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@ARTICLE{Toualbi:285071,
      author       = {L. Toualbi and M. Toms and P. V. Almeida$^*$ and R.
                      Harbottle$^*$ and M. Moosajee},
      title        = {{G}ene {A}ugmentation of {CHM} {U}sing {N}on-{V}iral
                      {E}pisomal {V}ectors in {M}odels of {C}horoideremia.},
      journal      = {International journal of molecular sciences},
      volume       = {24},
      number       = {20},
      issn         = {1422-0067},
      address      = {Basel},
      publisher    = {Molecular Diversity Preservation International},
      reportid     = {DKFZ-2023-02214},
      pages        = {15225},
      year         = {2023},
      abstract     = {Choroideremia (CHM) is an X-linked chorioretinal dystrophy
                      leading to progressive retinal degeneration that results in
                      blindness by late adulthood. It is caused by mutations in
                      the CHM gene encoding the Rab Escort Protein 1 (REP1), which
                      plays a crucial role in the prenylation of Rab proteins
                      ensuring correct intracellular trafficking. Gene
                      augmentation is a promising therapeutic strategy, and there
                      are several completed and ongoing clinical trials for
                      treating CHM using adeno-associated virus (AAV) vectors.
                      However, late-phase trials have failed to show significant
                      functional improvements and have raised safety concerns
                      about inflammatory events potentially caused by the use of
                      viruses. Therefore, alternative non-viral therapies are
                      desirable. Episomal scaffold/matrix attachment region
                      (S/MAR)-based plasmid vectors were generated containing the
                      human CHM coding sequence, a GFP reporter gene, and
                      ubiquitous promoters (pS/MAR-CHM). The vectors were assessed
                      in two choroideremia disease model systems: (1) CHM
                      patient-derived fibroblasts and (2) chmru848 zebrafish,
                      using Western blotting to detect REP1 protein expression and
                      in vitro prenylation assays to assess the rescue of
                      prenylation function. Retinal immunohistochemistry was used
                      to investigate vector expression and photoreceptor
                      morphology in injected zebrafish retinas. The pS/MAR-CHM
                      vectors generated persistent REP1 expression in CHM patient
                      fibroblasts and showed a significant rescue of prenylation
                      function by $75\%,$ indicating correction of the underlying
                      biochemical defect associated with CHM. In addition, GFP and
                      human REP1 expression were detected in zebrafish
                      microinjected with the pS/MAR-CHM at the one-cell stage.
                      Injected chmru848 zebrafish showed increased survival,
                      prenylation function, and improved retinal photoreceptor
                      morphology. Non-viral S/MAR vectors show promise as a
                      potential gene-augmentation strategy without the use of
                      immunogenic viral components, which could be applicable to
                      many inherited retinal disease genes.},
      keywords     = {Animals / Humans / Adult / Choroideremia: genetics /
                      Choroideremia: therapy / Choroideremia: metabolism /
                      Zebrafish: genetics / Zebrafish: metabolism / Retina:
                      metabolism / Mutation / Retinal Dystrophies: metabolism /
                      Plasmids / Adaptor Proteins, Signal Transducing: genetics /
                      Adaptor Proteins, Signal Transducing: metabolism / S/MAR
                      (Other) / choroideremia (Other) / inherited retinal disease
                      (Other) / non-viral gene therapy (Other) / CHM protein,
                      human (NLM Chemicals) / Adaptor Proteins, Signal Transducing
                      (NLM Chemicals)},
      cin          = {F160},
      ddc          = {540},
      cid          = {I:(DE-He78)F160-20160331},
      pnm          = {316 - Infektionen, Entzündung und Krebs (POF4-316)},
      pid          = {G:(DE-HGF)POF4-316},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:37894906},
      pmc          = {pmc:PMC10607001},
      doi          = {10.3390/ijms242015225},
      url          = {https://inrepo02.dkfz.de/record/285071},
}