A number of articles were published in various news sources on 11 July 2014, highlighting how scientists in Sheffield are working towards testing a promising treatment for a rare inherited form of MND caused by the SOD1 gene. Here we write about the research and what it means for people living with MND.
The Sheffield Institute for Translational Neuroscience (SITraN) specialises in research into MND and other neurodegenerative diseases. Recently the institute received an anonymous donation of £2.2 million to help translate their research from the lab to the clinic. This is a huge amount of money into MND research and this donation will enable the researchers to further our understanding of the disease.
We know that approximately 10% of cases of MND are inherited. This means that they are characterised by a strong family history and the disease is caused directly by a mistake in a specific gene. Of these 10% of cases, 2% are caused by the SOD1 gene (meaning that for every 100 cases of MND, 10 cases are inherited and of these, only 2 are directly caused by the faulty SOD1 gene).
Prof Mimoun Azzouz’s research at SITraN was reported in a number of news outlets, highlighting how his research is paving the way to a treatment for a rare form of MND. His research is at a relatively early stage, where he has only just begun investigating the use of a technique known as ‘gene therapy’ in mice affected by the SOD1 inherited form of MND. If the research goes to plan, he will be able to submit a proposal for regulatory approval by August 2015.
Regulatory approval is the process where a researcher submits an application for a clinical trial to the Medicines and Healthcare products Regulatory Agency (MHRA), who then review the application. It is only after approval has been granted, clinical trials will then start.
What is gene therapy?
Gene therapy is a technique where researchers treat a disease by preventing, and blocking, the faulty gene. In this case, Prof Azzouz is aiming to block the SOD1 gene.
The SOD1 gene corresponds to the SOD1 protein (see baking with genes and proteins as to how this occurs). When this gene is faulty in some inherited forms of MND, this means the resulting protein is not formed correctly and unable to do its job. The idea behind Prof Azzouz’s gene therapy research is to inhibit this gene, and stop production of the resulting protein, reducing the amount of SOD1 within the motor neurones.
The way in which gene therapy works, is a bit like a car company that produces a number of different cars. If the car company identifies that one of the car models is faulty (eg a white Ford Fiesta), then someone would go into the factory and stop that specific technician making that specific car. This would mean there would be less faulty white Ford Fiestas on the road, resulting in fewer accidents.
In this analogy, the person stopping the technician in the factory from making the white faulty cars is the gene therapy treatment, with the faulty SOD1 protein being the faulty white Ford Fiesta. As we inherit two copies of each gene, the healthy SOD1 (eg a blue Ford Fiesta) is still produced by another technician but the faulty SOD1 is not.
Therefore, the aim of the gene therapy treatment would be to stop the faulty SOD1 gene from making the SOD1 protein (the white Ford Fiesta), without affecting the healthy SOD1 (the blue Ford fiesta). This would result in less faulty SOD1 protein within the motor neurones, ultimately delaying the progression of MND.
Treatments for SOD1-MND
SOD1 was the first MND-causing gene to be discovered back in 1993, and as such we are beginning to see research into SOD1-specific therapies. Prof Azzouz’s research complements other SOD1-specific therapies, such as the ‘antisense therapy’ ISIS 333611.
In April 2013 we announced the results from the phase I clinical trial of ISIS 333611. Working in a similar way to Prof Azzouz’s research, this therapy interferes with the SOD1 genetic material by ‘hiding’ part of the gene, meaning that they are silenced when the final protein is made.
SOD1-targeted therapy is becoming a ‘hot topic’ in the MND research field and as a result research into this area will be discussed in a dedicated session at the forthcoming 25th International Symposium on ALS/MND in December 2015.
The announcement of Prof Azzouz’s research highlights a huge investment of £2.2million into MND research at SITraN.
Director of Research Development, Dr Brian Dickie, said: ““SOD1-specific therapies are leading the way in approaches to develop more personalised treatments for specific subtypes of MND. Inherited MND caused by the faulty SOD1 gene accounts for a small proportion of MND cases, however gene-therapy approaches may open up ways of treating other forms of inherited MND in the future.
Although Prof Azzouz’s research is encouraging, it must be stressed that this research is still in its infancy, with the results in mice still to be analysed. However, if results are positive (as they have been in previous mouse studies where the SOD1 gene has been inactivated) then SITraN is perfectly placed to transfer this knowledge from the lab to the clinic.”
It is also important to note that if a clinical trial of this treatment is approved, it would only be a safety trial at first (known as a phase I clinical trial), as this treatment has never been tested in humans before.”