iBet uBet web content aggregator. Adding the entire web to your favor.
iBet uBet web content aggregator. Adding the entire web to your favor.



Link to original content: https://pubmed.ncbi.nlm.nih.gov/25385330
Antisense oligonucleotide therapies: the promise and the challenges from a toxicologic pathologist's perspective - PubMed Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2015 Jan;43(1):78-89.
doi: 10.1177/0192623314551840. Epub 2014 Nov 9.

Antisense oligonucleotide therapies: the promise and the challenges from a toxicologic pathologist's perspective

Kendall S Frazier  1
Affiliations
Review

Antisense oligonucleotide therapies: the promise and the challenges from a toxicologic pathologist's perspective

Kendall S Frazier. Toxicol Pathol. 2015 Jan.

Abstract

Many antisense oligonucleotides (ASOs) from several classes of molecules are currently in drug development. Despite over 20 years of pharmaceutical research, few ASOs have been marketed due to problems with clinical efficacy or preclinical toxicologic challenges. However, a number of recent developments have renewed interest in this class including the registration of mipomersen, the advent of successful screening strategies to eliminate more toxic molecules, and new understanding of the risks of off-target nucleotide binding and mitigation of potential off-target effects. Recent advances in backbone chemistries, conjugation to other moieties, and new delivery systems have allowed better tissue penetration, enhanced intracellular targeting, and less frequent dosing, resulting in fewer toxicities. While these new developments provide invigorated interest in these platforms, a few lingering challenges and preclinical/clinical toxicity issues remain to be completely resolved, including: (1) proinflammatory effects (vasculitis/inflammatory infiltrates); (2) nephrotoxicity and hepatotoxicity unrelated to lysosomal accumulation; and (3) thrombocytopenia. Recent investigative work by several laboratories have helped elucidate mechanisms for these issues, allowing a better understanding of the clinical relevance and implications of particular toxicities. It is important for toxicologists, pathologists, and regulatory reviewers to be familiar with new developments in the ASO field and their implications, as a greater number of new types of antisense molecules undergo preclinical toxicity testing.

Keywords: drug development; mechanisms of toxicity; oligonucleotide.; safety assessment; toxicologic pathology.

PubMed Disclaimer

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

Substances