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Analysis of institutional authors

Isalan, MarkCorresponding AuthorHerrmann, FrankAuthorGarriga-Canut M.AuthorDierssen M.Author

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Article

Synthetic zinc finger repressors reduce mutant huntingtin expression in the brain of R6/2 mice

Publicated to:Proceedings Of The National Academy Of Sciences Of The United States Of America. 109 (45): E3136-E3145 - 2012-11-06 109(45), DOI: 10.1073/pnas.1206506109

Authors: Garriga-Canut, M; Agustín-Pavón, C; Herrmann, F; Sánchez, A; Dierssen, M; Fillat, C; Isalan, M

Affiliations

Ctr Genom Regulat CRG, EMBL CRG Syst Biol Res Unit, Barcelona 08003, Spain - Author
Ctr Genom Regulat CRG, Genes & Dis Programme, Barcelona 08003, Spain - Author
Ctr Invest Biomed Red Enfermedades Raras, Barcelona 08036, Spain - Author
EMBL/CRG Systems Biology Research Unit, Centre for Genomic Regulation (CRG), Dr. Aiguader 88, 08003 Barcelona, Spain. - Author
Hosp Clin Barcelona, Serv Bioqim & Genet Mol, E-08036 Barcelona, Spain - Author
Inst Invest Biomed August Pi & Sunyer IDIBAPS, Barcelona 08036, Spain - Author
Univ Pompeu Fabra UPF, Barcelona 08003, Spain - Author
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Abstract

Huntington's disease (HD) is a dominantly inherited neurodegenerative disorder caused by expanded CAG repeats in the huntingtin (HTT) gene. Although several palliative treatments are available, there is currently no cure and patients generally die 10-15 y after diagnosis. Several promising approaches for HD therapy are currently in development, including RNAi and antisense analogs. We developed a complementary strategy to test repression of mutant HTT with zinc finger proteins (ZFPs) in an HD model. We tested a "molecular tape measure" approach, using long artificial ZFP chains, designed to bind longer CAG repeats more strongly than shorter repeats. After optimization, stable ZFP expression in a model HD cell line reduced chromosomal expression of the mutant gene at both the protein and mRNA levels (95% and 78% reduction, respectively). This was achieved chromosomally in the context of endogenous mouse HTT genes, with variable CAG-repeat lengths. Shorter wild-type alleles, other genomic CAG-repeat genes, and neighboring genes were unaffected. In vivo, striatal adeno-associated virus viral delivery in R6/2 mice was efficient and revealed dose-dependent repression of mutant HTT in the brain (up to 60%). Furthermore, zinc finger repression was tested at several levels, resulting in protein aggregate reduction, reduced decline in rotarod performance, and alleviation of clasping in R6/2 mice, establishing a proof-of-principle for synthetic transcription factor repressors in the brain.

Keywords

AnimalsAntimicrobial peptideBase sequenceBrainCentral-nervous-systemDnaDrosophila-melanogasterGene expression regulationGene therapyGenes, reporterHumansInnate immunityMass-spectrometryMetabolismMiceMolecular sequence dataMouse modelPeptidesPhenotypeProteinProtein designProtein engineeringSynthetic biologyTherapyTranscription repressionTransgenic miceYoung adult

Quality index

Bibliometric impact. Analysis of the contribution and dissemination channel

The work has been published in the journal Proceedings Of The National Academy Of Sciences Of The United States Of America due to its progression and the good impact it has achieved in recent years, according to the agency WoS (JCR), it has become a reference in its field. In the year of publication of the work, 2012, it was in position 4/56, thus managing to position itself as a Q1 (Primer Cuartil), in the category Multidisciplinary Sciences.

From a relative perspective, and based on the normalized impact indicator calculated from World Citations provided by WoS (ESI, Clarivate), it yields a value for the citation normalization relative to the expected citation rate of: 2.83. This indicates that, compared to works in the same discipline and in the same year of publication, it ranks as a work cited above average. (source consulted: ESI Nov 14, 2024)

This information is reinforced by other indicators of the same type, which, although dynamic over time and dependent on the set of average global citations at the time of their calculation, consistently position the work at some point among the top 50% most cited in its field:

  • Weighted Average of Normalized Impact by the Scopus agency: 2.55 (source consulted: FECYT Feb 2024)
  • Field Citation Ratio (FCR) from Dimensions: 13.9 (source consulted: Dimensions Jun 2025)

Specifically, and according to different indexing agencies, this work has accumulated citations as of 2025-06-15, the following number of citations:

  • WoS: 134
  • Scopus: 165
  • Europe PMC: 92
  • OpenCitations: 160

Impact and social visibility

From the perspective of influence or social adoption, and based on metrics associated with mentions and interactions provided by agencies specializing in calculating the so-called "Alternative or Social Metrics," we can highlight as of 2025-06-15:

  • The use, from an academic perspective evidenced by the Altmetric agency indicator referring to aggregations made by the personal bibliographic manager Mendeley, gives us a total of: 293.
  • The use of this contribution in bookmarks, code forks, additions to favorite lists for recurrent reading, as well as general views, indicates that someone is using the publication as a basis for their current work. This may be a notable indicator of future more formal and academic citations. This claim is supported by the result of the "Capture" indicator, which yields a total of: 293 (PlumX).

With a more dissemination-oriented intent and targeting more general audiences, we can observe other more global scores such as:

  • The Total Score from Altmetric: 24.85.
  • The number of mentions on the social network Facebook: 1 (Altmetric).
  • The number of mentions on the social network X (formerly Twitter): 10 (Altmetric).
  • The number of mentions in news outlets: 1 (Altmetric).

It is essential to present evidence supporting full alignment with institutional principles and guidelines on Open Science and the Conservation and Dissemination of Intellectual Heritage. A clear example of this is:

  • The work has been submitted to a journal whose editorial policy allows open Open Access publication.

Leadership analysis of institutional authors

This work has been carried out with international collaboration, specifically with researchers from: United States.

There is a significant leadership presence as some of the institution’s authors appear as the first or last signer, detailed as follows: First Author (GARRIGA CANUT, MIREIA) and Last Author (Isalan M.).

the authors responsible for correspondence tasks have been ISALAN, MARK and Isalan M..