Splicing: The New Frontier in Therapeutics

Dear Colleagues,

Constitutive and alternative splicing were discovered more than 50 years ago and have been quite well studied biochemically; including how proteins and RNA interact to perform the splicing reaction or how various splice factors and cis-acting elements on RNA interact to regulate splice site choice.

What has not been clear until the last 10-15 years (and has been made possible by the advent of novel methods for genome-wide sequencing) was how widespread alternative splicing is in humans. Alternative splicing applies to virtually every multiple exon gene in humans and represents an important gene regulation process through which the coding capacity of every gene is multiplied several folds by the generation of splice isoforms that have sometimes very different, even opposing functions.

While there are thousands of splice isoforms whose physiological function is not yet understood, there are a similarly large numbers of splice isoforms that are specific to disease – therefore the manipulation of splicing forms a new and underexplored therapeutic space. For a long time only genetic disease with splicing mutations were on the radar of the splicing therapeutics development; however, it is now clear that principles of splicing therapeutics may be applied to virtually any disease.

Distinct splicing therapeutics ideas have been appearing in the field that mainly aggregate into two classes:

a. splicing inhibitors – usually small molecules that target core components of the spliceosome, whose utility is explored mainly in cancers with mutations in these components

b. alternative splicing modulation of specific splicing events – this is a form of targeted therapy that intends to switch a splice isoform (or ratio of splice isoforms) characteristic of disease, to a normal expression pattern therefore functionally rescuing the phenotype

In terms of therapeutic tools, either complementary oligonucleotides or small molecules are being developed. The oligonucleotides are usually either designed to overlap with splice sites or splice factors binding sites or are designed with tails capable of to bringing splice factors into the proximity of RNA. The small molecules may be classified in compounds that target specific splice factor kinases, compounds that interfere with splice factors binding to RNA or to each other at splice sites, or compounds that affect RNA tertiary structure at splice sites.

I believe that splicing therapeutics is an emerging field with potential for great expansion in the future and therefore invite in this special issue submission of reviews or research articles in any area of disease and therapeutics where a splicing component or mechanism is involved.

Dr. Sebastian Oltean
Guest Editor

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• constitutive splicing
• alternative splicing
• splicing switching oligonucleotides
• small molecule splicing modulators
• splicing therapeutics