The therapeutic potential of RNA regulation in neurological disorders

ABSTRACT

Introduction: Gene regulation is the term used to describe the mechanisms by which a cell increases or decreases the amount of a gene product (RNA or protein). In complex organs such as the brain, gene regulation is of the utmost importance; aberrations in the regulation of specific genes can lead to neurological disorders. Understanding these mechanisms can create new strategies for targeting these disorders and progress is being made. Two drugs that function at the RNA level (nusinersen and eteplirsen) have now been approved by the FDA for the treatment of Spinomuscular atrophy and Duchenne muscular dystrophy, respectively; several other compounds for neurological disease are currently being investigated in preclinical studies and clinical trials.

Areas covered: We highlight how gene regulation at the level of RNA molecules can be used as a therapeutic strategy to treat neurological disorders. We provide examples of how such an approach is being studied or used and discuss the current hurdles.

Expert opinion: Targeting gene expression at the RNA level is a promising strategy to treat genetic neurological disorders. Safe administration, long-term efficacy, and potential side effects, however, still need careful evaluation before RNA therapeutics can be applied on a larger scale.

KEYWORDS:

• Antisense oligonucleotide
• ASO
• genetics
• gene regulation
• miRNA
• RNA therapeutics
• short interfering RNA
• siRNA
• brain
• precision medicine

Article Highlights

1. Gene regulation at the level of RNA molecules is a feasible entry point to treat genetic neurological disorders.

2. RNA therapeutics (antisense oligonucleotides (ASO) and short interfering RNA (siRNA)) are an emerging class of therapeutics. So far, two neurological compounds are FDA approved and several others are in (pre-)clinical trials.

3. RNA therapeutics exhibit their effects through cleavage and degradation of mRNAs, altering splicing or targeting regulatory non-coding genes.

4. The CRISPR/Cas tools hold promise to become the future gene therapy, not only through changing the DNA sequence but also by altering expression levels and correcting transcripts at the RNA level.

5. Some pharmacological obstacles still exist before RNA therapeutics can be used in a routine basis. These obstacles include safe delivery, stability, immunogenicity, and off-target effects.

This box summarizes key points contained in the article.

Declaration of interest

S. Weckhuysen has received speakers fees from UCB and Zogenix. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded. J. Roovers is supported by the Agency for Innovation by Science and Technology, IWT under Grant 29382 .