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2.
Nat Commun ; 15(1): 4756, 2024 Jun 04.
Artículo en Inglés | MEDLINE | ID: mdl-38834544

RESUMEN

Given the absence of approved treatments for pathogenic variants in Peripherin-2 (PRPH2), it is imperative to identify a universally effective therapeutic target for PRPH2 pathogenic variants. To test the hypothesis that formation of the elongated discs in presence of PRPH2 pathogenic variants is due to the presence of the full complement of rhodopsin in absence of the required amounts of functional PRPH2. Here we demonstrate the therapeutic potential of reducing rhodopsin levels in ameliorating disease phenotype in knockin models for p.Lys154del (c.458-460del) and p.Tyr141Cys (c.422 A > G) in PRPH2. Reducing rhodopsin levels improves physiological function, mitigates the severity of disc abnormalities, and decreases retinal gliosis. Additionally, intravitreal injections of a rhodopsin-specific antisense oligonucleotide successfully enhance the physiological function of photoreceptors and improves the ultrastructure of discs in mutant mice. Presented findings shows that reducing rhodopsin levels is an effective therapeutic strategy for the treatment of inherited retinal degeneration associated with PRPH2 pathogenic variants.


Asunto(s)
Periferinas , Rodopsina , Periferinas/genética , Periferinas/metabolismo , Animales , Rodopsina/genética , Rodopsina/metabolismo , Ratones , Humanos , Modelos Animales de Enfermedad , Regulación hacia Abajo , Degeneración Retiniana/genética , Degeneración Retiniana/metabolismo , Degeneración Retiniana/terapia , Oligonucleótidos Antisentido/genética , Retina/metabolismo , Retina/patología , Enfermedades de la Retina/genética , Enfermedades de la Retina/metabolismo , Enfermedades de la Retina/patología , Enfermedades de la Retina/terapia , Ratones Endogámicos C57BL , Mutación , Femenino , Técnicas de Sustitución del Gen , Masculino
3.
Mol Ther Nucleic Acids ; 35(2): 102222, 2024 Jun 11.
Artículo en Inglés | MEDLINE | ID: mdl-38868364

RESUMEN

Inherited retinal degeneration (IRD) can cause a wide range of different forms of vision loss and blindness, and in spite of extensive advancements in gene therapy research, therapeutic approaches for targeting IRDs are still lacking. We have recently developed an approach for the intravitreal co-delivery of hyaluronic-acid nanospheres (HA-NSs) with sulfotyrosine (ST), effectively reaching the outer retina from the vitreal cavity. Here, our goal was to understand whether DNA-filled HA-NSs could generate gene expression in the outer retina. TxRed-labeled HA-NSs were compacted with plasmid DNA carrying a GFP reporter gene and intravitreally injected into the mouse retina. Follow-up at 4 weeks showed widespread gene expression in the outer retina and reduced, albeit present, expression at 8 weeks post-injection. Further analysis revealed this expression to be largely localized to the retinal pigment epithelium (RPE). These data show that intravitreal delivery of HA-NSs is a promising non-viral platform for the delivery of therapeutic genes and can generate pan-tissue, persistent gene expression in the RPE.

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