mRNA Transcript Diversity Creates New Opportunities for Pharmacological Intervention

Abstract

Most protein coding genes generate multiple RNA transcripts through alternative splicing, variable 3Ј and 5ЈUTRs, and RNA editing. Although drug design typically targets the main transcript, alternative transcripts can have profound physiological effects, encoding proteins with distinct functions or regulatory properties. Formation of these alternative transcripts is tissueselective and context-dependent, creating opportunities for more effective and targeted therapies with reduced adverse effects. Moreover, genetic variation can tilt the balance of alternative versus constitutive transcripts or generate aberrant transcripts that contribute to disease risk. In addition, environmental factors and drugs modulate RNA splicing, affording new opportunities for the treatment of splicing disorders. For example, therapies targeting specific mRNA transcripts with splicesite-directed oligonucleotides that correct aberrant splicing are already in clinical trials for genetic disorders such as Duchenne muscular dystrophy. High-throughput sequencing technologies facilitate discovery of novel RNA transcripts and protein isoforms, applications ranging from neuromuscular disorders to cancer. Consideration of a gene's transcript diversity should become an integral part of drug design, development, and therapy.

The Glutamate Hypothesis in ALS: Pathophysiology and Drug Development

“…RNA editing is recognized as a potential target for drug discovery at different diseases, but, so far, few studies have been reported [72]. Therapies that correct aberrant splicing of mRNA transcripts using splice-site-directed oligonucleotides are being tested in clinical trials of genetic disorders such as Duchenne muscular dystrophy [73].…”

Hypertension pharmacogenomics: in search of personalized treatment approaches

“…In the UK, the Ancestry and Biological Informative Markers for Stratification of Hypertension (AIM HY) study 102 will investigate pharmacogenomic and pharmacometabolomic signatures of antihypertensive drug response, and use this information to prospectively identify and test a personalized antihypertensive treatment approach. Lastly, transcriptomics — the study of the complete set of RNA transcripts that are produced by the genome — is another ‘omics’ approach that could be useful to elucidate drug response mechanisms 103 . Tools for studying genome-wide microRNAs that may affect expression, methylation, and other genetic modifiers are also gaining interest.…”

Altered Gamma-Aminobutyric Acid Type B Receptor Subunit 1 Splicing In Alcoholics

“…This suggested that unknown GABAB1 splicing variants are differentially expressed in alcoholic brain. Single nucleotide polymorphisms (SNPs) near splicing sites also alter splicing and may be associated with alcoholism (11-13). Chronic ethanol exposure and withdrawal increased 5’ splice variant expression of the N-Methyl-D-aspartic acid receptor subunit, NR1, without NR1 3’ variant expression changes (14).…”