**22. Conclusion**

miR-423-3p, 4 = hsa-miR-323-5p, 5 = hsa-miR-760, 6 = hsa-miR-149, 7 = hsa-miR-139-3p, 8 = hsamiR-744, 9 = hsa-miR-324-3p, 10 = hsa-miR-339-3p and 11 = hsa-miR-654-5p. From **Figure 6** we

The human mind is not satisfied to know the causative factors of a disease. Our main target is to reduce ailment and to do that we need good diagnostic system along with good therapeutics. miRNAs are one of a kind. Being a regulator of gene expression, it has far-reaching effect on our physiology. They are dysregulated in several diseases. Researchers are now trying to generate therapeutic targets to treat ALS. Presently, riluzole is the only FDA-approved drug to treat ALS [81] and it modestly slows the disease progression. A phase I clinical trial of an antisense oligonucleotide [ISIS 333611] has been proven effective. This oligonucleotide targets SOD1 mRNA and represses the production of mutant SOD1 and this is effective when delivered to the CSF of patients with fALS [82]. The same kind of drug is there which targets the sense strand of the C9orf72 hexanucleotide repeat and reduces the toxicity by suppressing RNA foci formation both in vivo and in vitro [30, 33, 83]. Several delivery systems are being invented day in and day out to deliver miRNA formulations and drugs to the CNS through blood-brain barrier. The first miRNA-based therapeutic is the miR-122 antagonist SPC3649, which is currently being evaluated in phase II clinical trials. It targets the hepatitis C virus. So

There are two basic approaches of miRNA-based therapeutics. One is miRNA antagonists which impede endogenous miRNAs that have a harmful gain of function in diseased tissues and involve the use of an anti-miR – a chemically modified antisense RNA – to knockdown miRNA. In one of the first endeavours to use antagomirs in ALS, delivery of anti-miR-155 to *SOD1* Gly93Ala mice via ventricular osmotic pumps delayed mortality of the patients successfully. A downfall associated with this approach is the potential for nonspecific binding to other RNAs inside the cells. As one miRNA can regulate several mRNAs, it limits usage of miRNAs as therapeutics. In the second approach to miRNA therapeutics that involves miRNA mimics and miRNA replacement therapies, miRNAs are reintroduced into cells exhibiting

It is really difficult to dissect all the pathways, which are regulated by one miRNA. Before releasing drugs in clinics, there should be several clinical trials to eliminate any deleterious effect. Williams and group [85] showed that miRNA-206 delayed ALS progression and promoted regeneration of neuromuscular synapses effectively in mice. This group investigat‐ ed pathological modifications in motor axons and nerve terminals that precede motor neuron degeneration and clinical symptoms and the role of the skeletal muscle-specific miR-206 in motor neuron-skeletal muscle fibre signalling. This miRNA is significantly upregulated in SOD1-G93A mouse model of ALS. The genetic ablation of miR-206 in these ALS mice accel‐ erates the disease progression. miR26 might be needed for compensatory regeneration of

can understand the multilayered regulation [9].

156 Update on Amyotrophic Lateral Sclerosis

**21. Usage of miRNAs in therapeutics**

far, this agent has not exhibited any adverse effects.

downregulation, thus reactivating key pathways [84].

Molecular neuropathology, genomics and proteomics related to it have made a real progress in the last few decades. Candidate genes and their involvement in molecular interactions and networks have opened new venues in therapeutics. ALS is polygenic and non-cell-autonomous disease. Due to the presence of many gene variants in this disease, it is difficult to predict the susceptible individuals. There is no such inheritance pattern. As miRNA population is dysregulated in ALS, candidate miRNAs can be used as biomarker and targets of therapeutics. Discoveries of ALS-related miRNAs are leading us to solve the intricate cellular networkrelated details. As of for now, we have drugs to slow down ALS. But we still have nothing to treat this disease completely. Intricacies in miRNA network are making the development of drug more difficult because of bystander effects. There are several scientist groups around the world trying to find out the possible therapeutics.

Truly, present write-ups address many milestones of biological consequences of microRNA that shed potential light on the in-depth mechanisms of ALS. It definitely explains the motor neuron development, thereby expanding our new knowledge of ALS post-transcriptionally. Apart from that, present knowledge laid a major foundation for development of therapeutic agents of ALS. Furthermore, covering specific miRNA signatures targeted by different genes of ALS are important for broad classification of ALS symptoms. This sectorization of micro‐ RNA expression might be important to improve the subclassification of ALS genes which provide a unique instructive role for therapeutic approaches.
