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@ARTICLE{Synofzik:163947,
      author       = {Synofzik, Matthis and van Roon-Mom, Willeke M C and
                      Marckmann, Georg and van Duyvenvoorde, Hermine A and
                      Graessner, Holm and Schüle, Rebecca and Aartsma-Rus,
                      Annemieke},
      title        = {{P}reparing n-of-1 {A}ntisense {O}ligonucleotide
                      {T}reatments for {R}are {N}eurological {D}iseases in
                      {E}urope: {G}enetic, {R}egulatory, and {E}thical
                      {P}erspectives.},
      journal      = {Nucleic acid therapeutics},
      volume       = {32},
      number       = {2},
      issn         = {1050-5261},
      address      = {New Rochelle, NY},
      publisher    = {Liebert},
      reportid     = {DZNE-2022-00621},
      pages        = {83 - 94},
      year         = {2022},
      note         = {(CC BY)},
      abstract     = {Antisense oligonucleotide (ASO) therapies present a
                      promising disease-modifying treatment approach for rare
                      neurological diseases (RNDs). However, the current focus is
                      on 'more common' RNDs, leaving a large share of RND patients
                      still without prospect of disease-modifying treatments. In
                      response to this gap, n-of-1 ASO treatment approaches are
                      targeting ultrarare or even private variants. While highly
                      attractive, this emerging, academia-driven field of
                      ultimately individualized precision medicine is in need of
                      systematic guidance and standards, which will allow global
                      scaling of this approach. We provide here genetic,
                      regulatory, and ethical perspectives for preparing n-of-1
                      ASO treatments and research programs, with a specific focus
                      on the European context. By example of splice modulating
                      ASOs, we outline genetic criteria for variant
                      prioritization, chart the regulatory field of n-of-1 ASO
                      treatment development in Europe, and propose an ethically
                      informed classification for n-of-1 ASO treatment strategies
                      and level of outcome assessments. To accommodate the ethical
                      requirements of both individual patient benefit and
                      knowledge gain, we propose a stronger integration of patient
                      care and clinical research when developing novel n-of-1 ASO
                      treatments: each single trial of therapy should inherently
                      be driven to generate generalizable knowledge, be registered
                      in a ASO treatment registry, and include assessment of
                      generic outcomes, which allow aggregated analysis across
                      n-of-1 trials of therapy.},
      keywords     = {Europe / Humans / Oligonucleotides / Oligonucleotides,
                      Antisense: genetics / Oligonucleotides, Antisense:
                      therapeutic use / antisense oligonucleotides (Other) /
                      ethics (Other) / n-of-1 (Other) / policy (Other) / rare
                      diseases (Other) / rare neurological diseases (Other) /
                      regulatory (Other) / Oligonucleotides (NLM Chemicals) /
                      Oligonucleotides, Antisense (NLM Chemicals)},
      cin          = {AG Gasser 1 / AG Maetzler},
      ddc          = {610},
      cid          = {I:(DE-2719)1210000 / I:(DE-2719)5000024},
      pnm          = {353 - Clinical and Health Care Research (POF4-353)},
      pid          = {G:(DE-HGF)POF4-353},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:34591693},
      pmc          = {pmc:PMC9058873},
      doi          = {10.1089/nat.2021.0039},
      url          = {https://pub.dzne.de/record/163947},
}