Antisense Therapy - How it Works

RDR Staff

Antisense therapy makes for great headlines in the news as the “next big thing,” and companies have been trying for years to make antisense therapy a reality. Despite the headlines, however, there is currently only one antisense therapy approved and available: Kynamro (mipomersen) for patients with homozygous familial hypercholesterolemia (HoFH).
At the 2014 National Lipid Association (NLA) Scientific Sessions in Orlando, FL,  P. Barton Duell, MD, director of the Lipid Disorders and LDL Apheresis Unit, and  director of the Lipid-Atherosclerosis laboratory, Division of Endocrinology, Diabetes & Clinical Nutrition at Oregon Health and Science University, held a presentation entitled “Antisense Therapy: A New Concept in Disease Management,” to provide the audience with an overview of how antisense therapy works, as well as an overview of some of the drugs that may come to market soon—
including many for rare diseases.
Antisense therapy refers to oligonucleotides that are complementary for gene target of interest. An antisense sequence binds to mRNA and prevents translation.
Some of the antisense drugs approved or in late-stage development include:

Challenges of Antisense Therapy

Dr. Duell listed several challenges to developing antisense therapy including:
  1. Need to identify appropriate gene target.
  2. Need to generate an antisense oligonucleotide that is specific for the gene of interest.
  3. Molecule needs to be modified to prevent degradation by RNases and other enzymes.
  4. Drug needs to be deliverable to the organ of interest.


Antisense therapy prevents protein synthesis by binding to mRNA to reduce specific proteins. In the case of Kynamro, it is a 20-base-pair oligonucleotide that binds to the mRNA associated with the synthesis of apolipoprotein B (ApoB)-100, a protein involved in lipid transport and removal. Kynamro is a second-generation ApoB antisense oligonucleotide developed by Isis Pharmaceuticals, which later partnered with Genzyme to market the drug. Kynamro was approved in 2013 as adjunct therapy to treat patients with HoFH.

The pivotal clinical trial that led to Kynamro’s approval was a randomized, double-blind, placebo-controlled, multicenter trial that enrolled 51 patients age 12 to 53 yrs (Raal et al 2010). Patients were randomly assigned to weekly injections of Kynamro (200 mg subcutaneously; n=34) or placebo (n=17) for 26 weeks. At the end of the study, the mean percentage change in low-density lipoprotein cholesterol (LDL-C) concentration was significantly greater with Kynamro (-24.7%; 95% CI, -31.6 to -17.7) than with placebo (-3.3%, -12.1 to 5.5; P =.0003).

According to Dr, Duell, common adverse events associated with Kynmaro are:
Due to the increased liver enzymes observed in some patients, Kynamro comes with a boxed warning.


Dr. Duell noted that antisense technology has great promise for specific suppression of translation of disease-associated proteins from target genes. Furthermore, new antisense drugs are being developed to target other aspects of lipid metabolism, as well as many rare diseases including rare cancers and Duchenne muscular dystrophy.

Currently, the only approved antisense drug is mipomersen [CHANGE TO “Kynamro”?] for HoFH.

About HoFH

HoFH is a rare genetic lipid disorder resulting in an accumulation of  LDL-C in the blood. Patients with untreated HoFH have extremely high LDL-C levels, typically between 400 mg/dL and 1000 mg/dL. These patients are at severely high risk for premature cardiovascular events, such as heart attack or stroke.

The current treatment options for these patients include dietary modifications, lipid-lowering agents (eg, statins), and in many cases, regular and costly LDL apheresis is necessary. These treatments are often ineffective in reducing LDL-C to recommended levels in patients with HoFH. Another form of FH, heterozygous FH, can usually be treated with statins and diet modification.


Raal FJ, Santos RD, Blom DJ, et al. Mipomersen, an apolipoprotein B synthesis inhibitor, for lowering of LDL cholesterol concentrations in patients with homozygous familial hypercholesterolaemia: a randomised, double-blind, placebo-controlled trial. Lancet. 2010;375(9719):998-1006.
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