Intrabodies R Us
About 30,000 Americans suffer from Huntington’s disease, a gradual loss of brain cells that affects the ability to speak, move, and even think. There is no cure as yet, but now a way to slow the disease’s progress may have been found by Caltech scientists.
Huntington’s has its roots in a mutation in the gene for a protein called huntingtin. Huntingtin is essential for normal brain development, although its exact function is unclear. The mutation creates an abnormally long version of the protein, which normally contains a string of 10 to 35 copies of an amino acid called glutamine. The mutation has a genetic stutter, causing this string to lengthen to as many as 120 glutamines. The abnormally long protein gets chopped up into smaller pieces that accumulate in a part of the brain called the basal ganglia, eventually killing the cells. As the cells die, decision-making skills and memories fade, coordination decreases, and twitches set in in the fingers, feet, and face.
Back in 2002, Senior Research Fellow in Biology Ali Khoshnan, biology staff member Jan Ko, and Paul Patterson, the Biaggini Professor of Biological Sciences, discovered that certain molecules could bind to the mutant protein and either block or exacerbate the mutant’s toxicity. These molecules belong to a class of molecules now known as “intrabodies,” or intracellular antibodies, because they work like antibodies but operate inside a cell rather than binding to a target protein on the cell surface. The intrabody gets into the cell by hitching a ride on a tame virus, which then hijacks the cell’s machinery to flood the cell with it.
Now, grad student Amber Southwell (PhD ’09), Ko, and Patterson have shown that an intrabody called Happ1 can reverse much of the loss of coordination and cognition in five different strains of mice bred to mimic various aspects of Huntington’s disease—the first time this has been demonstrated so effectively in mammals. (Previous studies had used cell cultures or fruit flies.) In one strain, Happ1 actually increased the mouse’s body weight and life span.
Happ1 binds to an amino-acid sequence unique to the huntingtin protein that is rich in the amino acid proline, and this sequence is expected to be extremely specific. “Our studies show that the use of intrabodies can block the parts of mutant huntingtin that cause its toxicity without affecting the wild type, or normal, huntingtin—or any other proteins,” says Patterson.
In other words, he says, this has the potential to be the kind of “silver-bullet therapy” that many medical researchers look for. Current treatments tend to address the disease’s symptoms, not its cause, but this approach might prevent it from doing significant damage in the first place.
The next step, says Patterson, is to improve the intrabody’s effectiveness and to “build a viral vector that can be controlled—induced and turned off—in case of unexpected side effects. This is a general goal shared by all types of experimental gene therapies.”
A paper describing the work, with Southwell as the lead author, was published in the October 28 issue of the Journal of Neuroscience. The research was funded by the Hereditary Disease Foundation, the CHDI Foundation, and the National Institute of Neurological Disorders and Stroke. —LO