Amyotrophic lateral sclerosis research
Research on
Disease models
Many models have been used by researchers in labs to study the disease pathways, mechanisms, and symptoms on simple organisms.[2] [1]
In vitro
In this strategy the disease is introduced to cell cultures in petri dishes.[2] In this case, motor cells can be grown, and the gene expression is controlled. CRISPR/Cas9 technique can be used to knock-out/in genes that are related to ALS, and it is very beneficial in increasing the expression of the genes to mimic the human model of ALS for a faster onset of the disease.[2] This type of model can be beneficial in high-throughput screening for drug candidates for ALS.[2]
Familial ALS is the most studied; however, a new technique that was recently introduced is the use of induced pluripotent stem cells (iPSC).[2] In this study the researcher can isolate skin fibroblast from a patient with familial or sporadic ALS and reprogram them into motor neuron to study ALS.[2] The main advantage of iPSC is that it allowed researchers to study and understand sALS, and it shows a remarkable contribution in cell-based therapy and drug screening.[2] A recent example had used iPSC of patient with SOD1 dominant mutation and they studied the motor neurons derived from the patient, and they found that the functional genes and the ER stress regulating genes of the mitochondria were reduced in SOD1 patients, similar to the effect of C9orf72 mutation on the patients.[3] In addition, some studies showed that iPSC is better than other types of stem cells due to its ability in differentiating into a mature neuron cell, and many other cells too. These iPSC derived cells can be used in transplant cell therapy, in which they can introduce the differentiated cells into the ALS patient to reduce the symptoms without harming the patient.[3]
In vivo
Many animals have been used over the years to study ALS and to search for a potential therapy.
The most studied model for ALS is the rodent, mouse model, which provide the most complex representation of nervous system that is considered the closest in mimicking human nervous system.[4] In this model, the phenotype, and genotype characteristics can be studied and controlled. Many researchers have used transgenic mouse models to study ALS, and one example is the expressing of C9orf72 mutation that can be introduced in mouse using the BAC C9orf72 gene with the multiple repeats of GGGGCC.[8] In that study they chose the bacterial artificial chromosome that has the human length of C9orf72 gene, and they introduced multiple repeats for faster onset of ALS.[8] Also, they have selected for the most stable clone using different conditions, and concluded that the 40 and 500 repeats in the low temperature condition was the most efficient in retaining expansion mutations.[8] Using different BAC C9orf72 transgenic mouse model, they were able to study the symptoms of ALS, such as gait abnormalities, anxiety-like behavior, reduced grip strength, and even death rates.[8] Also, the denervation of motor neurons and dysfunction of neurons can be visualized using fluorescent markers to study the neurodegenerative disorder progression in ALS.[8] Another study also used the SOD1 mutation transgenic mice where they have showed similar signs of ALS that included the axonal and mitochondrial dysfunction and denervation of motor neurons and the reduction of the overall number of neurons in the limbs of the mouse.[9] The TDP-43 transgenic mouse model was also used for ALS studies and it shows similar results to the SOD1 expression, which includes the axon denervation phenotype.[9] For this model which depends on the promoters, they have made many other transgenic mouse models that uses different promoter to compare their phenotype and progression of TDP-43 ALS.[9] Rat models, on the other hand is not very widely used, but their large size can be beneficial in intrathecal injection or mini pump insertion is needed in pharmacological trials. In fact, studied showed that using SOD1 transgenic rat models showed similar development of the genetic and phenotypic traits of the ALS disease.[9]
In silico
Since the early 2000s, computational approaches involving the application of
Potential treatments
Past clinical trials
From the 1960s until 2014, about 50 drugs for ALS were tested in randomized controlled trials (RCTs); of these,
Repetitive
One 2016 review of
Techniques to deliver drugs and medications in a better manner are also being investigated and those include altering and developing drugs with specific characteristics, such as size and charge, to allow for their passage through the blood-brain barrier.
References
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- ^ a b c d e "Scientific Focus Areas - Disease Models". ALSA.org. Retrieved 2017-11-01.
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- ^ PMID 23524377.
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- PMID 26696091.
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- ^ PMID 20015852.
- ^ PMID 16908980.
- ^ "Public summary of opinion on orphan designation Masitinib mesilate for treatment of amyotrophic lateral sclerosis" (PDF). EMA. European Medicines Agency, Committee for Orphan Medicinal Products. 22 September 2016. Archived (PDF) from the original on 6 November 2016. Retrieved 6 November 2016.
- PMID 23235621.
- PMID 26459114.
- ^ PMID 28700839.
Further reading
- Robert, Kueffner; et, al. (2019). "Stratification of amyotrophic lateral sclerosis patients: a crowdsourcing approach". Scientific Reports. 5562 (9): 690. PMID 30679616.