Targeting More with RNA Therapeutics

RNA Therapeutics: Targeting the other 85%

There is a daunting challenge in the therapeutic space: Many proteins are deemed “undruggable” by traditional small-molecule drugs or antibodies. To date, only 0.05% of the human genome has been targeted by currently approved protein-targeted therapeutics, and 85% of proteins lack a “cleft” or pocket for small molecule binding. RNA therapeutics could potentially remedy this problem. RNA has the potential to target any gene of interest by simply targeting a specific nucleotide sequence.

In addition to widening the overall range of proteins that are currently targetable, mRNA treatments are reversible and will not induce genetic risks, as DNA therapeutics have the potential to do. RNA aptamers can also be used that are designed to attach to and inhibit target molecules, similar to small molecules or antibodies.

Various RNA technologies are available for targeting otherwise untargetable proteins.

• Antisense oligonucleotides (ASOs)
  • Bind to target RNA to allow cleavage by RNase
  • Alternatively, ASOs can alter RNA splicing by promoting exon inclusion
• RNA interference (RNAi)
  • Small interfering RNAs (siRNAs) activate the endogenous RNAi process, which effectively silences the target sequence
• Aptamers
  • The 3D structure is used to bind to and inhibit proteins
  • Some aptamers can disrupt interactions between disease-associated targets
• Others
  • CRISPR, mRNA vaccines

RNA therapeutics are a very new field; The first Aptamers were not discovered until the 90s, and the first siRNA drug was not approved until August 2018. mRNA vaccines were also not approved before the COVID-19 pandemic.