The sense of antisense therapies in ALS.

Downregulating superoxide dismutase 1 (SOD1) by regular injections of antisense oligos (ASOs) interacting with SOD1 mRNA is a new FDA-approved therapy for patients with amyotrophic lateral sclerosis (ALS) with mutations in SOD1. Understanding the exact molecular mechanism of a disease is crucial in order to develop the correct ASO strategy as is convincingly shown by the failure of the C9orf72 ASO trials. Rare forms of genetic ALS benefit from individual treatment programs using specific ASOs directed against the disease-causing gene. Restoring splice defects in different mRNAs using ASOs counteracts the negative effects of nuclear depletion of TDP-43, which is observed in the majority of patients with ALS. ASOs influencing risk factors for ALS or proteins involved in general disease mechanisms underlying ALS could also open new therapeutic perspectives for patients with sporadic ALS. Treatment of patients with amyotrophic lateral sclerosis (ALS) has entered a new era now that encouraging results about antisense oligonucleotides (ASOs) are becoming available and a first ASO therapy for ALS has been approved by the FDA. Moreover, there is hope not only that ALS can be stopped but also that symptoms can be reversed. Until now, degrading ASOs seemed to be successful mostly for rarer forms of familial ALS. However, the first attempts to correct mis-splicing events in sporadic ALS are underway, as well as a clinical trial examining interference with a genetic modifier. In this review, we discuss the current status of using ASOs in ALS and the possibilities and pitfalls of this therapeutic strategy. [ABSTRACT FROM AUTHOR]