The preclinical development of nefiracetam as a novel myelin repair drug

Multiple Sclerosis (MS) is a progressive autoimmune neurological condition resulting from T lymphocytes invasion into the CNS and subsequent damage to the oligodendrocytes responsible for the maintenance of axonal myelin sheaths, resulting in impaired neuronal activity and direct axonal damage. Current treatments are dominated by immune-suppressants and immune-modulators. There is a considerable clinical need and focus on developing neuroprotective and myelin repair therapies to considerably improve MS treatment.

Our previous work investigated the possibility that nefiracetam, a known cognition enhancer, might be an effective agent in the treatment of the cognitive dysfunction seen in MS. We developed an in vitro model of hippocampal demyelination using exposure of organotypic slice cultures to lysophosphatidylcholine (LPC) to cause demyelination which recovered slowly over a period of days upon removal of the LPC. We found that treatment with nefiracetam led to a complete recovery of myelin basic protein expression within 24 hours.

The cuprizone toxin model of demyelination in the mouse reveals powerful myelin repair abilities with nefiracetam treatment in vivo. In order to identify the molecular mechanism of action of the myelin repair effect of nefiracetam we have carried out transcriptomics and proteomics studies on the corpus callosum and cortex of animals subjected to the cuprizone toxin to drive demyelination. We identified 246 genes and 196 proteins that are regulating during the early phase of nefiracetam-mediated acceleration of myelin repair in vivo.

This PhD project focuses on definitively identifying the mechanism of action, providing evidence of relevance to the human disease and identifying peripheral biomarkers that could be used as surrogate and early readouts of a successful myelin repair effect in clinical trials and beyond into clinical use.

The work will be structured in three work packages.
Workpackage 1: Establishing nefiracetam’s mechanism of action in vitro
Workpackage 2: Establishing nefiracetam’s mechanism of action in vivo.
Workpackage 3: Build the knowledge base to provide reassurance with respect to relevance of nefiracetam-mediated myelin repair to human disease.

Eligibility
Applications are invited from appropriately qualified EU students. Applicants must have a minimum of a 2.1 Honours degree in a relevant biological or biomedical subject area e.g. biochemistry, genetics, pharmacology, microbiology, neuroscience etc.

Funding
The scholarship cover tuition fees at the EU rate (€6810 per annum) and a stipend of €16,000 per annum for four years. Successful candidates will be required to demonstrate in laboratory practical classes on an ongoing basis as part of their funded scholarship

How to apply
Full details of the project and how to apply, can be found at http://www.ucd.ie/sbbs/research/researchvacancies/.

Closing date 17th July, 2017

School of Biomolecular and Biomedical Science, University College Dublin
The School of Biomolecular and Biomedical Science http://www.ucd.ie/sbbs/ has a strong reputation for research and innovation. Special emphasis is placed on translating fundamental discoveries to a greater understanding of health and disease, with the ultimate aim of developing novel diagnostic and therapeutic solutions. The School has a large cohort of graduate students enrolled in high quality structured Ph.D. programmes that provide training in specific, state-of-the-art and generic research skills.