8 March, 2017

Paper Nature Neuroscience (Basic Research)

AN INTERNATIONAL STUDY WITH THE PARTICIPATION OF THE UB SHOWS THAT HUNTINGTON'S DISEASE ALTERES NEURONS SINCE ITS DEVELOPMENT

The work of the consortium HD iPSC Consortium opens the door to developing targeted therapies in the stage prior to the onset of symptoms of the disease.

Huntington’s disease could cause disturbances of the neurons from the very beginning of its development, according to a study by the International Consortium HD iPSC Consortium, participating in this study was the laboratory team of Stem Cells and Regenerative Medicine Department biomedicine faculty of Medicine and Health Sciences, led by Dr. Josep M. Canals. The study, published in the journal Nature Neuroscience, shows pluripotent stem cells derived from patients (iPSC) and animal models of disease genes involved in the development of the striatum – the structure of the nervous system affected by trastorn – already altered in the process in which neurons originate. According to the researchers, these results could change the approach to treating the disease, but no cure, as they open the door to new therapies aimed at the stage prior to the onset of symptoms.

Huntington’s disease is a progressive and irreversible neurodegenerative disorder caused by mutation in the gene code for the protein huntingtin. It is a rare or minor hereditary characteristic which in the western countries has an incidence of five to seven per 100,000 people affected.

Despite being a genetic disease, it was thought that the development of the nervous system of patients would be regular until at an older age the symptoms would appear such as motor impairment (chorea, rigidity, etc.) and cognitive deficits and psychiatric disorders. Our results indicate that there is evidence of subtle alterations in development that make the neurons of these patients different from normal neurons, explains Josep M. Canals, who is also a researcher at the Institute of Neuroscience University of Barcelona and the Institute of Biomedical Research August Pi i Sunyer (IDIBAPS).

The study of the derivative iPSC cells in patients

The first phase of the study, led by the UB group, consisted of an analysis of striatal gene expressions during development in animal models which were then compared to gene expressions in neurons derived from human iPSC cells. The iPSC are skin cells reprogrammed with transcription factors to work as pluripotent stem cells, similar to embryonic stem cells, capable of differentiating into any type of specialized cell in these neurons. This process allows us to study the effects of genetic mutation in cells affected by the disease.

When the researchers compared gene expression data they found that over 600 genes responsible for development were altered in the cells of patients with Huntington’s disease. From this list of altered genes, they selected the most important and finally focused on a particular route, the expression of which can be controlled with a drug: the molecule ISX-9. This drug was administered to sick cells of the disease with neuroprotective effects, both in vitro and in mouse models. The drug reversed some markers; an increase was shown for both synapses and cognitive levels in the mice model. This in turn showed improvement on memory tests, says Monica Pardo, first author of the group UB.

The results show that the neurons of Huntington’s disease, though apparently having the same function as normal neurons, are not one hundred percent equal and that applying these methods to the development genes which were altered could alleviate and even reverse the symptoms, says Josep M. Canals.

A new view of the disease

According to the researchers, this study represents a change of approach in how we view the evolution of Huntington’s disease. Instead of waiting for the onset of symptoms as we do now, perhaps we should attack the poorly functioning neurons beforehand with pharmaceutical treatment or inducing the functionality of the affected neurons as is already being tested in other diseases such as Parkinson’s, says Josep M. Canals.

The objectives of the current HD iPSC Consortium is to expand the study with a larger sample of patients to find out which are the genes that are altered using a systematic and homogeneous population of patients. In this way, can find more precise therapeutic targets and in the future can develop drugs that prevent future illness.

The study forms part of the ADVANCE(CAT), which is integrated into the community NextHealth coordinated by Biocat and led by the UB and Ferrer. ADVANCE(CAT) facilitates the arrival of advanced therapies from the preclinical to the clinical application stages and  all the way to industrial production and is supported partially by ACCIÓ (Agency for the competitiveness of the company, Government of Catalonia) and by the European Union under the operational Programme ERDF (European Regional Development) Catalonia 2014-2020.