Understanding the causes and disease mechanisms underlying all forms of MND and finding the cellular pathways associated with motor neuron injury is a key goal of our laboratory research in order to find the relevant targets for therapeutic intervention. Therapies which are known to alter the effects of these dysregulated biochemical pathways can then be tested in our cellular and in vivo models.
Currently, we have the greatest understanding of disease mechanisms in the subtype of MND caused by a faulty SOD1 gene, but this accounts for only 20% of inherited forms of MND and approximately 2% of all MND cases as a whole. We have gained important insights into the cell specific toxicity produced by the mutant SOD1 protein. These include oxidative stress and increased cell death signalling, altered production of cytoskeletal components and axonal transport, and defects in energy production and metabolism within neurons.
More recently, we have gained a greater understanding of disease mechanisms in other inherited forms of MND such as those caused by changes in the C9ORF72, TDP43 and FUS genes which all show alterations in RNA processing and metabolism.
Major projects at SITraN are currently investigating several aspects of motor neuron injury including mitochondrial function, axonal transport, oxidative defence, glial dysfunction and RNA metabolism.
In order to evaluate new therapies and achieve a high probability of accurately predicting efficacy in human disease, we need model systems that mirror human disease as closely as possible. No existing laboratory model system perfectly replicates adult human motor neuron degeneration. At SITraN, we have specialist expertise in generating and optimising several cellular and in vivo model systems, recognising their particular strengths and limitations. Our aim is to perfect our model systems in order to evaluate potential therapies for the clinic in a timely way and create an optimal tool-kit of analysis systems for our pharmacological and gene therapy approaches.
Professor Mimoun Azzouz, previously Head of Neurobiology at Oxford Biomedica, is one of the leading experts in the UK in the use of gene therapy for neurodegenerative diseases. He leads an extensive programme at SITraN aiming to replace or silence faulty genes in forms of MND which are caused by a known gene mutation such as SOD1 and C9orf72.
Professor Azzouz has already proven and published the concept that switching off the expression of the mutant SOD1 gene that causes MND in mice extends survival by 80% and delays the onset of symptoms by over 100%. To silence the mutant SOD1 gene, the team uses inhibitory RNAs (RNAi) which are introduced into the cell using a virus-like carrier called adeno-associated virus (AAV9).
The SITraN team hopes to take the SOD1 gene therapy forward to clinical trials in the UK in the near future and develop similar approaches for other genetic variants of MND. Further promising new gene targets identified in our cellular models will be taken forward into in vivo studies in mice.
By the time motor symptoms occur, more than half of the motor neurons are already damaged beyond repair, and currently on average another year will be lost until a final diagnosis is made. Tools for pre-symptomatic diagnosis are therefore urgently required in order to detect the disease at a stage where neuroprotective agents would have the greatest chance of success.
Our biomarker discovery programme at SITraN investigates marker substances such as mediators or toxins released from the neighbouring glial cells that can be detected in the blood or cerebrospinal fluid of MND patients. We also use gene expression profiling to assess whether levels of certain RNAs and proteins can be used as early disease indicators and have identified some promising candidate microRNA biomarkers.
As part of our clinical biomarker research, Dr Tom Jenkins is currently assessing the potential value of measuring changes in muscle volume by whole-body magnetic resonance imaging (MRI) in diagnosing MND and monitoring clinical progression.
SITraN is part of the European SOPHIA project -
Sampling, biomarker OPtimizationand Harmonization in ALS -part of the EU Joint Programme (JPND) for Neurodegenerative Disease Research. JPND is the largest global research initiative aimed at tackling the challenge of neurodegenerative diseases. The aim of the SOPHIA project is to develop and standardise much -needed biomarkers of disease.
MND is currently unique in that it is one of the most actively sequenced human diseases with thousands of patient genomes being sequenced in the UK, EU and USA. Sequencing at the level of the genes or whole genomes is resulting in data that represent a whole new challenge and also a powerful new opportunity to understand the root causes of the disease. The challenge is that sequencing is not yet matched by the ability to act on the data it produces. Each genome can provide insight into the best potential for treatment for each patient but this can only occur if a reliable set of approaches is developed to interpret MND genomes.
Using a combination of computational biology, modelling and functional genomics, Professor Winston Hide has established a Centre for Genome Translation in Sheffield that provides prioritisation of key genes and pathways essential to the progression of the disease.
Working closely with genome sequencing consortia, the Harvard Stem Cell Institute and industry, the Centre translates genome information into systems that can be tested within the research groups at SITraN using model organisms and human induced pluripotent stem cells.
In turn, the Centre is able to evaluate the therapeutic potential of candidate repurposed drugs that can be rapidly tested in humans.
Interactive development of models from heterogenous high dimensional data. Working with data generators, data is captured from genome studies, basic research and clinical research.
It is integrated and analysed to result in models that are assessed for their predictive capacity through iterations of in silico and wet lab validation.