Therapy and Management of ALS

Amyotrophic Lateral Sclerosis (ALS)
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Description of the pathological causes and effects in ALS [1]

Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease that is characterized by the degradation of motor neurons throughout the affected person’s body. The degradation of the motor neurons causes muscular atrophy which ultimately results in the loss of function in muscles. The disease becomes fatal when the afflicted can no longer breathe due to muscular atrophy of respiratory muscles. Currently there is no known treatment that cures ALS, and there is only one FDA approved drug, Riluzole, that is used to treat ALS patients. Riluzole is a glutamate antagonist, which prevents the excitotoxicity of over active glutamate, yet Riluzole only prolongs the average ALS patient’s lie by about 2-3 months [3]. Resources are being put into finding alternative treatments with the hope of curing this disease. A supplement that is being looked into for managing ALS is Vitamin D supplementation, which acts as an anti-inflammatory agent counteracting the toxic inflammation response due to over excitation of glutamatergic neurons. It also strengthens muscles being increasing ATP production and Ca2+ uptake [1]. Another treatment being looked into is using stem cells to grow new motor neurons that can then be grafted onto an ALS afflicted patient and using stem cells for therapeutic application [2].


Currently there is only one FDA approved drug to treat ALS, and that drug is Riluzole. Riluzole is a 2-aminobenzothiazole that inhibits the neuro-toxic inflammatory response caused by over-excitation of glutamatergic neurons [3,7]. 2-aminobenzothiazoles are a known type of drug group that are used to treat inflammation, infections, epilepsy, and analgesia. The mechanism by which Riluzole modulates glutamate neurons is still unknown [7]. Riluzole is thought to block Ca2+ channels and Na+ channels in post-synaptic neurons, thus mitigating the excitation response of glutamatergic neurons [3,6-7]. Blocking Ca2+ channels also protects the cells from apoptosis, as too much calcium influx results in cell death [7]. Riluzole also is thought to affect glutamatergic neurons by blocking NMDA receptor excitatory response, yet the evidence for this seems to be inconsistent as some studies fail to provide an antagonistic link between Riluzole and NMDA receptors [7]. Riluzole seems to only be effective for treating ALS patients in the clinical model, being ineffective against other common neurodegenerative diseases such as Parkinson’s, Huntington’s, and trauma induced CNS damage [7]. Unfortunately even with treatment with Riluzole, the average ALS patient’s life span is only prolonged by 3 months [3,7]. It has been observed in a study done in Taiwan by Lee, Charles et al. (2013) that combining Riluzole treatment with a tracheotomy procedure, resulted in the best survival rate when compared to no treatment and treatment with just Riluzole [6].

Vitamin D

Vitamin D effects in ALS
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Potential effects of Vitamin D on an ALS patient [1]

To help manage ALS, researchers looked into the usage of Vitamin D as a potential therapeutic supplement that could slow down the degeneration of motor neurons. Patients with ALS tend to have a decreased level of Vitamin D in their blood, which in turn results in a quicker progression of ALS [8-10]. Vitamin D is transformed into its active form by contact with UV rays, so often Vitamin D is prescribed in its already activated form, 1,25(OH)2D3 [9]. Vitamin D is regarded as a neuro-protective agent for several reasons. One reason is that it acts as an anti-inflammatory and antioxidant, which combats the inflammatory response caused by over excitation of glutamatergic neurons [1,8-10]. In ALS it has been observed that there is a decrease in calcium binding proteins, such as calbindin, calretinin, and parvalbumin [1,8-10]. An absence or low levels of these proteins lead to Fas mediated cell death, and an overall increase of susceptibility to degeneration in ALS patients [8-9]. 1,25(OH)2D3 acts to increase the reuptake of Ca2+ in muscle cells and also increases the amount of Ca2+ binding proteins [9]. An increase in calcium reuptake in muscle cells strengthens the muscle in ALS patients, which counteracts the muscular atrophy caused by ALS [1]. Finally it has been shown that the activated form of Vitamin D recruits neurotropic factors which in turn prevent cell apoptosis by Fas death pathway. The Fas death pathway seems to be implicated in sporadic ALS and not familial ALS [9].

