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December 7, 2017

A new approach to treating schizophrenia

Ground-breaking research has uncovered a new therapeutic approach to treating genetic forms of schizophrenia. Elly Earls meets the lead author of the study to find out about its potential.

By Elly Earls

Researchers in Scotland have come up with a new approach to tackling hereditary schizophrenia, which they hope can target the underlying cause of the disease with pinpoint accuracy. Although it’s still a long shot, the scientists behind the breakthrough believe it’s an exciting starting point with unquestionable therapeutic potential, which could also be applied to a range of other diseases.

Uncovered by a coalition of researchers across Scottish universities, the new approach builds on research carried out over the last five decades, which has found that people with a hereditary form of schizophrenia are deficient in one particular protein.

DISC 1, or ‘Disrupted in schizophrenia 1’, as it was named in 2000, is a ‘scaffolding’ protein, which, in a large extended Scottish family – many of whom suffer from psychiatric illnesses ranging from schizophrenia to bipolar disorder – was discovered to be ‘translocated’ or disrupted.

Armed with this knowledge and assisted with funds from Pfizer, a team lead by George Baillie, professor of molecular pharmacology at the University of Glasgow’s Institute of Cardiovascular and Medical Sciences, decided to try and figure out how they could counteract this DISC 1 deficiency.

“Basically, one chromosome was fine but one was deficient in DISC 1. So we started looking at the way the protein was degraded normally in cells. If we could manipulate that process and stop the natural degradation of the protein, this would lead to its up-regulation,” Baillie says.

Disrupting protein-protein interactions

In the process of their research, Baillie and his team located for the first time the protein FPXW7, which tags the DISC 1 protein for destruction. “There was a protein-protein interaction,” Baillie explains, “and if we could find a way to disrupt the interaction between FPXW7 and DISC 1, that would be a really neat way to naturally up-regulate the protein.”

The team mapped the protein-protein interaction at the binding site and managed to identify a peptide, which was able to inhibit the interaction between FPXW7 and DISC 1, thereby stopping the degradation of DISC 1. “We could actually up-regulate DISC 1 back to normal levels in patient derived cells, which is a really good proof of concept that this is a good therapeutic strategy,” Baillie says.

If this approach were to eventually be turned into a pharmaceutical treatment, it would be a step change from the current standard of care for schizophrenia, a condition that affects around one in every 100 people, and is present in twice as many people as Alzheimer’s and five times as many as multiple sclerosis.

At present, schizophrenia is typically treated with a combination of antipsychotic medication and cognitive behavioural therapy tailored to each individual. But despite the condition’s prevalence and the fact that many patients respond inadequately or adversely to the commonly-prescribed treatments, there have been no substantial innovations in drug treatments over the last several decades.

Baillie believes this is for a number of reasons. “First, it’s a very difficult treatment to model in animals, and secondly it’s usually quite a long study to do, which is very expensive. As it’s such a multi-faceted disease, it’s very difficult to know what the underlying cause is and if you don’t know that, you can’t make a treatment.”

From peptide to compound

Baillie and his team are ploughing ahead to change this, but are also keen to stress that there are many hurdles to overcome before their novel therapeutic approach can be turned into a real-world treatment for patients, not least the fact that their proof of concept study used a peptide and peptides aren’t usually able to cross the blood-brain barrier.

In this regard, work is already well underway. “We configured the peptide into an assay for high throughput screening,” Baillie explains. “This means we can screen tens of thousands of small molecules to find a compound that will do the same as the peptide.”

Already, with the help of funds from Scottish Enterprise, the team have found some suitable compounds and proved they work in cells. The problem was they weren’t good starting points for making medicines for people. And so the second screening study – at the University of Dundee’s drug discovery unit – has begun.

“We’ve got some novel compounds that look like they’re better starting points for making a medicine, so that’s where we’re at now, but there is still a lot of development work to go,” Baillie says. “We’re now writing grants to get money to develop those compounds – firstly to make them better, secondly to prove they’re not toxic and thirdly to make sure they’re active in cells. We’ve got a really well defined path that we can go down but it depends on us getting some money from different places.”

An exciting starting point

If all went precisely to plan, Baillie says the best-case scenario would be a drug available for patients in 10 years’ time. And looking even further ahead, the approach the team have developed has implications far beyond schizophrenia.

Not only is the DISC 1 protein known to play a part in many other diseases of the central nervous system (CNS), including autism, Alzheimer’s disease and Parkinson’s disease, the approach of inhibiting proteins that tag other proteins for destruction could be applied far beyond CNS conditions.

“We’re already working on a range of other diseases where proteins are down-regulated and we can also do it the other way round – the tagging is reversible,” Baillie explains. “In some diseases like cancer there are proteins that are up-regulated – we’re looking at actively down-regulating those proteins in a number of diseases including cardiovascular disease and cancer.”

In the meantime, Baillie is happy just to have a starting point. “It’s a long shot, but it’s very exciting,” he concludes.

 

 

 

 

 

 

 

 

 

 

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