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@ARTICLE{Miller:120651,
      author       = {J. R. C. Miller and E. L. Pfister and W. Liu and R. Andre
                      and U. Träger$^*$ and L. A. Kennington and K. Lo and S.
                      Dijkstra and D. Macdonald and G. Ostroff and N. Aronin and
                      S. J. Tabrizi},
      title        = {{A}llele-{S}elective {S}uppression of {M}utant {H}untingtin
                      in {P}rimary {H}uman {B}lood {C}ells.},
      journal      = {Scientific reports},
      volume       = {7},
      issn         = {2045-2322},
      address      = {London},
      publisher    = {Nature Publishing Group},
      reportid     = {DKFZ-2017-01078},
      pages        = {46740 -},
      year         = {2017},
      abstract     = {Post-transcriptional gene silencing is a promising therapy
                      for the monogenic, autosomal dominant, Huntington's disease
                      (HD). However, wild-type huntingtin (HTT) has important
                      cellular functions, so the ideal strategy would selectively
                      lower mutant HTT while sparing wild-type. HD patients were
                      genotyped for heterozygosity at three SNP sites, before
                      phasing each SNP allele to wild-type or mutant HTT. Primary
                      ex vivo myeloid cells were isolated from heterozygous
                      patients and transfected with SNP-targeted siRNA, using
                      glucan particles taken up by phagocytosis. Highly selective
                      mRNA knockdown was achieved when targeting each allele of
                      rs362331 in exon 50 of the HTT transcript; this selectivity
                      was also present on protein studies. However, similar
                      selectivity was not observed when targeting rs362273 or
                      rs362307. Furthermore, HD myeloid cells are hyper-reactive
                      compared to control. Allele-selective suppression of either
                      wild-type or mutant HTT produced a significant, equivalent
                      reduction in the cytokine response of HD myeloid cells to
                      LPS, suggesting that wild-type HTT has a novel immune
                      function. We demonstrate a sequential therapeutic process
                      comprising genotyping and mutant HTT-linkage of SNPs,
                      followed by personalised allele-selective suppression in a
                      small patient cohort. We further show that
                      allele-selectivity in ex vivo patient cells is highly
                      SNP-dependent, with implications for clinical trial target
                      selection.},
      cin          = {D100},
      ddc          = {000},
      cid          = {I:(DE-He78)D100-20160331},
      pnm          = {314 - Tumor immunology (POF3-314)},
      pid          = {G:(DE-HGF)POF3-314},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:28436437},
      pmc          = {pmc:PMC5402279},
      doi          = {10.1038/srep46740},
      url          = {https://inrepo02.dkfz.de/record/120651},
}