Stem Cells

Since ALS is characterized by the degeneration of motor neurons, researchers have looked into producing novel motor neuron cells that could be implanted in ALS patients [11-12]. They have looked in many different types of stem cells, such as embryonic, mesenchymal and olfactory ensheathing stem cells [11-13]. Stem cells are usually administered to patients/animals via parenchymal injection [12]. Unfortunately stem cell research is a long and tedious process that requires lots of time and financial support [11]. On top of that, embryonic stem cells also have the burden of strict policies that slow down the process even more [11]. Overall stem cell research is still in its preliminary stages, and much is still to be done in finding a treatment for ALS via stem cells.

Embryonic Stem Cells

The hope for embryonic stem (ES) cells is that they will be able to differentiate into novel motor neurons and then implanted into ALS patients [11]. In the rat model, ES cells were able to differentiate into motor neurons, yet when grafted onto the rat, the cells struggled to obtain connections with muscles [11]. The problem arises from the long distance that the new cells have to project their axons in order to innervate the muscle [11-12]. For the ES cells to become effective, they need to create connections with muscles and then be able to innervate the muscles to prevent muscular atrophy [11-12]. This problem is exacerbated even more by having the novel neurons placed in a toxic environment. Since ALS creates a toxic environment for existing motor neurons, administering new motor neurons provides a huge challenge [11-12]. Along with problems with axonal projections and toxicity, many rats in the ALS model rejected ES cell grafts [11]. Overall preliminary studies of ES cell therapy on the rat model have so far been ineffective as the duration of rat survival has been unaffected [11].

Mesenchymal Stem Cells

Mesencymal Stem Cell Therapy
Video describing Mesenchmal Stem Cell Therapy and the potential benifits it could provide to an ALS patient [14]

Mesenchymal Stem Cells (MSCs) are being looked into for supplementing existing motor neurons, and not actually partaking in differentiation into novel neurons [11-12]. MSCs can be used to create new glial cells or immunomodulatory cells that help existing neurons from degradation and cell death [11-12]. MSCs provide neuro-protection to existing motor neurons by becoming a source of neurotrophic factors and anti-inflammatory factors [11-12]. MSCs can be harvested from many different sources, such as bone marrow, umbilical cord stem cells, adipose cells and muscle cells. The accessibility of acquiring MSCs is one of the reasons why it is one of the leading stem cells being researched for treatment not only for ALS, but other inflammatory based diseases [11-12]. Various trials have attempted to mobilize MSCs in patients without the need to implant foreign MSCs. These trials used granulocyte colony stimulating factor to achieve this mobilization [12]. Although mobilization was achieved, and some anti-inflammatory characteristics were observed, nevertheless ALS progression was not slowed [12].

Olfactory Ensheathing Stem Cells

Olfactory Ensheathing Stem Cells (OESCs) are a type of glial cells that are currently implicated in axonal regeneration and protection. Because of their axonal regenerative ability, they are currently used to treat trauma induced spinal cord injury [11]. Researchers wanted to see whether OESCs ability to induce axonal regeneration would help against the degeneration of motor neurons in the ALS model. Several studies have been conducted and no consistent evidence has been produced that shows OESCs slowing down ALS progression [11,13]. Researchers have observed a problem in treating ALS with OESCs when compared to trauma induced damage treatment, in that in the ALS model the damage is much more wide spread while the trauma induced damage is more localized [13]. The problem lies in that injection of OESC tends to localize to the injections site, which is fine for the trauma induced damage, yet with ALS, the deterioration of motor neurons is wide spread throughout the periphery of the human body [13]. Further advancements in the application and distribution of OESCs in the ALS model are needed for any positive effect to be observed [11,13].

Potential of Dexpramipexole

Dexpramipexole (RPPX) is a mitochondrial protective drug that is part of the same drug group as Riluzole. The S enantiomer of PPX is currently used to treat symptoms in Parkinson’s disease and researchers have been looking into the clinical application in the ALS model of the R enantiomer of PPX [4]. The R enantiomer is used because humans withstand greater concentrations of the R enantiomer than the S enantiomer. Treatment for ALS patients requires a much higher dosage of PPX than that in a Parkinson’s patient [4]. RPPX protects neurons from degradation via mechanisms stemming from protection of the mitochondria and RPPX also protects the entire neuron by opposing the apoptotic pathway. RPPX accomplishes neuronal protection by lowering the amount of excitotoxicity and oxidative stress [4]. Currently RPPX is on Clinical trial phase III, where patients are subjected to 150mg of RPPX twice a day. The goal is to determine whether exposing patients to these levels of RPPX results in the slowing of ALS disease progression. Phase I and II of the clinical trials established the safety of using RPPX on humans with no adverse side effects [4].

