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Synthetic Biology underpins advances in the bioeconomy

Biological systems - including the simplest cells - exhibit a broad range of functions to thrive in their environment. Research in the Imperial College Centre for Synthetic Biology is focused on the possibility of engineering the underlying biochemical processes to solve many of the challenges facing society, from healthcare to sustainable energy. In particular, we model, analyse, design and build biological and biochemical systems in living cells and/or in cell extracts, both exploring and enhancing the engineering potential of biology. 

As part of our research we develop novel methods to accelerate the celebrated Design-Build-Test-Learn synthetic biology cycle. As such research in the Centre for Synthetic Biology highly multi- and interdisciplinary covering computational modelling and machine learning approaches; automated platform development and genetic circuit engineering ; multi-cellular and multi-organismal interactions, including gene drive and genome engineering; metabolic engineering; in vitro/cell-free synthetic biology; engineered phages and directed evolution; and biomimetics, biomaterials and biological engineering.

Publications

Citation

BibTex format

@article{Agustín-Pavón:2016:10.1186/s13024-016-0128-x,
author = {Agustín-Pavón, C and Mielcarek, M and Garriga-Canut, M and Isalan, M},
doi = {10.1186/s13024-016-0128-x},
journal = {Molecular Neurodegeneration},
title = {Deimmunization for gene therapy: host matching of synthetic zinc finger constructs enables long-term mutant Huntingtin repression in mice},
url = {http://dx.doi.org/10.1186/s13024-016-0128-x},
volume = {11},
year = {2016}
}

RIS format (EndNote, RefMan)

TY  - JOUR
AB - Background: Synthetic zinc finger (ZF) proteins can be targeted to desired DNA sequencesand are useful tools for gene therapy. We recently developed a ZF transcription repressor (ZFKOX1)able to bind to expanded DNA CAG-repeats in the huntingtin (HTT) gene, which arefound in Huntington’s disease (HD). This ZF acutely repressed mutant HTT expression in amouse model of HD and delayed neurological symptoms (clasping) for up to 3 weeks. In thepresent work, we sought to develop a long-term single-injection gene therapy approach in thebrain.Method: Since non-self proteins can elicit immune and inflammatory responses, we designed ahost-matched analogue of ZF-KOX1 (called mZF-KRAB), to treat mice more safely incombination with rAAV vector delivery. We also tested a neuron-specific enolase promoter(pNSE), which has been reported as enabling long-term transgene expression, to see whetherHTT repression could be observed for up to 6 months after AAV injection in the brain.Results: After rAAV vector delivery, we found that non-self proteins induce significantinflammatory responses in the brain, in agreement with previous studies. Specifically, microglialcells were activated at 4 and 6 weeks after treatment with non-host-matched ZF-KOX1 or GFP,respectively, and this was accompanied by a moderate neuronal loss. In contrast, the hostmatchedmZF-KRAB did not provoke these effects. Nonetheless, we found that using a pCAGpromoter (CMV early enhancer element and the chicken β-actin promoter) led to a strongreduction in ZF expression by 6 weeks after injection. We therefore tested a new non-viralpromoter to see whether the host-adapted ZF expression could be sustained for a longer time.Vectorising mZF-KRAB with a promoter-enhancer from neuron-specific enolase (Eno2, rat)resulted in up to 77% repression of mutant HTT in whole brain, 3 weeks after bilateralintraventricular injection of 1010 virions. Importantly, repressions of 48% and 23% were stilldetected after 12 and 24 weeks
AU - Agustín-Pavón,C
AU - Mielcarek,M
AU - Garriga-Canut,M
AU - Isalan,M
DO - 10.1186/s13024-016-0128-x
PY - 2016///
SN - 1750-1326
TI - Deimmunization for gene therapy: host matching of synthetic zinc finger constructs enables long-term mutant Huntingtin repression in mice
T2 - Molecular Neurodegeneration
UR - http://dx.doi.org/10.1186/s13024-016-0128-x
UR - http://hdl.handle.net/10044/1/39532
VL - 11
ER -