TY  - JOUR
AU  - Toualbi, Lyes
AU  - Toms, Maria
AU  - Almeida, Patrick Vingadas
AU  - Harbottle, Richard
AU  - Moosajee, Mariya
TI  - Gene Augmentation of CHM Using Non-Viral Episomal Vectors in Models of Choroideremia.
JO  - International journal of molecular sciences
VL  - 24
IS  - 20
SN  - 1422-0067
CY  - Basel
PB  - Molecular Diversity Preservation International
M1  - DKFZ-2023-02214
SP  - 15225
PY  - 2023
AB  - 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
KW  - Animals
KW  - Humans
KW  - Adult
KW  - Choroideremia: genetics
KW  - Choroideremia: therapy
KW  - Choroideremia: metabolism
KW  - Zebrafish: genetics
KW  - Zebrafish: metabolism
KW  - Retina: metabolism
KW  - Mutation
KW  - Retinal Dystrophies: metabolism
KW  - Plasmids
KW  - Adaptor Proteins, Signal Transducing: genetics
KW  - Adaptor Proteins, Signal Transducing: metabolism
KW  - S/MAR (Other)
KW  - choroideremia (Other)
KW  - inherited retinal disease (Other)
KW  - non-viral gene therapy (Other)
KW  - CHM protein, human (NLM Chemicals)
KW  - Adaptor Proteins, Signal Transducing (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:37894906
C2  - pmc:PMC10607001
DO  - DOI:10.3390/ijms242015225
UR  - https://inrepo02.dkfz.de/record/285071
ER  -