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.
We use robust cell models of MND based on a mouse motor neuron/neuroblastoma cell line (NSC34). Dr Adrian Higginbottom is advancing and refining our cell culture models and is currently developing inducible cell models which will allow us to investigate early changes that cause motor neuron injury in the presence of a disease-causing mutation.
Mutations in several genes (TDP43, FUS, C9ORF72) have been associated with widespread changes in RNA metabolism and this strategy will allow us to identify which of these changes are most relevant to the disease process.
Motor Neurons cultured in the lab
Zebrafish are not only ideally suited to investigate early neuronal development in MND and other neurodegenerative diseases, but they are also ideal to screen and evaluate drugs, before advancing to studies in rodent models. Dr Tennore Ramesh and his team have developed a SOD1 MND zebrafish model which shows the hallmarks of human MND.
In a project funded by the Broad Appeal and the MND Association, Dr Ramesh is currently using the new zebrafish model to screen over 2,000 potential new drugs for their effectiveness in MND. He is also generating zebrafish models of other types of MND.
Zebra fish motor neurons are highlighted with green fluorescent protein
Colonies of mouse models overexpressing the SOD1 G93A mutant human SOD1 or normal human SOD1 as control have been established and refined in Sheffield by Dr Richard Mead. These mice develop a disease which closely mimics human MND clinically and pathologically and represent the best currently available animal model of MND.
Interestingly, defects in the neuronal transport system as well as the energy generators (mitochondria) can be observed in the mouse motor neurons before the onset of symptoms. Mouse models of other genetic subtypes of MND have also recently been established. The mouse studies represent an important and necessary step towards translation into human treatment.
Computerised gait analysis
We have advanced our expertise in stem cell technology growing motor neurons and their supporting cells from patients’ reprogrammed skin cells, so-called induced pluripotent stem cells (iPSC). Dr Ke Ning, Senior Lecturer at SITraN, was awarded funding by the MRC China Initiative to develop this technology in collaboration with experts from the Stem Cell Research Centre at Tongji University in Shanghai. In order to build on this exciting new technology, we are planning to appoint a Chair in Stem Cell Neurobiology in the near future.