Identification of therapeutic targets in C9orf72-linked FTD and MND

Motor Neuron Disease (MND) is a devastating and incurable adult-onset motor disorder. It affects the neurons controlling muscle movement, thus causing muscle weakness and degeneration, leading to paralysis and death by respiratory failure. The most common genetic cause of MND is a mutation in the gene C9orf72.

Interestingly, mutations in this gene are also the most frequent cause of frontotemporal dementia (FTD), which, in turns, affects neurons involved in higher functions, such as language and behaviour.

Although the two pathologies share the same genetic cause, they trigger two different diseases that in some patients progress from one to the other. The factors involved in the development of one or the other disorder are still unknown and this is a significant challenge for the identification of therapeutic targets. In addition, in vitro and in vivo models used in the laboratory to study disease mechanisms and identify therapeutic targets rely on the expression of the mutant gene C9orf72, which is common to both disorders.

The challenge is, therefore, to understand more in depth the underlying pathological consequences of the mutation in the cells affected by the disease, both neurons and surrounding non-neuronal cells and then model them accordingly. This may then provide the opportunity to identifying key points of intervention to alter these ongoing disease mechanisms and design therapeutics for specific patient benefit.

Gaining this human biological insight and constructing models to test the biological hypotheses is a key challenge for companies such as Cerevance in their identification of new targets for the design of truly novel therapeutics for neurodegenerative disease.

To solve this challenge, Dr Ferraiuolo's team at the Sheffield Institute for Translational Neuroscience (SITraN) and Cerevance have come together to share complementary expertise and technologies. Dr Ferraiuolo has developed an in vitro model that recapitulates important and distinct aspects of the two neurodegenerative diseases and, therefore, it is likely to be a suitable model for target validation and drug discovery.

Cerevance has optimised cutting-edge NETSseq (Nuclear Enriched Transcript Sort sequencing) technology to unravel disease mechanisms and developed novel drug development strategies. The consortium between Dr Ferraiuolo at SITraN and Cerevance aims to

1. Perform deep transcriptomic on cortical and spinal tissue of glia and neurons from C9orf72 MND & FTD patients and controls to identify the presence of different physiological and pathological pathways occurring in the areas that are affected or spared in the 2 diseases.

2. Perform deep transcriptomic on in vitro induced astrocytes and cortical and motor neurons from C9orf72 MND & FTD patients and controls to assess the presence of the pathways identified in post-mortem tissues

3. Apply bioinformatic analysis of said datasets showing impact of disease on individual cell types and network function / dysfunction

4. Validate potential therapeutic targets by suppressing or overexpressing specific molecules in the human derived cellular systems 5. Test drugs for potential therapeutic targets.

To accomplish these aims, Dr Myszczynska, who has recently completed her PhD training and is currently a post-doctoral researcher in Dr Ferraiuolo's team, will spend 2-years at Cerevance. Dr Myszczynska will receive world-class training in novel approaches for drug development and NETSseq, a cutting edge technique for deep transcriptomics of complex tissues.

In turn, she will support Cerevance with her expertise acquired in over 6-years at SITraN in the field of MND and FTD, in vitro disease modelling using patient-derived cells and bioinformatics. In conclusion the knowledge exchange between Cerevance and SITraN through the secondment of Dr Myszczynska, will not only answer important biological questions, but will also bridge knowledge gaps in the academic and industrial sectors.