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Zinc Finger based gene therapy in Huntington’s disease


About This PhD Project

Project Description

We are looking for a candidate to take up a BBSRC-funded DTP PhD Studentship in "Zinc Finger based gene therapy in Huntington’s disease". The project will be co-supervised by Prof. Mark Isalan (http://www.imperial.ac.uk/people/m.isalan) and Prof. Stephen Brickley (http://www.imperial.ac.uk/people/s.brickley) and will train the PhD student in working at the interface between neuroscience and synthetic biology, with a strong exposure to molecular biology methods, gene therapy and mouse imaging approaches. Moreover, we will be using gene delivery approach including vectorology. The student is expected to start in October 2019.

Project details

Huntington's disease (HD) is an inherited neurodegenerative disorder, caused by a CAG repeat expansion in the HTT gene, leading to toxic gene products. The disease has a high prevalence for an inherited disorder, affecting approximately 700,000 people worldwide (one in 10,000). Suffering is high for both patients and carers, with death generally occurring within 10 - 20 years of diagnosis. In this study, we will repress the leading therapeutic target in HD (mutant HTT) using cutting-edge imaging to observe the consequences in the CNS. We will use a synthetic designed zinc finger (ZF) against mutant HTT to attack HD pathology at its source (1,2). We will use our established AAV2- and AAV9-based delivery system, while exploring new delivery strategies (Isalan). The efficacy will be measured by biochemical (metabolomic, transcriptomic) and phenotypic effects, especially ex vivo 2 photon whole-brain imaging in mice (3,4) (Brickley). Overall, we aim to develop a practical therapeutic strategy that is based on gene therapy, which will lead to clinical applications in HD, as well as providing detailed imaging data on HD development.

How to apply

Please email Mark Isalan and Stephen Brickley (; ) and include in your application:

• A cover letter

• Your CV

• Your transcript

• Three references sent directly from the referees

References

1. Agustín-Pavón C, Mielcarek M, Garriga-Canut M & Isalan M. Deimmunization for gene therapy: host matching of synthetic zinc finger constructs enables long-term mutant Huntingtin repression in mice. Molecular Neurodegeneration 11(1):64 (2016).
2. Garriga-Canut, M., et al. & Isalan M. Synthetic zinc finger repressors reduce mutant Huntingtin expression in the brain of R6/2 mice. Proc Natl Acad Sci USA 109 (45):E3136-E3145 doi:10.1073/pnas.1206506109 (2012).
3. Song JH, Lucaci D, Calangiu I, Brown MTC, Park JS, Kim J, Brickley SG, Chadderton P (2018) Combining mGRASP and Optogenetics Enables High-Resolution Functional Mapping of Descending Cortical Projections. Cell Reports 24(4):1071-1080 24.
4. Houston CM, Diamanti E, Diamantaki M, Kutsarova E, Cook A, Sultan F, Brickley SG (2017) Exploring the significance of morphological diversity for cerebellar granule cell excitability. Scientific Reports 7, 46147

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