Abstract
Most protein coding genes generate multiple RNA transcripts through alternative splicing, variable 3′ and 5′UTRs, 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 tissue-selective 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 splice-site–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.
Footnotes
This work was supported in part by the National Institutes of Health National Institute of General Medical Sciences [Grant U01-GM092655].
Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.
ABBREVIATIONS:
- Δ9
- exon 9-lacking
- ASO
- antisense oligonucleotide
- CACNA1C
- voltage dependent L-type calcium channel α-subunit 1c
- CETP
- cholesterylester transfer protein
- CNS
- central nervous system
- COX
- cyclooxygenase
- D2L
- dopamine D2 receptor long form
- D2S
- dopamine D2 receptor short form
- DMD
- Duchenne muscular dystrophy
- DRD2
- dopamine D2 receptor
- FD
- familial dysautonomia
- HDL
- high-density lipoprotein
- IL
- interleukin
- IL-1R
- interleukin-1 receptor
- miR
- microRNA
- MOR
- μ opioid receptor
- MyD88
- myeloid differentiation primary response
- NAT1
- N-acetyltransferase 1
- NF-κB
- nuclear factor κ-light-chain enhancer of activated B cells
- NSAID
- nonsteroidal anti-inflammatory drug
- OPRM1
- μ opioid receptor 1
- RA
- rheumatoid arthritis
- SCN1A
- neuronal Nav1.1 sodium channel
- SMA
- spinal muscular atrophy
- SMN
- survival of motor neuron
- snRNA
- small nuclear RNA
- SSO
- splice-switching oligonucleotide
- TNF
- tumor necrosis factor
- UGT
- UDP-glucuronosyltransferase
- UTR
- untranslated region
- VEGF
- vascular endothelial growth factor.
- Received October 31, 2011.
- Accepted February 7, 2012.
- Copyright © 2012 The American Society for Pharmacology and Experimental Therapeutics
MolPharm articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|