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25 February 2014

Huntington's disease: A treatment in sight?

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New biomarkers will follow disease progress and rapidly detect effects of a novel drug.

A treatment to directly fight Huntington’s disease could finally be in sight. Until now, therapies for this severely debilitating genetic disorder have only focused on alleviating physical and psychiatric symptoms. Recently, however, Selisistat, a drug developed at Siena Biotech, in Siena, Italy, has rekindled hope that, in the next few years, the disorder could be tackled at its roots. Scientists hope this can be done by modulating the amount of the so-called ‘Huntington’s protein’, the mutated form of which, gives rise to the disease.

Now, researchers in a pan-European project, called Paddington, due to be completed in 2013, have discovered new drug-specific biomarkers to follow patients’ response to the drug. "We have indications that we are going to get a new biomarker which is specific for our drug. It is not a general Huntington’s disease marker, but a drug-specific biomarker," says Giovanna Tripepi, clinical research group leader responsible for ADME/PK, the study of absorption, distribution, metabolism, excretion and pharmacokinetics, at Siena Biotech and Paddington project coordinator.

Despite focusing on drug-specific—as opposed to disease-specific—biomarkers, this approach still offers some benefits. "The advantage of using biomarkers detectable in patients' blood is that changes in reaction to a drug can be detected easily and over clinically useful time scale," adds Tripepi. This means, the effectiveness of the drug could be determined within three to five years, researchers expect, thus bringing new hope for treating Huntington’s.

Selisistat selectively controls expression of certain genes, including, potentially, the Huntington gene, present in all humans. Its mutated form codes for an altered protein, called mutHtt (mutated Huntintin), deemed to be responsible for the symptoms of Huntington’s disease. Indeed, mutHtt is toxic for neurons in the brain, causing increased damage to certain brain areas, affecting muscle control, and causing the deterioration of mental capabilities. But protein production requires expression of the corresponding gene.

So far, 55 patients took part in clinical studies, as part of the project. "The results were really encouraging and we got a couple of pharmacological biomarkers," says Giuseppe Pollio, research group leader of molecular neuroscience at Siena Biotech. However, there is still a lot of work ahead before the drug can be registered and made available to all patients. 

First, scientists need to show that the drug really attacks the root of Huntington's disease by interfering with its causative gene expression and activity. "The clinical plan has not yet been completed, and we still have to run a proof of concept programme," says Tripepi. In addition, these kinds of studies are quite expensive. "What we need is to find an investor to finance this study. When we have done this study and have the results, we will be able to register the compound quite quickly and make it available," says Tripepi.

Some experts in the field express caution that treatment may yet be a number of years away. "There are still many problems to be solved... I do not expect any solution for the next ten years or so,” says Jan Kobal, who also researches Huntington biomarkers at the University Medical Centre in Ljubliana, Slovenia. He tells “I've been working on Huntington's for twenty years, but treatment still remains a problem."

However, the project’s approach has received some support from other experts in the field. Because Huntington's is caused by a single gene, the approach by the project consortium makes sense, according to Anthony Chan, who researches Huntington's and Alzheimer's at Emory University in Atlanta, Georgia, USA. He tells "I hope that at the end of the clinical studies they will provide strong evidence that the compound they are using is actually changing the cause, and that then Big Pharma comes in to perform a much larger-scale clinical study."

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