Treatment Of Motor Neuron Diseases Research Articles

Edaravone for the Treatment of Motor Neurone Disease: A Critical Review of Approved and Alternative Formulations against a Proposed Quality Target Product Profile.

Edaravone is one of two main drugs for treating motor neurone disease (MND). This review proposes a specific quality target product profile (QTPP) for edaravone following an appraisal of the issues accounting for the poor clinical uptake of the approved IV and oral liquid edaravone formulations. This is followed by a review of the alternative oral formulations of edaravone described in the published patent and journal literature against the QTPP. A total of 14 texts published by six research groups on 18 novel oral formulations of edaravone for the treatment of MND have been reviewed. The alternative oral formulations included liquid and solid formulations developed with cyclodextrins, lipids, surfactants, co-surfactants, alkalising agents, tablet excipients, and co-solvents. Most were intended to deliver edaravone for drug absorption in the lower gastrointestinal tract (GIT); however, there were also four formulations targeting the oral mucosal absorption of edaravone to avoid first-pass metabolism. All the novel formulations improved the aqueous solubility, stability, and oral bioavailability (BA) of edaravone compared to an aqueous suspension of edaravone. A common limitation of the published formulations is the lack of MND-patient-centred data. Except for TW001, no other formulations have been trialled in MND patients. To meet the QTPP of an oral edaravone formulation for MND patients, it is recommended that a tablet of appropriate size and with acceptable taste and stability be designed for the effective sublingual or buccal absorption of edaravone. This tablet should be designed with input from the MND community.

Genome Editing Approaches Using Zinc Finger Nucleases (ZFNs) for the Treatment of Motor Neuron Diseases

Genome Editing Approaches Using Zinc Finger Nucleases (ZFNs) for the Treatment of Motor Neuron Diseases

Antisense Oligonucleotides (ASOs) in Motor Neuron Diseases: A Road to Cure in Light and Shade.

Antisense oligonucleotides (ASOs) are short oligodeoxynucleotides designed to bind to specific regions of target mRNA. ASOs can modulate pre-mRNA splicing, increase levels of functional proteins, and decrease levels of toxic proteins. ASOs are being developed for the treatment of motor neuron diseases (MNDs), including spinal muscular atrophy (SMA), amyotrophic lateral sclerosis (ALS) and spinal and bulbar muscular atrophy (SBMA). The biggest success has been the ASO known as nusinersen, the first effective therapy for SMA, able to improve symptoms and slow disease progression. Another success is tofersen, an ASO designed to treat ALS patients with SOD1 gene mutations. Both ASOs have been approved by the FDA and EMA. On the other hand, ASO treatment in ALS patients with the C9orf72 gene mutation did not show any improvement in disease progression. The aim of this review is to provide an up-to-date overview of ASO research in MNDs, from preclinical studies to clinical trials and, where available, regulatory approval. We highlight the successes and failures, underline the strengths and limitations of the current ASO research, and suggest possible approaches that could lead to more effective treatments.

Role of Biomarkers in Pathogenesis and Updated Treatment of Motor Neuron Disease: A Review Article

Role of Biomarkers in Pathogenesis and Updated Treatment of Motor Neuron Disease: A Review Article

Progress in the Treatment of Motor Neurone Disease with Traditional Chinese and Western Medicine

Motor neurone disease (MND) is commonly referred to as amyotrophic lateral sclerosis, which is characterized by progressive muscle weakness and muscle atrophy. At present, Western medicine has limited effective treatment measures for motor neurone disease. A large number of clinical trials have proved that TCM has achieved obvious curative effect in the treatment of MND through dialectical treatment, which can alleviate the clinical symptoms of patients to a certain extent. Therefore, this paper further discusses the progress of TCM and western medicine in the treatment of MND.

High Efficiency Power Management Unit for Implantable Optical-Electrical Stimulators

Battery-less active implantable devices are of interest because they offer longer life span and eliminate costly battery replacement surgical interventions. This is possible as a result of advances in inductive power transfer and development of power management circuits to maximize the overall power transfer and provide various voltage levels for multi-functional implantable devices. Rehabilitation therapy using optical stimulation of genetically modified peripheral neurons requires high current loads. Standard rectification topologies are inefficient and have associated voltage drops unsuited for miniaturized implants. This paper presents an integrated power management unit (PMU) for an optical-electrical stimulator to be used in the treatment of motor neurone disease. It includes a power-efficient regulating rectifier with a novel body biased high-speed comparator providing 3.3 V for the operation of the stimulator, a 3-stage latch-up charge pump with 12 V output for the input stage of the optical-electrical stimulator, and 1.8 V for digital control logic. The chip was fabricated in a 0.18 lm CMOS process. Measured results show that for a regulated output of 3.3 V delivering 30.3 mW power, the peak power conversion efficiency is 84.2% at 6.78 MHz inductive link tunable frequency reducing to 70.3% at 13.56 MHz. The charge pump with on chip capacitors has 90.9% measured voltage conversion efficiency.

