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Deimmunization for gene therapy: host matching of synthetic zinc finger constructs enables long-term mutant Huntingtin repression in mice

Overview of attention for article published in Molecular Neurodegeneration, January 2016
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About this Attention Score

  • In the top 5% of all research outputs scored by Altmetric
  • One of the highest-scoring outputs from this source (#2 of 585)
  • High Attention Score compared to outputs of the same age (98th percentile)
  • High Attention Score compared to outputs of the same age and source (83rd percentile)

Mentioned by

news
17 news outlets
blogs
4 blogs
twitter
20 tweeters
patent
1 patent
facebook
2 Facebook pages

Citations

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12 Dimensions

Readers on

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56 Mendeley
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Title
Deimmunization for gene therapy: host matching of synthetic zinc finger constructs enables long-term mutant Huntingtin repression in mice
Published in
Molecular Neurodegeneration, January 2016
DOI 10.1186/s13024-016-0128-x
Pubmed ID
Authors

Carmen Agustín-Pavón, Michal Mielcarek, Mireia Garriga-Canut, Mark Isalan, Agustín-Pavón, Carmen, Mielcarek, Michal, Garriga-Canut, Mireia, Isalan, Mark

Abstract

Synthetic zinc finger (ZF) proteins can be targeted to desired DNA sequences and are useful tools for gene therapy. We recently developed a ZF transcription repressor (ZF-KOX1) able to bind to expanded DNA CAG-repeats in the huntingtin (HTT) gene, which are found in Huntington's disease (HD). This ZF acutely repressed mutant HTT expression in a mouse model of HD and delayed neurological symptoms (clasping) for up to 3 weeks. In the present work, we sought to develop a long-term single-injection gene therapy approach in the brain. Since non-self proteins can elicit immune and inflammatory responses, we designed a host-matched analogue of ZF-KOX1 (called mZF-KRAB), to treat mice more safely in combination 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 whether HTT repression could be observed for up to 6 months after AAV injection in the brain. After rAAV vector delivery, we found that non-self proteins induce significant inflammatory responses in the brain, in agreement with previous studies. Specifically, microglial cells 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 host-matched mZF-KRAB did not provoke these effects. Nonetheless, we found that using a pCAG promoter (CMV early enhancer element and the chicken β-actin promoter) led to a strong reduction in ZF expression by 6 weeks after injection. We therefore tested a new non-viral promoter 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 bilateral intraventricular injection of 10(10) virions. Importantly, repressions of 48 % and 23 % were still detected after 12 and 24 weeks, respectively, indicating that longer term effects are possible. Host-adapted ZF-AAV constructs displayed a reduced toxicity and a non-viral pNSE promoter improved long-term ZF protein expression and target gene repression. The optimized constructs presented here have potential for treating HD.

Twitter Demographics

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Mendeley readers

The data shown below were compiled from readership statistics for 56 Mendeley readers of this research output. Click here to see the associated Mendeley record.

Geographical breakdown

Country Count As %
United Kingdom 1 2%
Finland 1 2%
Unknown 54 96%

Demographic breakdown

Readers by professional status Count As %
Student > Ph. D. Student 12 21%
Researcher 12 21%
Student > Bachelor 11 20%
Student > Master 10 18%
Student > Postgraduate 2 4%
Other 6 11%
Unknown 3 5%
Readers by discipline Count As %
Biochemistry, Genetics and Molecular Biology 17 30%
Agricultural and Biological Sciences 14 25%
Neuroscience 6 11%
Medicine and Dentistry 4 7%
Chemistry 3 5%
Other 6 11%
Unknown 6 11%

Attention Score in Context

This research output has an Altmetric Attention Score of 168. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 03 April 2019.
All research outputs
#88,446
of 14,015,228 outputs
Outputs from Molecular Neurodegeneration
#2
of 585 outputs
Outputs of similar age
#3,485
of 264,044 outputs
Outputs of similar age from Molecular Neurodegeneration
#1
of 6 outputs
Altmetric has tracked 14,015,228 research outputs across all sources so far. Compared to these this one has done particularly well and is in the 99th percentile: it's in the top 5% of all research outputs ever tracked by Altmetric.
So far Altmetric has tracked 585 research outputs from this source. They typically receive more attention than average, with a mean Attention Score of 8.6. This one has done particularly well, scoring higher than 99% of its peers.
Older research outputs will score higher simply because they've had more time to accumulate mentions. To account for age we can compare this Altmetric Attention Score to the 264,044 tracked outputs that were published within six weeks on either side of this one in any source. This one has done particularly well, scoring higher than 98% of its contemporaries.
We're also able to compare this research output to 6 others from the same source and published within six weeks on either side of this one. This one has scored higher than all of them