Professor David Rubinsztein, University of Cambridge, has discovered a method of identifying small molecules which can induce autophagy - the waste disposal and recycling mechanism used by cells to rid themselves of unwanted or misfolded proteins.
Several neurodegenerative diseases are caused by defective genes that lead to malformed proteins building up in brain cells. The huntingtin gene that lies at the origin of Huntington's disease has a trinucleotide repeat expansion that leads to a mutant form of huntingtin protein which then builds up in neurons, chiefly in the basal ganglia and cerebral cortex. In Western countries, it's estimated that about five to seven people per 100,000 are affected by Huntington's, according to the World Health Organisation.
This causes neuronal cell death and leads to symptoms such as abnormal movements, psychiatric disturbances like depression and a form of dementia. Although there are no current treatments that slow the progression of Huntington's, Prof Rubinsztein hoped that increasing cell autophagy could help clear the build up of damaging protein and reduce the effects of the disease.
"We have shown that stimulating autophagy in the cells - in other words, encouraging the cells to eat the malformed huntingtin proteins - can be an effective way of preventing them from building up," said Prof Rubinsztein.
Prof Rubinsztein first discovered that an existing immunosuppressant drug, namely Wyeth's Rapamune (rapamycin/sirolimus), induced autophagy in mice and fruit flies. Although Rapamune is precribed over long periods to prevent rejection in transplant patients, there are side-effects associated with its use, including an increased risk of infection. Therefore, Prof Rubinsztein explained that his team would ideally like to find an alternative therapy.
To do so, he teamed up with Professor Stuart Schreiber from the Broad Institute of Harvard and the Massachusetts Institute of Technology, US, and Dr Cahir O'Kane from the University of Cambridge. Prof Rubinsztein explained to Drugresearcher.com that the scientists screened 50,000 small molecules to see if they enhance or inhibit the effect of Rapamune on the growth of yeast cells.
From those experiments, two smaller subsets of compounds were created - those that inhibited cell growth and those that enhanced it. Around 40 compounds were subsequently tested in mammalian cells; only this time, instead of measuring cell growth, they measured autophagy levels more directly.
Of those molecules that increased the growth-supressing effects of Rapamune, the team found that three compounds induced autophagy in mammalian cells - independently of Wyeth's immunosuppressant.
"These compounds appear to be promising candidates for drug development," said Prof Rubinsztein. "However, even if one of the candidates does prove to be successful, it will be a number of years off becoming available as a treatment."
He explained that the group does not as yet know the full mechanism of the three compounds but hope that they could offer treatment with fewer side effects because they have a different mechanism to Rapamune. The team have also generated other similar compounds, bringing the total number of potential drugs to 20.
Although Prof Rubinsztein and his team specialise in Huntington's disease, and have the most advanced data on this disease, these molecules might also prove useful to treat other neurodegenerative disorders such as Alzheimer's or Parkinson's diseases - something the team will be examining in the future. Should the preclinical studies run successfully, the team will probably need to partner with a pharma firm before undertaking clinical development explained Prof Rubinsztein.
The scientists want to ensure they can get the potential drugs "in the right places, in the right concentrations and with minimal toxicity".