PuraMatrix hydrogel enhances the expression of motor neuron progenitor marker and improves adhesion and proliferation of motor neuron-like cells.

Objective(s):Cell therapy has provided clinical applications to the treatment of motor neuron diseases. The current obstacle in stem cell therapy is to direct differentiation of stem cells into neurons in the neurodegenerative disorders. Biomaterial scaffolds can improve cell differentiation and are widely used in translational medicine and tissue engineering. The aim of this study was to compare the efficiency of two-dimensional with a three-dimensional culture system in their ability to generate functional motor neuron-like cells from adipose-derived stem cells. Materials and Methods:We compared motor neuron-like cells derived from rat adipose tissue in differentiation, adhesion, proliferation, and functional properties on two-dimensional with three-dimensional culture systems. Neural differentiation was analyzed by immunocytochemistry for immature (Islet1) and mature (HB9, ChAT, and synaptophysin) motor neuron markers. Results:Our results indicated that the three-dimensional environment exhibited an increase in the number of Islet1. In contrast, two-dimensional culture system resulted in more homeobox gene (HB9), Choline Acetyltransferase (ChAT), and synaptophysin positive cells. The results of this investigation showed that proliferation and adhesion of motor neuron-like cells significantly increased in three-dimensional compared with two-dimensional environments. Conclusion:The findings of this study suggested that three-dimension may create a proliferative niche for motor neuron-like cells. Overall, this study strengthens the idea that three-dimensional culture may mimic neural stem cell environment for neural tissue regeneration.

Advances in syndrome and treatment of motor neuron disease with traditional Chinese medicine

Motor neuron disease(MND) is a group of progressive motor neuron diseases and the pathogenesis is not well defined.The pathologic hallmark of is death of lower motor neurons(consisting of anterior horn cells in the spinal cord and their brainstem homologues innervating bulbar muscles) and upper, or corticospinal, motor neurons.The clinical manifestations of are mucsle weakness, muscle atrophy, fasciculations, bulbar paralysis and positive pyramidal signs.Traditional Chinese medicine(TCM) named as flaccidity syndrome.Recently, some scholars have proposed that MND can be regarded as an independent research object of TCM.At present, symptomatic supportive treatment is the main treatment for MMD in western medicine, which can only slow the progress of the disease.TCM treatment for has advantages of more effective than western medicine, fewer adverse reactions and lower price.So TCM can be used as an effective method for combined treatment of MND.This article reviews the research progress of syndrome and treatment of with TCM. Key words: Motor neuron disease; Amyotrophic lateral sclerosis; Medicine, chinese traditional; Flaccidity syndrome; Hoarseness disease and miliaria; Etiology and pathogenesis; Treatment according to syndrome differentiation; Review

Autologous stem cell-based interventions in Australia: exploring patient experience in light of regulatory exceptionalism

Background & Aim Over the last decade there has been a growing prevalence of privately owned clinics in Australia providing autologous interventions to patients based on ‘stem cells’ isolated from their own fat, blood or bone marrow. These claimed stem cell-based interventions have primarily been marketed for osteoarthritis treatment, but have also been available for facial rejuvenation, hair restoration, and the treatment of motor neurone disease, Parkinson's disease and dementia. Such interventions are rarely part of a clinical research program, lack high level evidence of efficacy, and are not reimbursed by public or private insurers, resulting in patients paying significant out of pocket expenses (AUD$6,000 or more per intervention). Due to a regulatory exemption that broadly excluded the manufacturing and administration of autologous cells and tissues from the oversight of the Australian Therapeutic Goods Administration, clinics have been able to market directly and aggressively to patients in a manner that both exaggerates benefits and underplays risks. This study explores how Australian patients and their carers understood and experienced these interventions, and in particular how their presumptions about autologous stem cells, the ethics of medical practice, and the regulatory environment in Australia have conditioned their preparedness to undergo unproven treatments. Methods, Results & Conclusion Findings were drawn from two workshops conducted in 2016 with patients, their carers and family members (22 participants) and 15 semi-structured interviews (conducted in 2017). Patients’ consideration of, and decision to undergo, an autologous stem cell-based intervention was shaped by five factors: illness experience, disillusion with current medical practice, unrealistic expectations about the intervention, lack of information from providers, and trust in the health care system and clinicians more broadly. While recently announced regulatory amendments may in time provide greater patient protection, the previous ‘light touch’ regulatory approach clearly created the preconditions in Australia for clinical practices with questionable evidentiary basis, and for a market where patient vulnerability and risk could be monetized. In future, we argue, efforts to enhance consumer awareness of the unregulated and unproven nature of autologous stem cell-based interventions need to be coupled with sound regulation and periodic policy review to avoid exceptionalism and patient exploitation.

