DiMeN Doctoral Training Partnership: Novel therapeutic strategies for motor neurone disease and fro

3 days left

Location
United Kingdom
Posted
Dec 12, 2017
Closes
Jan 22, 2018
Organization Type
University and College
Hours
Full Time
Details

Hexanucleotide repeat expansions in the C9ORF72 gene are the most common known cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), a spectrum of fatal adult brain diseases characterised by the progressive death of neurons which respectively lead to paralysis and altered cognitive functions/ personality features.

Abnormal C9ORF72 repeat transcripts are substrates of repeat-associated non-AUG (RAN) translation, an unconventional form of translation producing dipeptide repeat proteins (DPRs) with aggregating properties in all frames and in the absence of canonical start codons. A growing body of evidence pinpoints accumulation of DPRs as one of the primary driver of pathogenesis in cellular and animal models of C9ORF72-ALS/FTD. Accordingly, we recently showed that reducing the expression levels of DPRs confers neuroprotection in patient-derived motor neurons and suppresses neurodegeneration-associated motor deficits in Drosophila (Hautbergue et al. Nature Communications 2017;8:16063). Significantly, these findings showed that altering the RAN translation of DPRs provides a valid therapeutic strategy for neuroprotection in vitro and in vivo. Supporting this, the investigators have filed a patent application for the use of DPRs antagonists in the treatment of C9ORF72-ALS/FTD by gene therapy approaches (PCT/GB2017/051539).

The mechanisms involved in the RAN translation of C9ORF72 repeat transcripts remain completely unknown. Therapeutically manipulating RAN translation has therefore not been possible in the absence of target(s). We recently uncovered two of the RAN-translation associated factors that are named RTA1 and RTA2 in this proposal. Moreover, partial depletion of either of these factors rescues DPR-mediated neurotoxicity in neuronal cell models and neurodegeneration-associated locomotor deficits in adult Drosophila (unpublished data).

In this PhD program, we propose to evaluate the therapeutic efficiency of our novel neuroprotective strategies using a gene therapy approach based on Adeno-associated virus in a pre-clinical mouse model of C9ORF72-ALS/FTD. The potential neuroprotective effects conferred by the partial depletion of the newly uncovered RAN-translation associated factors RTA1 and RTA2 will be assessed at the molecular, neuronal and motor function levels. The research project is based on diverse and cutting edge techniques including molecular and cellular biology, RNA-interference, transcriptomics, engineering of gene therapy vectors and animal research that will build a very strong curriculum for the student. Adeno-associated virus 9 (AAV9) will be generated to allow expression of control, RTA1 and RTA2 -RNAi cassettes that will lead to inhibition of the RAN translation of DPRs. The functionality of produced AAV9 virus will be validated in C9ORF72-ALS/FTD neuronal cell models and the specificity of depletion will be investigated at genome-wide level using micro-arrays. The gene therapy programme will involve a single-dose injection of virus in the brain of a preclinical mouse model of C9ORF72-ALS/FTD which exhibits neurodegeneration and motor and cognitive deficits. The efficacy of the gene therapy approaches and their effects on neuron counts will be evaluated using histology techniques in the brain and spinal cords of mice. The motor function will be evaluated in parallel over time using rotarod and catwalk analysis.

The research is based in the recently created RNA biology and Gene Therapy labs in the Sheffield Institute for Translational Neuroscience (SITraN). SITraN brings together under one roof, state-of-the-art laboratories and equipment with a multi-disciplinary team of scientists and clinical academics in a collaborative environment that hosts expertise in neuroscience, clinical neurology, neuropathology, viral vector technology, pharmacology, biochemistry, cellular, molecular and computational biology. Such a vibrant scientific community is very well suited for a motivated and passionate student who aspires to learn numerous aspects of research both experimentally and intellectually while making a significant contribution to the international research devoted to the understanding and treatment of neurodegenerative diseases.

Please, contact Dr Guillaume Hautbergue (g.hautbergue@sheffield.ac.uk) about the position and consult the Web page (http://www.sheffield.ac.uk/neuroscience/staff) for further information on the research undertaken in his research group and SITraN.

 

Funding Notes

  • This studentship is part of the MRC Discovery Medicine North (DiMeN) partnership and is funded for 3.5 years. Including the following financial support:
  • Tax-free maintenance grant at the national UK Research Council rate
  • Full payment of tuition fees at the standard UK/EU rate
  • Research training support grant (RTSG)
  • Travel allowance for attendance at UK and international meetings
  • Opportunity to apply for Flexible Funds for further training and development
  • Please carefully read eligibility requirements on our website