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@ARTICLE{MartinezDominguez:285737,
      author       = {Martinez Dominguez, Maria Victoria and Falke, Lisa and
                      Beretta, Stefania and Dauer, Katharina and Wagner, Karl G.
                      and Boeckers, Tobias M.},
      title        = {{M}anufacturing and testing of a polymer formulation for
                      long-time release delivery of antisense oligonucleotides in
                      hi{PSC}-derived motoneurons},
      journal      = {Journal of drug delivery science and technology},
      volume       = {119},
      issn         = {1773-2247},
      address      = {Paris},
      publisher    = {Ed. de Santé},
      reportid     = {DZNE-2026-00294},
      pages        = {108171},
      year         = {2026},
      abstract     = {Antisense oligonucleotides (ASOs) are an emerging
                      therapeutic approach for genetically induced neurological
                      disorders such as spinal muscular atrophy (SMA). For SMA,
                      the Food and Drug administration (FDA)-approved ASO
                      Nusinersen (Spinraza®) restores exon 7 inclusion in
                      survival motor neuron (SMN) 2, leading to improved
                      motoneuron survival. However, current administration to
                      patients requires repeated intrathecal (IT) injections via
                      lumbar puncture, an invasive procedure with considerable
                      side effects. There is therefore an urgent need for more
                      efficient and sustained drug-delivery strategies capable of
                      overcoming these limitations. In this study, we developed
                      and tested a system for the controlled, long-term release of
                      Nusinersen ASO. Using motoneurons derived from human induced
                      pluripotent stem cells (hiPSCs) from SMA and control
                      patients, two formulations were evaluated: (I) pure ethylene
                      vinyl acetate (EVA, $40\%$ vinyl acetate) and (II) a
                      composite of EVA $(40\%$ vinyl acetate) and silica (50:50
                      w/w). Both formulations were found to be biocompatible in
                      the co-cultures in vitro. Moreover, the efficient uptake of
                      ASOs and the optimization of ASO dose and time-response in
                      motoneurons was achieved. Additionally, fluorescently
                      labeled ASOs confirmed sustained release from the implants.
                      Importantly, sustained polymer-released ASO significantly
                      increased exon 7 inclusion in SMN2 transcripts and
                      motoneuron viability over time, demonstrating therapeutic
                      efficacy and preserved biological activity. These findings
                      demonstrate the initial feasibility for a minimally
                      invasive, long-term ASO delivery system that could overcome
                      the limitation for repeated lumbar punctures in SMA patients
                      and potentially be adapted as ASO delivery systems for other
                      neurodegenerative diseases.},
      cin          = {AG Böckers},
      ddc          = {610},
      cid          = {I:(DE-2719)1910002},
      pnm          = {352 - Disease Mechanisms (POF4-352)},
      pid          = {G:(DE-HGF)POF4-352},
      typ          = {PUB:(DE-HGF)16},
      doi          = {10.1016/j.jddst.2026.108171},
      url          = {https://pub.dzne.de/record/285737},
}