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Antisense Gene Therapy

Antisense gene therapy is a gene silencing technique similar to RNA interference, but uses a slightly different mechanism. The therapy is called a gene silencing technique because, instead of repairing the gene, it aims to “silence” the gene’s effect. Recall that people with Huntington’s disease (HD) have two copies, or alleles, of the Huntington gene, one of which codes for the normal huntingtin protein and one of which codes for the “bad” huntingtin protein that is associated with the symptoms of the disease. Like all proteins, both good and bad huntingtin proteins are formed using the information present in the genetic code. Proteins are produced in two steps. First, the genetic code of DNA is transcribed into mRNA, which then travels to ribosomes. Next, ribosomes use mRNA as instructions to build the correct protein in a step known as translation. The step is called translation because the information is translated from the language of genetic code into the language of amino acids, which are the building blocks of proteins. To learn more about the relationship between DNA and proteins, click here. Antisense gene therapy seeks to “silence” a gene by inhibiting the translation step and preventing the bad protein from being formed.

How does antisense gene therapy work?^

In antisense gene therapy, short single-stranded pieces of chemically modified nucleotides, known as oligonucleotides are inserted into cells. These short strands are sometimes abbreviated as “oligos” and are chemically engineered to be complementary to specific mRNA in the cell. For example, in treating HD, these strands would be complimentary to the mRNA that codes for the harmful huntingtin protein. After being inserted into the cell, these oligos bind to the target mRNA and inhibit the protein from being produced in one of two ways: physically blocking translation or recruiting an enzyme known as RNase H to degrade the mRNA. This way, the information in the DNA that codes for the bad huntingtin protein never makes it to the ribosome and the mutated form of the protein is never formed.

How is antisense gene therapy different from RNA interference?^

The intended effect of both RNA interference (RNAi) and antisense gene therapy is the same, but their mechanisms are slightly different. Like antisense therapy, RNAi is a gene silencing technique that inhibits the actions of genes by interfering with the translation of proteins. However, antisense technology destroys target mRNA by recruiting the enzyme RNase H, while RNAi recruits a different RNase enzyme known as dicer. In addition, RNAi molecules are twice as large as antisense oligonucleotides (because they are double stranded rather than single stranded). Their larger size makes it more difficult for them to get into the body’s cells where they can have a beneficial effect. For more information on RNAi, please click here.

Challenges to antisense technology^

One major challenge to antisense technology (and RNAi) is the difficulty of getting it into the body. Delivery of the treatment to the brain, for use in diseases like HD, is especially challenging because it must cross the blood-brain barrier. Brain entry is very difficult and cannot be accomplished through a simple injection or pill that contains the antisense oligos. Isis Pharmaceuticals, the leading company in antisense technology, plans to solve this problem by inserting a pump into the chest that can carry the drug to the brain through a catheter, or tube. Another possible solution is to use an inactivated virus to “infect” cells with the drug.

The second major challenge to antisense technology is its inevitable toxic effects. Although antisense technology is engineered to be very specific, it can still cause unintended damage because it would regulate both the mutant and normal Huntington alleles. The challenge is to determine the right dosage and composition of an antisense molecule to strike a balance between reducing the symptoms of HD and avoiding side effects caused by altering the “good” Huntington gene. For this reason, it is likely that antisense therapy will only be able to go so far in mitigating the symptoms of HD. It is also possible that antisense technology may be most effective if engineered specifically for each patient’s needs, but this type of personalized medicine is not now of primary concern.

Current development of antisense gene therapy^

Isis Pharmaceuticals has taken the lead in the arena of antisense gene therapy technology. Though they have not yet engineered an antisense drug for HD, they have already been successful in getting one antisense drug, Vitravene©, on the market. This drug uses antisense technology to treat an eye disease associated with AIDS. In addition, Isis has made a number of promising advances in scientific trials of antisense technology to treat other conditions including high cholesterol and Parkinson’s disease. Perhaps most exciting is that in 2007, CHDI, a Los Angeles non-profit dedicated to finding a cure for HD, granted Isis 9.9 million to work on developing an antisense drug for HD. So far, Isis has successfully used antisense technology to inhibit the action of the Huntington gene in mouse cells, mouse brains and human cells. Isis is currently testing the technology on transgenic mice (mice that are genetically modified to have the mutated HD allele). If that goes well, the next step will be to try it in monkeys, and then eventually humans.

For further reading^

  • Achenbach, TV, Brunner, B and Heermeier, K. 2003. Oligonucleotide-Based Knockdown Technologies: Antisense Versus RNA Interference. ChemBioChem 4: 928-35.
    This is a very scientific in-depth discussion and comparison of RNA interference and antisense technology.
  • La Spada, Alberta R. (2009). Getting a handle on Huntington’s disease: silencing neurodegeneration. Nature Medicine 15: 252-53.
    This is a scientific journal article that discusses the potential of gene silencing in treatment of Huntington’s disease.
  • Veritas, Gene. (2008). An Exciting Interview at Isis. Huntington’s Disease Drug Works. 23 Apr.
    This is a news article about Isis’s initiative to develop antisense therapy for HD.
  • Isis Website:
  • CHDI Website:

– C. Garnett, 10-19-09