Nutritional Care

Nutritional Guide
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Schematic outlining the protocol that nutritionists follow when dealing with ALS patients [5]

During the progression of ALS, patients tend to lose appetite and therefore end up malnourished [5,15]. Patients also end up with a lower serum level of Vitamin D, which results in a quicker progression of ALS [8-10]. The ALS Functional Rating Scale (ALSFRS) assists nutritionists in seeing the progression of the disease and specifically in what areas there is the most pathological decline [5]. Patients with ALS are often dehydrated and are acquiring lower than normal calorie intake [5,15]. These problems tend to arise due to ALS patients developing dysphagia, a difficulty of swallowing, so nutritionists have to come up with ways in which a patient has to eat and drink [5]. Nutritionists have to come up with food suggestions that have viscosity levels that are in line with the severity of the dysphagia that the patient is experiencing. Often when dysphagia is severe, water has to be thickened due to a risk of interfering with breathing [5]. Eating fruit or foods with high water content helps patients maintain proper hydration. Overall it is important for nutritionists to keep an eye on the patient’s intake levels of protein, carbohydrates, fiber, fats, and appropriate vitamins and minerals [5,15].

ALS main page

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2. Lunn, Simon et al. Stem Cell Therapies for Amyotrophic Lateral Sclerosis: Recent Advances and Prospects for the Future. Stem Cells. (2014) 10.1002/stem.1628
3. Gordon, Paul. Amyotrophic Lateral Sclerosis: An update for 2013 Clinical Features, Pathophysiology, Management, and Therapeutic Trials. Aging and Disease. (2013); 4(5):295-310
4. Corcia, P. & Gordon Paul. Amyotrophic lateral sclerosis and the clinical potential of dexpramipexole. Ther Clin Risk Manag. (2012); 8:359-66
5. Salvioni, CC. et al. Nutritional care in motor neurone disease/ amyotrophic lateral sclerosis. Arg Neuropsiquiatr. (2014); 72(2):157-63
6. Lee, Charles et al. Riluzole and Prognostic Factors in Amyotrophic Lateral Sclerosis Long-term and Short-term Survival: A Population-Based Study of 1149 Cases in Taiwan. J Epidermiol. (2013); 23(1):35-40
7. Cheah, B.C. et al. Riluzole, neuroprotection and amyotrophic lateral sclerosis. Curr Med Chem. (2010); 17(18):1942-199
8. Long, Kv. & Nguyen, LT. Roles of vitamin D in amyotrophic lateral sclerosis: possible genetic and cellular signaling mechanisms. Mol Brain. (2013); 6(16) doi: 10.1186/1756-6606-6-16
9. Camu, William et al. Vitamin D confers protection to motoneurons and is a prognostic factor of amyotrophic lateral sclerosis. Neurobiol Aging. (2014); 35(5):1198-205
10. Karam, Chafic et al. Vitamin D deficiency and its supplementation in patients with amyotrophic lateral sclerosis. Journal of Clinical Neuroscience. (2013); 20(11):1550-1553
11. Lunn, J. et al. Stem Cell Therapies for Amyotrophic Lateral Sclerosis: Recent Advances and Prospects for the Future. Stem Cells. (2014); doi: 10.1002/stem.1628
12. Thomsen, Gretchen et al. The past, present, and future of stem cell clinical trials for ALS. Experimental Neurology. (2014); doi: 10.1016/j.expneurol.2014.02.021.
13. Piepers, Sanne & van den Berg, Leonard. No benefits from experimental treatment with olfactory ensheathing cells in patients with ALS. Amyotrophic Lateral Sclerosis. (2010); 11(3):328-30
15. Goyal, Namita & Mozaffar, Tahseen. Respiratory and Nutritional Support in Amyotrophic Lateral Sclerosis. Curr Treat Options Neurol. (2014); 16(2):270

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