Endogenous precursor messenger RNA (pre-mRNA) (pre-mRNA)

Endogenous precursor messenger RNA (pre-mRNA) is the immediate product of DNA transcription by RNA polymerase II, containing both coding exons and non-coding introns. Before it can be translated into protein, pre-mRNA must undergo splicing, a highly regulated process where introns are removed and exons are joined together by the spliceosome (Wang & Cooper, 2007, Nature Reviews Genetics). Mutations that disrupt splice sites or regulatory elements within the pre-mRNA are a major cause of human genetic diseases, often leading to the production of truncated or non-functional proteins. In modern pharmacology, pre-mRNA has emerged as a critical therapeutic target for antisense oligonucleotides (ASOs) and small molecule splicing modifiers. For instance, Nusinersen and Risdiplam target the SMN2 pre-mRNA to correct a splicing defect, effectively treating spinal muscular atrophy by increasing functional SMN protein levels (Hua et al., 2011, Genes & Development). Similarly, exon-skipping ASOs like Eteplirsen target the DMD pre-mRNA to restore the reading frame in Duchenne muscular dystrophy patients (Lim et al., 2017, Nature Reviews Neurology). This target class represents a paradigm shift in drug discovery, allowing for the precise modulation of genetic output at the transcript level.

Other names

Heterogeneous nuclear RNAhnRNAPrimary transcriptUnprocessed messenger RNA

Drugs targeting pre-mRNA primarily function as splicing modifiers. Antisense oligonucleotides (ASOs) bind to specific sequences (e.g., exonic or intronic splicing silencers/enhancers) to sterically block the splicing machinery, thereby inducing exon skipping or inclusion (Bennett, 2019, Annual Review of Medicine). Small molecules like Risdiplam stabilize the transient complex between the pre-mRNA and the U1 small nuclear ribonucleoprotein (snRNP) to promote the inclusion of specific exons (Ratni et al., 2018, Journal of Medicinal Chemistry).