New Target to Fight Motor Neurone Disease Using Gene Therapy

In the UK, six people die each day from Motor Neurone Disease, which results in paralysis that is progressive as the nerves supplying muscles deteriorate for reasons that are not fully known. At a given time, there are almost half a million people all over the world that have this condition but in most of the cases the reason why the nerves supplying muscles or the motor neurons die is not known. The most common known reason is a gene mutation known as C9ORF72.About 1 out of 10 Motor Neurone Disease cases is related to having an extended repeating region of DND in a portion of the C9ORF72 gene that is uncommonly converted into protein.

Scientists at SITraN have stumbled upon an important trail in the C9ORF72-linked Motor Neurone Disease by probing into the molecular principals of the behaviour pattern of this gene’s products in the cell. Testing patients’ cells and minute models of the Motor Neurone Disease indicatethat focusing on this plan is a unique way to tackle the nerve cells degeneration that takes place in Motor Neurone Disease.

Dr Guillaume Hautbergue from the University of Sheffield, who has spent over 25 years studying the molecular biology of RNA, also studied mechanisms that transfer messenger RNA to the cell cytoplasm from the nucleus through a model of how this functions in humans. Interpreting the findings in vital discovery science into actual profits for patients is the ultimate goal for SITraN and so using Dr Hautbergue’s findings in the RNA biology field has now led to the innovation of a new beneficial approach of neuroprotection in Motor Neurone Disease and possibly other diseases that are neurodegenerative.

While the primary function of DNA is to code for proteins that are to be built in the cell, we are aware that many DNA does not, after all, code for protein, like the region that is repetitive of the C9ORF72 gene. The repeated region is simply left out of the RNA replica of the gene before it is sent out of the nucleus, in its healthier version. Dr Hautbergue and his colleagues have developed their expertise in the field of RNA nuclear export mechanisms.

They have also put in a research in the area of the pathological recurring originator RNA molecules that is generally restrained in the nucleus itself. These may be getting exported out to the cell cytoplasm where the protein is produced, which is toxic in nature. Findings showed that only one component of the nuclear-cytoplasm transport system was the reason for the transportation of the RNA out of the nucleus and into the cytoplasm. This is a protein called SRSF1 and a significant discovery found in this research is that this protein in required only to assist the pathological C9ORF72 RNA to exit the nucleus.

Rest of all the other useful RNAs that code proteins can get to the cytoplasm without this. There were no undesirable effects in the fruitfly models and culture cells from the MND patients once the SRFS1 was partially removed from them using gene therapy and the only result was that the toxic dipeptide replicates were prevented from being formed. This is the first instance where the nuclear export of the RNAs that are pathologically repeated has been made clear in a neurologically degenerative disease and it is revealed for the first time that focusing on this method provides a reliable remedial approach of neuroprotection.

Surprisingly there are a number of other genes that cause diseases that are neurodegenerative such as Huntington’s disease, Myotonic Dystrophy, Fragile-X associated Tremor/Ataxia Syndrome and other disorders that have an effect on muscle dexterity. These include related recurring expansions like those found in the C9ORF72-MND gene.

So observing whether those expansions are transformed into proteins that are toxic and whether this can be avoided by deactivating a particular nuclear exporter also, this might give rise to a whole new avenue of possibilities for research in the field of neurodegenerative disorders treatment. An application with exclusive copyrights was filed for the use of SRSF1 adversary in the treatment of neurological disorders.
 
The Technology Explained
 
The approach of gene therapy used in the research utilised a virus that was engineered therapeutically, to get an RNA molecule inside the cell that would meddle with RNA for the manufacture of SFSR1. Interfering RNA thwarts the production of the targeted protein. Efficiently pulling down the quantity SFSR1 in the cell blocked the toxic C9ORF72 dipeptide repeat protein from being produced and salvaged the cell from neurodegeneration. Using viruses in the gene therapy is exceptionally successful as the virus remains inside the cell and incessantly creates the therapeutic interfering RNA for an extensive duration while the treatment of a genetic disease is going on.

At SITraN, Dr Hautbergue along with colleagues Prof MimounAzzouz and Prof Pamela Shaw are at present making efforts to collaborate with companies such as AveXis Inc. and Pfizer to further develop on a translational gene therapy program.