Novel Therapeutics for ALS: Becoming reality
Amyotrophic lateral sclerosis (ALS) is a relentlessly progressive neurodegenerative condition that is almost always fatal; usually in three to five years after diagnosis. Most recently we have lost Steven Hawkin who was a very great scientist-he suffered from this disorder. The etiology of ALS remains unresolved and no effective treatment exists. This study looked at an area of ALS potential treatment that is understudied. Reprogramed induced pluripotent stem cells from patient cells reverse key hallmarks of cellular age. Increased recognition of cell type-specific aging paradigms underscores the importance of tipping the balance from a state of compensated dysfunction to decompensation and progression.
The pathophysiology of amyotrophic lateral sclerosis (ALS) is particularly challenging due to the heterogeneity of its clinical presentation and diversity of cellular, molecular, and genetic peculiarities involved. Molecular insights unveiled several novel genetic factors to be inherent in both familial (a disorder that is found in generations of family members) and sporadic disease entities. Apart from genetically well-defined high confidence and other susceptibility loci, the role of DNA damage and repair strategies of the genome as a whole. Advancing our knowledge in this field will increase the better understanding of this relentless disease, for therapeutic options other than symptomatic treatments that are mostly unavailable. ALS is also known as Lou Gehrig’s disease or motor neuron disease and is a relentless disorder with a progressive loss of upper motor neurons in the cerebral motor cortex (Penndorf, Witte & Kretz, 2018).
Researchers at the Institute of Neuroscience in China have discovered a new cellular mechanism for ALS. This discovery suggests a novel therapeutic strategy targeting the RNA degradation pathway and identified an asthma drug as a potential medication for this disorder. ALS is the most common motor neuron disease and one of the most devastating neurodegenerative diseases caused by progressive motor neuron degeneration. There is no cure and limited treatment options. As a result, the disease progresses quickly and is always fatal. Recent genetic studies have found C9orf72 is the most common genetic cause of familial ALS and is also seen in some sporadic ALS. Unfortunately, even with these strides, the underlying mechanism is not fully understood. Tranilast asthma medicine has been in use since the 1980s and has a good tolerance record. Recently if was found that this medicine crosses the blood/brain barrier. It also presented as the most promising NMD (non-mediated mRNA decay)-activating drug and found it could rescue cells from C9orf72 DPR (dipeptide repeats)-induced neurotoxicity. This research paves the way for more studies into how Tranilast and other NMD-activating compounds in ALS patients with defective RNA metabolism (CASH, 2019).
What is known now
Gene therapy is at the cutting-edge of techniques used to develop novel therapies. This gives researchers a platform to explore methods to correct disease-causing DNA mutations, eliminate toxic RNA/proteins and/or increase the expression of therapeutic proteins. Recent advances in basic science and technology have enabled enhanced pre-clinical strategies resulting in the emergence of sophisticated treatment options available for afflicted patients. This research has discussed gene therapy as a method to treat neurological disorders including amyotrophic lateral sclerosis (ALS), spinal muscular atrophy, neuropathic pain, stroke, peripheral nerve injury, and repair. This research forum describes many important characteristics of diverse gene therapy applications and gives hope that treatment options for many CNS and PNS disorders can lead to a viable clinical option (Tosolini & Smith, 2018).
CHCHD10 mutations are linked to ALS but their mode of action is unclear. As the researchers were studying a 29-year-old patient with rapid disease progression found a novel mutation (Q108P) in the CHCH part of the DNA strand. The recent identification of mutations in CHCHD10 implicates mitochondrial dysfunction in the pathogenesis of frontotemporal dementia and ALS. Mutations have been reported mainly in the N-terminus. However, the exact molecular function of the protein and the effect of these mutations remain unknown. A study done on an extended family with variable clinical presentations including classic motor neuron disease, cerebellar ataxia and frontal lobe cognitive symptoms provided much information. The mutation S59L was found in these patients and it demonstrated a ragged-red fiber myopathy usually seen in the mitochondrial disease. Unusual phenotypes of genetically determined diseases offer an opportunity to explore molecular pathomechanisms. The study identified a novel CHCHD10 mutation in a young ALS patient with an aggressive disease course. Rescue of mitochondrial import Mia40 overexpression that suggests Q108P reduces binding affinity to Mia40 can be compensated. R15L mutation had a much smaller effect (Lehmer et al, 2018).
