ALS May Be Best Treated With Combinations of Small Molecule Inhibitors & ASOs With Gene Therapy

Margarida Azevedo, MSc avatar

by Margarida Azevedo, MSc |

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shutterstock_224787517A new clinical review entitled “Aberrant RNA homeostasis in amyotrophic lateral sclerosis: potential for new therapeutic targets?”, conducted by Christopher Donnelly from the Department of Neurology of the Johns Hopkins University and colleagues, explores the current status of Amyotrophic lateral sclerosis (ALS) evidence. The study was published in the journal Neurodegenerative Disease Management.

Amyotrophic lateral sclerosis (ALS) is a chronic neurodegenerative disease of sporadic nature characterized by progressive motor neurone degeneration. ALS is a multifaceted disorder where multiple cellular and molecular pathways interplay in the disease pathogenesis. Current evidence shows that mutations in RNA-DNA regulating genes named TARDBP/TDP-43, FUS/TLS or C9ORF72 may be the cause of ALS. However, at the moment there is no cure for this fatal condition and there is only one approved treatment called Riluzole that has been found to increase survival. The mechanism of action of Riluzole is through antiglutamatergic pathways, ranging from blocking presynaptic glutamate release to increasing glutamate uptake via astrocytic glutamate transporters.

In their review, the authors discussed the latest study findings on RNA toxicity pathways in ALS that may provide and understanding for the development of potential novel therapeutic approaches.

It is now agreed upon between clinical experts that ALS manifests in different subtypes. In this regard, therapeutic intervention approaches need to be developed according to those subtypes. In this basis of ALS subtypes is the result of different mutations in RNA processing. Thus, RNA processing deficits should be classified into defined subpopulations.

However, the fact that cytoplasmic inclusions of TDP-43 are present in the majority of sporadic and familial ALS cases suggests that disrupted RNA homeostasis via RNA binding/processing protein mutations and RNA toxicity likely represent diseases pathway that if targeted therapeutically, could be beneficial to this larger patient population.

Furthermore, the recent finding that the C9ORF72 mutation is highly prevalent in ALS enhances the potential for targeted therapeutic developments, thus leading to a personalized medicine approach in ALS.

The researchers additionally point out that this strategy should be supported by the use of human adult patient-derived induced pluripotent stem cells, which allow for the screening of patient specific and mutation-specific therapeutics as well as accompanying biomarker assays.

These novel-screening targets increase the need clinical trials that will provide better clinical trial outcomes, performed on select patient populations. Future genome wide sequencing projects may discover other novel mutations in ALS, maybe similar in prevalence to C9ORF72 or even higher.

These discoveries may lead to the classification of all ALS patients into familial ALS patients and thereby eliminate the presence of sporadic ALS.

Since ALS is a multi faceted condition, the researchers conclude that in order to provide ALS patients with an effective treatment, therapies should combine different approaches, involving small molecule inhibitors or ASOs together with gene therapy.