Arches. Photo by Daniel Chia
HOPES: Huntington's Outreach Project for Education, at Stanford
Jul
06
2010

XIAP Gene Therapy

The X-Linked Inhibitor of Apoptosis Protein (XIAP) gene is a gene present in normal body cells that inhibits the activity of caspases 9, 3, and 7. A caspase is an enzyme that degrades proteins and is involved in certain types of cell death, also known as apoptosis. In Huntington’s disease (HD), the presence of mutant huntingtin clumps, or aggregates, activates caspases. Once a caspase is activated, it can cut mutant huntingtin protein into smaller pieces, making the mutant huntingtin protein more toxic and causing brain cells to die. Remember that some evidence exists that apoptosis of brain cells is the root of the neurodegenerative problems in HD. To learn more about cell death in HD, click here.

Because the XIAP gene inhibits caspase activity, it can prevent cell death, which means it has great potential in the treatment of neurodegenerative diseases such as HD. The goal of XIAP gene therapy is to inject this gene into cells that are affected by HD so that apoptosis does not occur.

How has XIAP gene therapy been shown to prevent apoptosis?^

In 2005, researchers working for the pharmaceutical company Neurologix Incorporated tested the potential of the XIAP gene both in vitro (outside of a living organism) and in vivo (inside of a living organism). In vitro, the scientists added the XIAP gene (also known as dXIAP) to brain cells that were designed to have the HD mutation. The study found that the addition of dXIAP significantly decreased the number of cells that died due to apoptosis. The scientists also confirmed the potential of XIAP gene therapy in rat models. The rats were engineered to have symptoms of Parkinson’s disease, a disease that, like HD, results in brain cell death. Researchers found that the neurons of rats that were injected with dXIAP were protected against apoptosis.

In the same study, the scientists also aimed to determine more specifically how XIAP gene therapy works. To do this, they engineered four mutant versions of the dXIAP gene. In each mutant version, a different small section of the gene was mutated so that its function was disrupted. Each of these mutant versions was injected into HD-mutant cells to test their effectiveness. The scientists found that only a mutation in a section called BIR3 prevented dXIAP from effectively stopping cell death. This means that the BIR3 section, specifically, is most crucial to the success of XIAP gene therapy. This was useful because the scientists already knew that the BIR3 domain commonly interacts with caspase 9. Thus they concluded that the neuroprotective effect of the XIAP gene may primarily work by stopping the activity of caspase 9 rather than caspase 3 or 7.

What’s the potential of XIAP gene therapy in HD?^

Neurologix Incorporated has taken the initiative to determine how the XIAP protein could be used to treat neurodegenerative symptoms in HD patients. In 2008, the company was given exclusive rights to use XIAP to develop a treatment for HD. As mentioned above, Neurologix has already shown that XIAP gene therapy has some effect in preventing cell death in rodents, but it is not yet ready to be tested in humans. Many more experiments with rodent models of HD have to be done before XIAP gene therapy can even be considered a possible treatment for HD in humans. Neurologix does plan to conduct clinical trials in humans, but it is unknown when they will be ready and able to begin these trials.

For Further Reading^

  • Musatov, Sergei, Joshua Goldfein, Justin Fraser, John Pena, and Michael G. Kaplitt. “Neuroprotective Effects of XIAP Gene Therapy in Models of Neurodegenerative Diseases.” Molecular Therapy 11 (2005). Abstract.: n. pag. Print.
    A journal article explaining the in vivo and in vitro pre-clinical trials of XIAP gene therapy to treat HD and Parkinson’s disease
  • Neurologix, Inc. clinical-stage biotechnology company. Huntington’s Disease. Web. 26 Dec. 2009. <http://www.neurologix.net/products/huntingtons.html>.
    Information posted on the Neurologix Incorporated website about their progress and investment in studying XIAP gene therapy and its potential for HD treatment.
  • “Neurologix Licenses to Aegera’ XIAP Gene for Use in Huntington’s.” GEN News Highlights. Genetic Engineering and Biotechnology News, 3 Sept. 2008. Web. 29 July 2009. <http://www.genengnews.com/news/bnitem.aspx?name=41256917>.
    News article About Neurologix’s involvement in XIAP gene therapy studies
  • Sanchez Mejia, Rene O., and Robert M. Friedlander. “Caspases in Huntington’s Disease.” Neuroscientist 7 (2001): 480-89. Sage Journals Online. Web.
    A journal article about the role of caspases in cell death in Huntington’s disease

-C. Garnett, 2-28-10