Finding the Sense in Antisense

The first medicine based on antisense technology was approved by the FDA in 1998. With scarcely a follower in the years since, many in the industry have questioned the potential of these treatments. Recent developments, however, suggest they may be on the rise again.

05.06.2015   |   12:56 BST

In 2013, the FDA approved a second antisense therapy—this one designed to treat a genetic defect that leads to high cholesterol.1

And now, more than 40 antisense therapies are in clinical trials for diseases such as cancer, diabetes and neurodegenerative diseases; over 20 of those therapies are in advanced stages of development.2

“There’s really a nice potential for antisense therapies to be able to fix, modify or even eliminate disease that is caused by genetic mutation,” Scott Smith, President of Global Inflammation and Immunology at Celgene, said. “And there is antisense research being done in asthma, arthritis and other inflammatory diseases.”

Antisense therapies target molecules called messenger RNA (mRNA)—the intermediary between a gene and the protein it codes for. If the DNA molecules that make up the genome can be envisioned as a twisted ladder (the famous “double helix”), with steps consisting of partnered nucleotide pairs, RNA resembles that ladder cut down the middle lengthwise. This single-stranded, unpaired structure is essential to the production of proteins from a given gene.

Although the theory behind antisense dates back to the 1970s, the technology only became practical in the 1990s, when the human genome was mapped, lending researchers the gene sequences they would need to design an antisense molecule. With the right sequence, antisense therapies are meant to bind to a disease-associated mRNA, and thereby block production of the relevant dysfunctional, or simply overabundant, protein.3

But their single-stranded nature leaves antisense molecules vulnerable to enzymes that can break them down, creating obstacles for scientists looking to turn them into therapies. As a result, researchers have been working on improving their life span, distribution and binding power, often through chemical modifications.

At the University of Rome Tor Vergata, Professor Giovanni Monteleone is leading the quest for an antisense therapy for inflammatory diseases. His mission has been to overcome some of the hurdles these therapies have faced. Designing a new administration method has been a focus for Monteleone and others interested in this technology platform.4

“If you give the drugs orally, they get degraded—broken down—before getting to the target tissue,” Smith said. “And if you give them intravenously, they are circulating in the whole body and not necessarily hitting the target tissue, which can lead to side effects.”

One new possibility researchers are exploring is to administer an antisense therapy topically.4 That way, the entire body is not exposed to potential off-target consequences that could lead to side effects. And a topical formulation would allow specific, targeted application to the disease area.

Only clinical trials will tell us whether the promise of these therapies will bear out. Monteleone and Smith, along with others at Celgene, are optimistic.

“I think there is a lot of hope for antisense therapies in the future, but it does require some different thinking,” Smith said. “As an industry, we need to find a more eloquent way to deliver the drug to diseased cells. If some of the delivery problems can be overcome, there’s tremendous potential for these drugs.”


1Sinha G. Antisense battles small molecule for slice of rare lipid disorder market. Nature Biotechnology 2013;31,179–180.
2Lindow M and Mellerup S, Oligonucleotide development programs. (Accessed: June 2015).
3Lander E.S. Initial impact of the sequencing of the human genome. Nature 2011; 470, 187–197.
4Monteleone G, Neurath M.F., Ardizzone S. et al. Mongersen, an Oral SMAD7 Antisense Oligonucleotide, and Crohn’s Disease. The New England Journal of Medicine 2015. 372: 1104-1113.

Date of Preparation: June 2015