Riluzole blocks HU210-facilitated ventral tegmental long-term depression by enhancing glutamate uptake in astrocytes

The lifetime prevalence of addiction to cannabis (marijuana or cannabinoids) is among the highest of that of all illicit drugs in developed countries, and no effective treatment for cannabis addiction is currently available. Previous studies in our research group suggested that astrocyte-mediated long-term depression (LTD) in ventral tegmental area (VTA) dopamine neurons plays a pivotal role in the development of cannabis addiction. The present study was designed to investigate the effects and potential mechanisms of riluzole, a drug used for the treatment of motor neuron diseases, on cannabinoid-facilitated LTD induction. We demonstrated that riluzole significantly inhibited HU210-induced glutamate release through increased expression of glial glutamate transporter-1 (GLT-1) in cultured astrocytes, and an infusion of riluzole into the bilateral VTA in rats prevented the potent cannabinoid HU210-facilitated LTD induction in 2-month-old animals, which was blocked by bath application of dihydrokainate (DHK), a selective GLT-1 inhibitor. Our results show the effects and potential mechanism of action of riluzole in cannabinoid-facilitated LTD induction, which may provide insights into new therapeutic approaches for cannabis addiction.

Chemotherapeutic agent 5-fluorouracil increases survival of SOD1 mouse model of ALS.

Amyotrophic lateral sclerosis (ALS) is a lethal motor neuron disease with no cure. Currently there are only two ALS drugs approved by the FDA, both with a limited therapeutic effect. In the search for drug candidates for ALS, we studied the effect of known stem cell mobilizing agents (treatment) and antimetabolite 5-fluorouracil (5-FU) (anti-treatment) in SOD1G93A model of ALS. Surprisingly, we found that anti-cancer drug 5-FU increases lifespan, delays the disease onset and improves motor performance in ALS mice. Although we were not able to demonstrate the mechanistic basis of the beneficial 5-FU action in ALS mice, our findings suggest that 5-FU or similar drugs are possible drug candidates for the treatment of motor neuron diseases through drug repurposing.

Motor neuron disease in 2017: Progress towards therapy in motor neuron disease.

In 2017, dramatic advances have been made in the treatment of motor neuron diseases. New therapies have been approved for spinal muscular atrophy and amyotrophic lateral sclerosis, and a host of other therapies that are currently under development are showing promising results.

Motor Neurone Disease: Treatment by Modern and Conventional Medicines

Motor neuron disease (MND) is a neurodegenerative disease. It is a fatal and progressive disease that attacks specific nerve cells (motor neurons) in the spinal cord and the brain. Motor neurons control the voluntary movement of muscles. MND is also known as Lou Gehrig´s disease, maladie de Charcot and amyotrophic lateral sclerosis (ALS).‘Amyotrophic’ refers to the loss of muscle mass; ‘lateral’ refers to the nerve tracks that run down both sides of the spinal cord, where many of the neurons affected by MND are found; ‘sclerosis’ refers to the scar tissue that remains after the nerves damage. Motor neurons reach to the spinal cord from brain and to the muscles throughout the body from spinal cord. When motor neurons are not working, the capacity of the brain to initiate and control muscle movement is lost. Patients are often initially prompted to seek medical advice because of a persistent muscle twitch, muscle fatigue, or even muscle wasting. This generally initiates in the hands or lower legs, frequently accompanied by cramps. As MND progresses, patients lose the ability to dress and feed themselves, sit up, walk, or even speak. The bodily functions that remain intact until or near death are the control of urination and bowel movements, sexual function, eye movement, and intellect. Generally, patients survive three to five years after diagnosis. Death generally occurs due to respiratory failure. MND is most common in the age range of 40 to 70 years and about 20 per cent more common in men than in women. The cause of the disease is still unclear. Present treatment of MND is aimed at symptomatic relief, prevention of complications and maintenance of optimal function and optimal quality of life. Researchers have shown that the antibiotic stops “cell suicide” (neuronal apoptosis). Apoptosis includes the activation of nitric oxide and caspase enzyme. The present paper includes the information about the possible treatment of MND by herbal medicines.

