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Applications for the MRC DTP iCASE studentships September 2019 are now closed.

Projects for September 2019 Entry

Supervisor Details:

Co-supervisor 1A: Professor Michael Malim

Email: michael.malim@kcl.ac.uk

Co-supervisor 1B: Dr Davide Danovi

Email: davide.danovi@kcl.ac.uk

Partner Details: Orchard Therapeutics Limited

Project Description:

Developments from academic and biotech sectors have driven gene and stem cell therapy to the clinical setting, with data demonstrating an encouraging long term safety profile and durable correction of several inherited genetic blood disorders such  as  ADA-SCID  (Strimvelis)  and  X-CGD  (OTL-102).   Despite  this  progress,  there  is  an  urgent  need  to  improve  manufacturing processes for therapeutic gene modified cells in order to reduce the associated production costs, as this presents  a  major  barrier  to  sustainability  of  access to  patients.  As production  of  sufficient  quantities  of  viral  vectors required to genetically modify a patients’ stem cells incurs the most significant costs, this studentship project will focus on approaches to reduce vector use, with an emphasis on identifying optimal therapeutic stem cells, and increasing their susceptibility to lentiviral transduction.

Specific aims are:

i) To identify a refined population of true long-term repopulating haematopoietic stem cells from within peripheral blood stem cells,  which  are  capable  of  delivering  a therapeutic  effect,  and  evaluate  clinically  applicable methods  for  their  isolation (Years 1 & 2, industry placement).

ii) To examine the efficiency of gene transfer to stem cell subsets using lentiviral vectors and apply targeted approaches to improve cell transduction (Years 2 & 3).

iii) To demonstrate the  function  and  therapeutic potential of optimally  transduced  and selected  stem  cell  subsets in  a  preclinical model of stem cell transplantation (Years 3 & 4).

Candidates will develop core  laboratory  skills in immunological,  vector,  gene  transfer  and  cell  biology  techniques,  in  addition to working with directly translational research methods, using preclinical models and clinical grade platforms.

Supervisor Details:

Co-supervisor 1A: Professor Christopher Shaw

Email: chris.shaw@kcl.ac.uk

Website: https://www.kcl.ac.uk/ioppn/depts/bcn/DRI/Lab-Groups/Chris-Shaw-Group/Chris-Shaw-Group.aspx

Co-supervisor 1B: Professor Mark Richardson

Email: mark.richardson@kcl.ac.uk

Website: https://kclpure.kcl.ac.uk/portal/mark.richardson.html

Partner Details: Autifony Therapeutics

Project Description:

We have been engaged in developing reliable neurophysiological biomarkers that can track disease progression and monitor the effects of new therapeutics in clinical trials. Specific potassium channels might be implicated in neuronal degeneration in amyotrophic lateral sclerosis (ALS) and they represent a target for new drug development by Autifony Therapeutics.

Non-invasive brain stimulation methods, such as transcranial magnetic stimulation (TMS), can provide a window into these observations. High-density surface muscle recordings provide a more enriched dataset than conventional techniques. By combining this with TMS and brain recordings, we hope to develop more sensitive markers of neuronal degeneration in ALS. We hypothesise that progressive changes in motor function will be detected by TMS measures, allowing correlation with measures of neurological decline and therapeutic effect. Importantly, if earlier cortical abnormalities could be reliably identified, institution of neuroprotective agents at that stage may result in a slower disease progression and prolonged survival.

In a longitudinal study, we will explore TMS output measures to identify early deficits in ALS patients.

YR1: Training in methodology and analysis; ethical applications; attachment at Autifony laboratory

YR2/3: Data collection and analysis, including a pilot study to assess the short-term effects of a potential novel therapy

YR4: Write up scientific papers and thesis.

This project will give a strong training in brain stimulation technique, analysis methodology and its application to ALS clinical population. There will be opportunity to present the results at international ALS conferences. Thanks to the industrial collaboration it also will provide an introduction to preclinical work related to drug development.

Supervisor Details:

Co-supervisor 1A: Dr Jude Oben

Email: jude.1.oben@kcl.ac.uk

Website: www.kcl.ac.uk/wh

Co-supervisor 1B: Dr Paul D Taylor

Email: paul.taylor@kcl.ac.uk

Website: https://kclpure.kcl.ac.uk/portal/paul.taylor.html

Partner Details: Yaqrit Ltd

Project Description:

The United Kingdom adult population prevalence of obesity is 30% and with 30% of children – overweight or obese. Additionally, 26% of women of reproductive age are obese and one in five pregnant women is obese. We have recently shown, that the offspring of obese mothers have increased appetite, body weights, fat mass and markers of obesity-induced liver disease (non-alcoholic fatty liver disease, NAFLD) compared with offspring of lean mothers. Our results have been confirmed in humans such that the children of obese mothers show increased obesity and NAFLD. NAFLD is predicted to become the commonest cause of liver cirrhosis/failure and transplantation within the next decade or less. The precise mechanism by which this trans-generational transmission of obesity and NAFLD occur remains unclear.

Obesity and NAFLD are known to develop at least partially in response to gut bacteria. Commensal bacteria are transferred between co-housed animals and can cause the transmission of both obesity and NAFLD traits. Therefore, it is likely that the transmission of obesity from mother to offspring during the peri-natal and post-natal periods is at least partially via the transmission of maternal commensal micro-organisms to the new born. This has recently been strongly supported through the use of germ-free mice and their colonisation with stools from the offspring of obese human subjects. We now seek to study this further using agents that target the pathways through which the gut microbiota act.

All iCASE projects are available as a straight 4 year PhD. Applicants may apply for one project only. You may contact project supervisors for further information about project opportunities. This does not commit a candidate to these laboratories. iCASE Projects available will be published on Monday 4th March, 2019.

When choosing an iCASE project from those available for September 2019 Entry, in the funding section of the online application from please enter the funding code ‘MRCDTP2019_’ followed by the project number that corresponds to your chosen project e.g:

MRCDTP2019_3.5

Deadline for applications: Friday 5th April, 23:59

Interviews: Thursday 2nd May –  iCASE studentships will commence in September 2019. For further information please visit our application support page or contact mrc-dtp@kcl.ac.uk.

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