Half‐Life as a Therapeutic Design Axis: Targeting Short‐Lived lncRNAs With Antisense Oligonucleotides

ABSTRACT Engineering RNA stability has become a cornerstone of modern therapeutics, almost entirely in one direction: mRNA vaccines established stabilisation of exogenous transcripts as a powerful design axis. The symmetric operation— exploitation of instability in endogenous targets—has been comparatively underexplored. We argue that target RNA half‐life is an underused but quantitatively consequential design parameter for antisense oligonucleotide (ASO) therapeutics, and that short‐lived long noncoding RNAs (lncRNAs) are a particularly attractive target class. Under sustained ASO dosing, the time to a new steady state is set by the sum of the target's own decay rate and the ASO‐induced decay rate, so—for a given depth of knockdown—endogenous half‐life becomes a major determinant of pharmacodynamic onset alongside ASO potency and delivery, most directly for RNase H‐dependent gapmers; we treat the resulting first‐order relationships as a qualitative design heuristic rather than a quantitative pharmacokinetic/pharmacodynamic model. Two back‐to‐back 2012 surveys—BRIC‐seq in human HeLa and actinomycin‐D microarray in mouse Neuro‐2a—yielded similar median lncRNA half‐lives of 3.4 and 3.5 h, with a short‐lived fraction we term short‐lived noncoding transcripts (SLiTs; t 1/2 < 4 h). SLiTs include several disease‐relevant regulators (GAS5, NEAT1, CDKN2B‐AS1/ANRIL, HOTAIR, TUG1); their rapid turnover supports fast onset, reversibility and tight titratability. We (i) develop a kinetic framework for how target half‐life shapes ASO pharmacodynamic onset, (ii) survey the cross‐species half‐life landscape, (iii) propose a decay‐pathway‐aware ASO design framework aligning modality choice with endogenous decay machinery, (iv) re‐read representative clinical ASO cases (nusinersen, tofersen, tominersen, MALAT1 ASOs) through the half‐life lens, and (v) outline a half‐life‐aware preclinical roadmap. Treating half‐life symmetrically—engineered up in vaccine RNAs, exploited downward in endogenous targets—highlights a largely unoccupied design space for next‐generation oligonucleotide therapeutics.