Midazolam prevents motor neuronal death from oxidative stress attack mediated by JNK-ERK pathway.

Midazolam is a sedative used by patients with mechanical ventilation. However, the potential clinical value is not fully explored. In this report, we made use of a neuroblastoma-spinal cord hybrid motor neuron-like cell line NSC34, and elucidated the potential role of Midazolam on these cells under the insult of oxidative stress. We found the protective effect of Midazolam on motor neurons against cytotoxicity induced by the combination of oligomycin A and rotenone (O/R) or phenylarsine oxide. The characteristics of apoptosis, such as the ratio of TUNEL+ cells or the expression level of cleaved Caspase-3, was decreased by 22 or 45% in the presence of Midazolam. Furthermore, this effect was correlated with the JNK-ERK signaling pathway. Either phosphorylation of ERK or JNK was positively or negatively modulated with the treatment of Midazolam in NSC34 cells attacked by reactive oxygen species. Meanwhile, inhibition or activation of the JNK-ERK pathway regulated the protective effect of Midazolam on NSC34 cells with oxidative stress insult. Collectively, this study elucidated a previously unidentified clinical effect of Midazolam, and put forward the great promise that Midazolam may be considered as a potential candidate to the treatment of motor neuron disease.

Clinical utility of riluzole in patients with motor neurone disease (amytrophic lateral sclerosis)

Amyotrophic lateral sclerosis (ALS), also known as motor neurone disease (MND), is a devastating, progressive disease for which there is no cure. This disease affects both upper and lower motor neurones and the patient typically succumbs to respiratory failure within 2 to 4 years. The UK and US regulatory agencies have only endorsed one neuroprotective drug for ALS, riluzole, which has been reported to extend the patient's length of survival by up to 21 months, depending on the study. New drugs and riluzole add-ons have not proven more beneficial than monotherapy with riluzole. This literature review addresses studies on the use of riluzole, updates current literature on the neuroprotectant, highlights National Institute for Health and Care Excellence (NICE) guidance on the use of riluzole for the treatment of MND in the UK and discusses the clinical utility of the drug regarding to multidisciplinary teams, pharmacological management, and adverse events. Optimal use of riluzole is based upon early diagnosis of MND/ALS and offering this medication to patients in the early stage of this fatal disease.

Motor Neuron Disease Presenting With Acute Respiratory Failure: A Case Study.

Motor neuron diseases (MNDs) refer to a heterogeneous group of progressive neurologic disorders caused by degeneration of motor neurons. The diseases affect either the upper motor neurons, lower motor neurons, or both, and are characterized by weakness, atrophy, fasciculation, spasticity, and respiratory failure. We report a case of a 61-year-old male patient with no past history of cardiovascular or pulmonary disease, who presented with only dyspnea, and no indication of any other symptom such as muscle weakness, atrophy, or bulbar dysfunction. Neuromuscular conduction study, including a study of the phrenic nerve, confirmed the diagnosis of MND. The patient greatly improved giving respiratory assistance at night, using a noninvasive ventilator. This case indicates that MNDs should be considered as differential diagnoses for patients showing acute respiratory failure of unknown causes. This report will aid in the prompt diagnosis and treatment of MNDs.

Altered mRNA Splicing in SMN-Depleted Motor Neuron-Like Cells

Spinal muscular atrophy (SMA) is an intractable neurodegenerative disease afflicting 1 in 6–10,000 live births. One of the key functions of the SMN protein is regulation of spliceosome assembly. Reduced levels of the SMN protein that are observed in SMA have been shown to result in aberrant mRNA splicing. SMN-dependent mis-spliced transcripts in motor neurons may cause stresses that are particularly harmful and may serve as potential targets for the treatment of motor neuron disease or as biomarkers in the SMA patient population. We performed deep RNA sequencing using motor neuron-like NSC-34 cells to screen for SMN-dependent mRNA processing changes that occur following acute depletion of SMN. We identified SMN-dependent splicing changes, including an intron retention event that results in the production of a truncated Rit1 transcript. This intron-retained transcript is stable and is mis-spliced in spinal cord from symptomatic SMA mice. Constitutively active Rit1 ameliorated the neurite outgrowth defect in SMN depleted NSC-34 cells, while expression of the truncated protein product of the mis-spliced Rit1 transcript inhibited neurite extension. These results reveal new insights into the biological consequence of SMN-dependent splicing in motor neuron-like cells.

