Researchers at Isis Pharmaceuticals report that antisense drugs delivered systemically show activity in a wide range of tissues and organs, supporting their broad therapeutic potential in many disease indications. The scientists published their study (“Characterization of Target mRNA Reduction Through In Situ RNA Hybridization in Multiple Organ Systems Following Systemic Antisense Treatment in Animals”) in Nucleic Acid Therapeutics, a peer-reviewed journal from Mary Ann Liebert, Inc., publishers.

The team compared two antisense drug chemistries (Generation 2.0 and 2.5) designed to target a gene that is expressed by virtually all cells in mice and nonhuman primates. They demonstrated antisense activity in many tissues and cell types including liver, kidney, lung, muscle, adipose, adrenal gland, and peripheral nerves. The Generation 2.5 antisense compound was more effective in a wider range of tissues, according to researchers.

“We have developed a sensitive RNA in situ hybridization technique using the noncoding RNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) as a surrogate target. We have used this technique to evaluate the effects of 2’-O-methoxy ethyl (MOE) and constrained ethyl bicyclic nucleic acid (cEt) gapmer antisense oligonucleotides (ASOs),” wrote the investigators in the journal article. “ASO tissue distribution was also characterized using immunohistochemical techniques, and MALAT1 mRNA reductions were confirmed by quantitative real-time polymerase chain reaction.

“Our findings demonstrate that systemic antisense drug administration in both mice and nonhuman primates resulted in marked reductions in MALAT1 RNA in many tissues and cell types other than liver including kidney, muscle, lung, adipose, adrenal gland, and peripheral nerve tissue. As expected, ASOs with cEt chemistry were more efficacious than MOE ASO in all tissues examined.”

“This seminal work addresses one of the most important questions facing the field, the demonstration and evaluation of multiple organ targeting by nucleic acid therapeutics,” says Graham C. Parker, Ph.D., the journal’s executive editor who is based in The Carman and Ann Adams Department of Pediatrics, Wayne State University School of Medicine, Children’s Hospital of Michigan in Detroit. “This publication provides a benchmark for convergent analyses in multiple models for preclinical efficacy evaluation.”

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