Antisense technology: an overview and prospectus

Crooke, Stanley T.; Baker, Brenda F.; Crooke, Rosanne M.; Liang, Xiaojing

doi:10.1038/s41573-021-00162-z

Cited by 408 publications

(419 citation statements)

References 200 publications

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“…Our results also demonstrate that tASOs are agents effective in controlling ACE2 levels in vivo in mouse tissues, including the lung. In perspective, as ASOs are established medicines approved for a number of disorders (Crooke et al, 2021) and as telomeric DDR increases with age in normal and pathological conditions (Rossiello et al, Nature Cell Biology, under submission) we suggest that, upon additional validation, tASOs can have a potential as therapeutic agents to reduce susceptibility to SARS-CoV-2 infection.…”

Section: Resultsmentioning

confidence: 89%

DNA damage response at telomeres boosts the transcription of SARS-CoV-2 receptor ACE2 during aging

Sepe

Rossiello

Cancila

et al. 2021

Preprint

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The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is known to be more common in the elderly, who show also more severe symptoms and a higher risk of hospitalization and death. Here we show that the expression of the Angiotensin Converting Enzyme 2 (ACE2), the SARS-CoV2 cell receptor, increases during aging in mouse and human lungs, and following telomere shortening or dysfunction in mammalian cells and in mouse models. This increase is regulated at the transcription level, and Ace2 promoter activity is DNA damage response (DDR)-dependent. Indeed, ATM inhibition or the selective inhibition of telomeric DDR, through the use of antisense oligonucleotides, prevents Ace2 upregulation following telomere damage, in cultured cells and in mice.We propose that during aging telomeric shortening, by triggering DDR activation, causes the upregulation of ACE2, the SARS-CoV2 cell receptor, thus making the elderly likely more susceptible to the infection.

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Section: Resultsmentioning

confidence: 89%

DNA damage response at telomeres boosts the transcription of SARS-CoV-2 receptor ACE2 during aging

Sepe

Rossiello

Cancila

et al. 2021

Preprint

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“…The dimethyl amino moiety of the phosphoramidate in PMO can also be replaced by a piperazine, which is positively charged under physiological condition. And this positively charged PMO is termed PMOplus (for reviews in ASO drug development, see [173][174][175][176]).…”

Section: The Chemical Space Of Rna Splicing Modifiers 41 Chemical Modification Of Asomentioning

confidence: 99%

RNA-Targeting Splicing Modifiers: Drug Development and Screening Assays

et al. 2021

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RNA splicing is an essential step in producing mature messenger RNA (mRNA) and other RNA species. Harnessing RNA splicing modifiers as a new pharmacological modality is promising for the treatment of diseases caused by aberrant splicing. This drug modality can be used for infectious diseases by disrupting the splicing of essential pathogenic genes. Several antisense oligonucleotide splicing modifiers were approved by the U.S. Food and Drug Administration (FDA) for the treatment of spinal muscular atrophy (SMA) and Duchenne muscular dystrophy (DMD). Recently, a small-molecule splicing modifier, risdiplam, was also approved for the treatment of SMA, highlighting small molecules as important warheads in the arsenal for regulating RNA splicing. The cellular targets of these approved drugs are all mRNA precursors (pre-mRNAs) in human cells. The development of novel RNA-targeting splicing modifiers can not only expand the scope of drug targets to include many previously considered “undruggable” genes but also enrich the chemical-genetic toolbox for basic biomedical research. In this review, we summarized known splicing modifiers, screening methods for novel splicing modifiers, and the chemical space occupied by the small-molecule splicing modifiers.

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“…However, the use of unmodified ASOs, bearing a phosphodiester backbone, has important drawbacks, such as the lack of biological stability due to nuclease degradation or the limited passive diffusion because of the large size and negative charge. Hence, different chemical modifications aimed at increasing efficacy and stability and decreasing immune response and off-target toxicity have been described [34,35]. One of these modifications is the use of morpholino oligonucleotides, which are polymers constituted by the DNA standard nucleobases attached to a backbone of methylenemorpholine rings linked through phosphorodiamidate groups.…”

Section: Biologicalsmentioning

confidence: 99%

Small-Molecule Therapeutic Perspectives for the Treatment of Progeria

Macicior

Marcos‐Ramiro

Ortega-Gutiérrez

2021

IJMS

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Hutchinson–Gilford progeria syndrome (HGPS), or progeria, is an extremely rare disorder that belongs to the class of laminopathies, diseases characterized by alterations in the genes that encode for the lamin proteins or for their associated interacting proteins. In particular, progeria is caused by a point mutation in the gene that codifies for the lamin A gene. This mutation ultimately leads to the biosynthesis of a mutated version of lamin A called progerin, which accumulates abnormally in the nuclear lamina. This accumulation elicits several alterations at the nuclear, cellular, and tissue levels that are phenotypically reflected in a systemic disorder with important alterations, mainly in the cardiovascular system, bones, skin, and overall growth, which results in premature death at an average age of 14.5 years. In 2020, lonafarnib became the first (and only) FDA approved drug for treating progeria. In this context, the present review focuses on the different therapeutic strategies currently under development, with special attention to the new small molecules described in recent years, which may represent the upcoming first-in-class drugs with new mechanisms of action endowed with effectiveness not only to treat but also to cure progeria.

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Antisense technology: an overview and prospectus

Cited by 408 publications

References 200 publications

DNA damage response at telomeres boosts the transcription of SARS-CoV-2 receptor ACE2 during aging

DNA damage response at telomeres boosts the transcription of SARS-CoV-2 receptor ACE2 during aging

RNA-Targeting Splicing Modifiers: Drug Development and Screening Assays

Small-Molecule Therapeutic Perspectives for the Treatment of Progeria

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