Proteome Systems to assist in Huntington's research

A US foundation that sponsors research into Huntington's disease has turned to Sydney proteomics company Proteome Systems to search for prognostic markers and targets for drugs to treat the fatal neurodegenerative disorder.

Geneticists traced the huntingtin gene to chromosome 5 in 1983, and cloned it 10 years later, but progress towards understanding the molecular basis of the disease has been painfully slow, and no therapy is in sight.

Proteome Systems CEO Keith Williams said he believed proteomics would gain traction where molecular genetics had been wheel-spinning for more than a decade.

The company will apply its mass spectrometry and 2D gel electrophoresis platform technology, ProteomIQ, to characterise changes in gene expression associated with the onset and progression of the disease, and will also look for potential drug-binding sites on the giant huntingtin protein molecule.

Although a DNA diagnostic has been available since 1993 that can detect pathological changes to the sequence of the huntingtin gene, only about 50 per cent of individuals from affected families take the test.

Typically, the first symptoms -- loss of coordination, and cognitive impairment -- do not appear until carriers of the defective gene are in their 40s or 50s, when some may already have passed it on to their own children.

Huntington's disease is now known to be due to a genetic mechanism that causes a repetitive DNA element in the huntingtin gene's promoter to expand spontaneously between generations. If the number of repeats exceeds 35, the individual is at risk of developing the disorder. The higher the number of repeats, the earlier the age of onset.

Some people who were potentially affected were reluctant to take the test, Williams said, because they saw no upside in knowing that they had a disease for which no therapy yet exists.

Since it was established in 2002, the High Q Foundation has funded a number of research projects into Huntington's disease, most based in molecular genetics.

Williams said Proteome Systems' success in identifying early prognostic markers for cystic fibrosis, and its search for therapeutic targets, encouraged the foundation to try a similar approach with Huntington's.

"We're one of two proteomics groups they're going to fund," he said. "The gene, and the mechanism for the disease -- the expansion of the gene -- have been known for some time.

"What hasn't been clear is why some people with the same number of repeats develop the disorder at different ages.

"With no biomarker to tell us when the disease began, and no way to assess how far it has progressed, there's no way to assess the benefit of any potential treatment -- we're not going to be able to evaluate whether a new drug is working or not.

"To do that, we need a window on when things in the brain start to go bad. In return for us becoming involved, the High Q Foundation will give us the commercial rights to any IP coming out of the project."

Williams said the company's ProteomIQ platform was the only one in the world that could easily characterise the huntingtin protein, which has a molecular mass of 300,000.

"We're going to have a close look at the protein, because there is some evidence that post-translational modification is a critical factor in the disease," he said.

Williams said DNA-binding motifs or domains that interact with other proteins, and changes in the abundance of other proteins in post-mortem brain tissues, may provide insights into the molecular mechanisms of Huntington's disease.

"We're happy to be involved in developing a prognostic test, and identifying potential drug targets," Williams said. "But as with similar developments that may come out of our cystic fibrosis program, these will be niche products."

Williams said that, just as the cystic fibrosis program had provided an entry point for Proteome Systems to investigate pathological changes in other lung diseases like asthma and chronic obstructive pulmonary disorder, the Huntington's project would be the basis for a wider exploration of pathological changes in protein patterns in other brain disorders like Parkinson's disease and Alzheimer's disease.