What is antisense therapy?
Most human diseases are caused by production of abnormal proteins or malfunctioning proteins. Antisense therapy involves inhibiting production of these proteins. When a gene is known to cause a specific disease and the genetic sequence of that gene is known, it is theoretically possible to synthesize a complementary molecule that will bind to that gene and inactivate it. If you prevent the abnormal protein from being made, you prevent its damaging effects on cells, and therefore reduce or delay symptoms.
Where does the name “antisense” come from?
The first step in the production of a protein is the unwinding of the DNA double helix and the production of a single stranded messenger RNA (mRNA) molecule. The sequence of nucleotides (building blocks) in the mRNA molecule is called the “sense” sequence. The “antisense” molecule is the complementary RNA strand that targets the mRNA molecule and is designed to essentially “shoot the messenger” so the protein won’t be made. Another name for this therapy is antisense oligonucleotide (ASO) therapy and it is sometimes also referred to as a type of gene silencing.
Are any antisense therapies commercially available?
In January, the FDA approved the antisense product Kynamro (mipomersen) to treat homozygous familial hypercholesterolemia. Vitravene (formivirsen) was approved in 1998 to treat cytomegalovirus (CMV) retinitis in AIDS patients.
What’s new with antisense therapy?
Last month, the first human trial using antisense therapy for a neurodegenerative disease was reported in the Lancet Neurology. This was a phase 1 placebo controlled trial for a genetic form of amyotrophic lateral sclerosis (ALS or Lou Gehrig’s disease) and participants had a mutation in the superoxide dismutase (SOD1) gene. SOD1 gene mutations are associated with approximately 20% of familial ALS and about 2% of all ALS. Injection of antisense molecules into the spinal cord targeted to the mRNA for the SOD1 protein was found to be safe. More research will be needed to determine if this therapy can benefit ALS patients with this gene mutation.
Is research underway to look at antisense therapy for other rare disorders?
What are the challenges in development of antisense therapy?
Antisense technology was first developed 35 years ago, but it has been extremely difficult to translate the technology into useful clinical applications. ASOs need to be chemically modified so they won’t be rapidly broken down by enzymes and will accurately bind to their intended targets. Another challenge is delivering the product where it is needed in order to provide a beneficial effect. Additionally, antisense products could build up in certain organs such as the liver and lead to toxic side-effects. The rare disease community is cautiously optimistic that significant progress is being made to overcome these obstacles and provide new therapeutic options for patients. NORD will be following advancements in the development of antisense therapies and providing updates when appropriate.
RareDisease Dialog is the official blog for the National Organization for Rare Disorders (NORD). NORD’s staff and friends will share information of interest to the entire rare disease community.
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