Huntington鈥檚 disease may be about to meet its match with the development of a therapy designed to knock out production of the defective protein that causes the condition.
Huntington鈥檚 is an untreatable inherited disease in which repetitive sequences of DNA lead to the production of a faulty version of a protein called huntingtin, giving it multiple copies of the amino acid glutamine. As adults, its victims lose their cognitive abilities, suffer involuntary movements and, after a decade or more, die.
This week at the American Society of Gene Therapy meeting in Baltimore, Maryland, researchers led by Beverly Davidson of the University of Iowa described their progress treating the disease with a technique called RNA interference, or RNAi.
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RNAi uses short sequences of RNA just over 20 bases long to trigger a natural 鈥済ene-silencing鈥� mechanism, shutting down the production of specific proteins by targeting the RNA that carries the instructions for making them.
Blocked message
Last year, Davidson raised the hopes of people carrying the Huntington鈥檚 gene when she used engineered viruses to treat mice with the mutated gene. The viruses produce 鈥渟mall interfering鈥� RNA sequences designed to block the RNA carrying the message to make huntingtin.
When injected into the mice鈥檚 brains, the viruses reduced levels of the protein and improved the animals鈥� behavioural symptoms.
However, Huntington鈥檚 patients have one mutated and one normal copy of the huntingtin gene, and the small interfering RNA used in Davidson鈥檚 initial experiments targets abnormal and normal huntingtin alike. The protein is important for embryological development, but its function in the adult brain is unclear.
Davidson is now looking for methods to silence only the abnormal gene. For the 40 per cent of Huntington鈥檚 patients who carry a particular version of the gene she may have the answer. This version has a second mutation which her team has been able to target exclusively with a small interfering RNA sequence.
Very optimistic
So far the experiments have only been carried out in cultured cells, and Davidson, who is collaborating with Sirna Therapeutics, a firm based in San Francisco, US, warns that it may be several years before the therapy is ready for testing in people. 鈥淲e need to be careful and do good science, but we鈥檙e very optimistic,鈥� she says.
Gene therapists are also optimistic that RNAi will prove effective against other devastating neurodegenerative conditions, such as Alzheimer鈥檚 disease.
Researchers led by Inder Verma of the Salk Institute for Biological Studies in La Jolla, California, and Fred 鈥淩usty鈥� Gage of the University of California, San Diego, have already used RNAi to target an enzyme called beta-secretase, which is involved in the formation of the protein plaques that accumulate in the brains of Alzheimer鈥檚 patients.
They have found that the treatment restores the ability of mice with an Alzheimer鈥檚-like condition to perform in a water maze test, in which they have to remember the position of a submerged platform. 鈥淚t鈥檚 pretty impressive,鈥� says Verma, who hopes to begin experiments in monkeys by the end of the year.