Research up to this writing
In neurodegenerative disorders, neuroprotection by diet and natural bioactive compounds have been proposed to prevent the onset and progress of neurodegeneration by modification of pathogenic factors. Plant food-derived phytochemicals protect neurons via targeting oxidative stress, mitochondrial dysfunction, neurotrophic factor deficit, apoptosis, and abnormal protein accumulation. Phytochemicals regulate mitochondrial functions apoptosis signaling, mitochondrial biogenesis, and degradation by autophagy and exhibit neuroprotection. Phytochemicals protect neuron by targeting multiple pathogenic factors of a neuron by targeting multiple pathogenic factors of neurodegenerative disorders. Intervention with food-derived compounds has been proposed as the therapeutic strategy for age-dependent neurodegeneration. However, the beneficial effects of phytochemicals in clinical studies have not been fully confirmed. Phytochemicals and derivatives are currently given as preventive and therapeutic compounds in patients with neuropsychiatric and neurodegenerative disorders and depression. It is hoped with this study results showing such promise that it will promote further development of a novel series of therapeutic agents (Naoi, Shamoto-Nagai & Maruyama, 2019).
Exosomes are small vesicles involved in intercellular communication. This study found Schwann cells express exosomes CD9 and Alix. Twelve proteins were found to be closely related to CNS repair and classified them by different potential mechanisms such as axon regeneration and inflammation inhibitions. In the peripheral neural system, an injury is helped to repair by Schwann cells promote nerve regeneration through secreting growth factors, clearing myelin and axonal debris, activating macrophages and making a new medullary sheath. Schwann cells are the main functional glial cells in the peripheral nervous system and play a very important role in axon regeneration after PNS injury. The findings give researchers new promising strategy for other neurodegenerative disorders. There is an urgent need to look at exosomes content to help researchers gain a deeper understanding of the potential therapeutic mechanism. Cellular processes involving biological regulation share close ties with exosomes and with microenvironment regulation. It was found that SCDE can create more permissive microenvironment related to each component in the central nervous system for regeneration (Wei et al, 2019).
This study was conducted to improve understanding of the biological processes that induce this immune dysregulation will help to identify therapeutic strategies that circumvent or ameliorate the pathogenesis of ALS. Emerging cell-based therapies hold the promise of accomplishing this goal and therefore improving the quality of life and extending survival in patients with ALS. The pathophysiological process underlying ALS are multifactorial and reflect a complex interaction between genetic and environmental factors. Testing is being investigated on cell-based therapies with ALS. Mesenchymal stem cells derived from bone marrow or fat have been infused into the cerebral spinal fluid on several patients with ALS in phase 1 studies. In one of the phase 2 studies, 14 ALS patients were injected and potential benefits were attributed to enhance neurotrophic growth factor secretion. Mesenchymal stem cell-mediated stimulation of regulatory T cells leads to a suggestion that this major mechanism of action of the potential benefits for these stricken people. ALS-linked mutant immune genes provide evidence that immune dysregulation contributes to the pathogenesis of ALS. Even those patients that represent with sporadic ALS without known genetic abnormalities present with immune dysregulation. Cell-based strategies that enhance the anti-inflammatory reactivity and reverse immune dysregulation offer the potential of slowing progression of the disease and increasing quality of life of patients so afflicted (Beers & Appel, 2019).
Beers D. R. & Appel, S. H. (2019). Immune dysregulation in amyotrophic lateral sclerosis: Mechanisms and emerging therapies. The Lancet Neurology, 18(2).
Chinese Academy of Sciences Headquarters. (2019). Researchers reveal novel therapeutic strategy for ALS. Institute of Neuroscience of the Chinese Academy of Sciences.
Lehmer, C. et al. (2018). A novel CHCHD10 mutation implicates a Mia 40-dependent mitochondrial import deficit in ALS. EMBO Molecular Medicine, 10(e8558).
Naoi, M., Shamoto-Nagai, M. & Maruyama,W. (2019). Neuroprotection of multifunctional phytochemicals as novel therapeutic strategies for neurodegenerative disorders: Antiapoptotic and anti-amyloidogenic activities by modulation of cellular signal pathways. Future Neurology,14(1).
Penndorf, D, Witte, O.W. & Kretz, A. (2018). DNA plasticity and damage in amyotrophic lateral sclerosis. Neuronal Regeneration Research, 13(2).
Tosolini,A.P. & Smith, G.M. (2018). Editorial: Gene therapy for the central and peripheral nervous systems. Frontiers in Molecular Neuroscience, 11(54).
Wei, Z. et al. (2019). Proteomics analysis of Schwann cell-derived exosomes: A novel therapeutic strategy for central nervous system injury. Molecular and Cellular Biochemistry.
Ziff, O.J. & Patrani,R. (2018). Harnessing cellular aging in human stem cell models of Amyotrophic lateral sclerosis. Aging Cell, 18(11).