaBLI produced emissions in vivo that were brighter by a factor of 100 to 1000 than conventional systems, allowing noninvasive visualization of single cells deep inside freely moving animals. Single tumorigenic cells trapped in the mouse lung vasculature could be visualized. In the mouse brain, genetic labeling with neural activity sensors allowed tracking of small clusters of hippocampal neurons activated by novel environments. In a marmoset, we recorded video-rate bioluminescence from neurons in the striatum, a deep brain area, for more than 1 year. AkaBLI is therefore a bioengineered light source to spur unprecedented scientific, medical, and industrial applications.
Ropinirole, a New ALS Drug Candidate Developed Using iPSCs Okano, Hideyuki; Yasuda, Daisuke; Fujimori, Koki ...
Trends in pharmacological sciences (Regular ed.),
February 2020, 2020-Feb, 2020-02-00, 20200201, Volume:
41, Issue:
2
Journal Article
Peer reviewed
Open access
Induced pluripotent stem cells (iPSCs) are increasingly used in the study of disease mechanisms and the development of effective disease-modifying therapies for neurodegenerative diseases, including ...amyotrophic lateral sclerosis (ALS). Recently, three candidate anti-ALS drugs – ropinirole (ROPI), retigabine, and bosutinib – have been identified in iPSC-based drug screens and are now being evaluated in clinical trials for safety and effectiveness. We review the preclinical data, clinical research design, and rationale for ROPI as an anti-ALS drug candidate compared with those of the other two drugs. We also discuss the use of iPSCs for understanding and monitoring treatment response as well as for new insights into the development of new drugs and therapeutic interventions for major neurodegenerative diseases.
iPSC-based drug discovery is a promising technology for developing novel therapeutics for neurodegenerative diseases lacking useful disease models, such as amyotrophic lateral sclerosis (ALS).Ropinirole, retigabine, and bosutinib were identified as candidate therapeutic agents for ALS by the combination of iPSC-based drug discovery and drug repositioning.The potential anti-ALS mechanism of ropinirole is independent of antioxidant activity, rescue of mitochondria, reduction of stress granules, and abnormal proteins such as phosphorylated TDP-43 and FUS, and dopamine D2 receptor (D2R) agonism.Retigabine inhibits the hyperexcitability of motor neurons in ALS and bosutinib prompts autophagy and reduces abnormal proteins such as SOD-1 and phosphorylated TDP-43 via the Src/c-Abl pathway in motor neurons in ALS.Stratification of ALS, personalized medicine strategies, and the identification of common mechanisms with other neurodegenerative diseases are key aspects in the development of ALS therapies.
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