Cognitive impairment in amyotrophic lateral sclerosis: the hidden challenges

Motor neurone disease (MND) or amyotrophic lateral sclerosis (ALS) is a devastating, neurological condition. It is a progressive disease that attacks the nerves in the brain and spinal cord, leading to progressive weakness and wasting of muscles. This can lead to difficulties in walking, speech, eating, drinking and breathing (MND Association, 2016). MND is a rapidly progressive disease with death usually occurring 2–5 years from onset of first symptom. Diagnosis is usually made around 12 months from first symptom, with the diagnosis typically being made around the midpoint (50% of total disease duration elapsed) of the disease pathway (Mitchell et al, 2010). Although it is progressive, the rate and nature of progression can be unpredictable, with damage to affected areas occurring in no specific order (MND Association, 2016). The incidence of MND in England, Wales and Northern Ireland is approximately 1–2 cases per 100 000 people per year, very similar to multiple sclerosis. However, due to the rapid progression of MND the prevalence is only about 4–5 per 100 000 compared to about 50 per 100 000 for MS. (MND Association, 2015). People with MND are said to have a series of losses, including the: ■Loss of movement ■Loss of speech ■Loss of ability to eat, drink and breathe. They can have many health and social care professionals involved in their care at any one time. Although often grateful for the support and advice, it can be overwhelming and patients are often confused about roles (Oliver and Webb, 2000). The management of MND is usually provided by a multidisciplinary team based in the hospital and community. There is no cure for MND, with treatment limited to one drug, Riluzole, known to extend survival by only 2–3 months, and has been recommended by the National Institute of Health and Care Excellence (NICE, 2001). The main areas of intervention, are therefore symptom management, and supportive, including interventions to improve quality of life. These may include enteral feeding (Miller et al, 2012; Stavroulakis et al, 2014) and ventilation (Baxter et al, 2013). The physical manifestations of MND/ALS are well known and widely researched. In comparison cognitive impairment in MND is less well recognised.

Stem Cell Strategy for the Treatment of Motor Neuron Diseases

Motor Neuron disease is a neurodegenerative disease of central nervous system leading to death of motor neurons from CNS and spinal cord. Due to the lack of effective treatment modalities, recently, many scientists have considered stem cells as a potential strategy for the treatment of this disease. Amongst the different types of stem cells, MSCs have been thought as a promising source of stem cells in regenerative medicine applications. These cells can be transplanted into the injured nervous system as a new therapeutic strategy. Although many challenges and concerns still remain, and the exact mechanism by which stem cells act is still unknown, the positive effect of stem cells following transplantation has encouraged many researchers to consider this as a treatment option in the future. There has been a lot of research ongoing on the derivation of motor neurons from stem cells in vitro and many scientists are attempting to bring these cells into clinical applications by conducting a number of clinical trials. Here, in this review, we discuss the current progress in pre-clinical studies and the status of clinical trials using stem cells in motor neuron diseases. We also discuss the hurdles which need to be overcome while moving from bench to bedside. Based on current information available, stem cell derived motor neurons can pave the way as a new treatment option for patients with the disease which seems to be highly promising.

Epidemiological characteristics of motor neuron disease in Chinese patients

The epidemiology, diagnosis, and treatment of motor neuron disease (MND) in Chinese patients are ill known. A registered study of 461 MND patients was conducted across 10 facilities in 7 Chinese cities from February 2009 to March 2010. Patients were classified as amyotrophic lateral sclerosis (ALS) (84.4%), progressive bulbar palsy (PBP) (4.1%), progressive muscular atrophy (PMA) (10.4%), or primary lateral sclerosis (PLS) (0.9%). MND was predominant in men (men/women; 1.6:1.0). Mean onset age was 52.6years, with the highest incidence being observed between 51 and 60years. Notably, 26.0% of MND patients were employed in forestry, fishery, or animal husbandry industries. Ten cases (2.7%) reported family history of MND, and 54.2% exhibited cervical onset. MND was also associated with head/neck trauma. Non-invasive positive pressure ventilation was the most common supportive therapy. As a novel comprehensive report of a Chinese population, this study reveals that epidemiological characteristics of MND patients were similar to those observed in international populations. MND is age-related, male gender predominant, and may be associated with both environmental and genetic risk factors.