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000285071 1001_ $$aToualbi, Lyes$$b0
000285071 245__ $$aGene Augmentation of CHM Using Non-Viral Episomal Vectors in Models of Choroideremia.
000285071 260__ $$aBasel$$bMolecular Diversity Preservation International$$c2023
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000285071 520__ $$aChoroideremia (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.
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000285071 650_7 $$2Other$$aS/MAR
000285071 650_7 $$2Other$$achoroideremia
000285071 650_7 $$2Other$$ainherited retinal disease
000285071 650_7 $$2Other$$anon-viral gene therapy
000285071 650_7 $$2NLM Chemicals$$aCHM protein, human
000285071 650_7 $$2NLM Chemicals$$aAdaptor Proteins, Signal Transducing
000285071 650_2 $$2MeSH$$aAnimals
000285071 650_2 $$2MeSH$$aHumans
000285071 650_2 $$2MeSH$$aAdult
000285071 650_2 $$2MeSH$$aChoroideremia: genetics
000285071 650_2 $$2MeSH$$aChoroideremia: therapy
000285071 650_2 $$2MeSH$$aChoroideremia: metabolism
000285071 650_2 $$2MeSH$$aZebrafish: genetics
000285071 650_2 $$2MeSH$$aZebrafish: metabolism
000285071 650_2 $$2MeSH$$aRetina: metabolism
000285071 650_2 $$2MeSH$$aMutation
000285071 650_2 $$2MeSH$$aRetinal Dystrophies: metabolism
000285071 650_2 $$2MeSH$$aPlasmids
000285071 650_2 $$2MeSH$$aAdaptor Proteins, Signal Transducing: genetics
000285071 650_2 $$2MeSH$$aAdaptor Proteins, Signal Transducing: metabolism
000285071 7001_ $$aToms, Maria$$b1
000285071 7001_ $$0P:(DE-HGF)0$$aAlmeida, Patrick Vingadas$$b2
000285071 7001_ $$0P:(DE-He78)15dff5647002b4dcfe892b251cd14b62$$aHarbottle, Richard$$b3$$udkfz
000285071 7001_ $$00000-0003-1688-5360$$aMoosajee, Mariya$$b4
000285071 773__ $$0PERI:(DE-600)2019364-6$$a10.3390/ijms242015225$$gVol. 24, no. 20, p. 15225 -$$n20$$p15225$$tInternational journal of molecular sciences$$v24$$x1422-0067$$y2023
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