Challenging Safety and Efficacy of Retinal Gene Therapies by Retinogenesis

Overview

Journal Int J Mol Sci

Publisher MDPI

Specialties Biochemistry
Chemistry
Molecular Biology

Date 2021 Jun 2

PMID 34071252

Citations 5

Authors

Elena Marrocco

Rosa Maritato

Salvatore Botta

Marianna Esposito

Enrico Maria Surace

Affiliations

Soon will be listed here.

Abstract

Gene-expression programs modulated by transcription factors (TFs) mediate key developmental events. Here, we show that the synthetic transcriptional repressor (TR; ZF6-DB), designed to treat Rhodopsin-mediated autosomal dominant retinitis pigmentosa (RHO-adRP), does not perturb murine retinal development, while maintaining its ability to block Rho expression transcriptionally. To express ZF6-DB into the developing retina, we pursued two approaches, (i) the retinal delivery (somatic expression) of ZF6-DB by Adeno-associated virus (AAV) vector (AAV-ZF6-DB) gene transfer during retinogenesis and (ii) the generation of a transgenic mouse (germ-line transmission, TR-ZF6-DB). Somatic and transgenic expression of ZF6-DB during retinogenesis does not affect retinal function of wild-type mice. The P347S mouse model of RHO-adRP, subretinally injected with AAV-ZF6-DB, or crossed with TR-ZF6-DB or shows retinal morphological and functional recovery. We propose the use of developmental transitions as an effective mode to challenge the safety of retinal gene therapies operating at genome, transcriptional, and transcript levels.

Citing Articles

A DNA base-specific sequence interposed between CRX and NRL contributes to RHODOPSIN expression.

Maritato R, Medugno A, DAndretta E, De Riso G, Lupo M, Botta S Sci Rep. 2024; 14(1):26313.

PMID: 39487168 PMC: 11530525. DOI: 10.1038/s41598-024-76664-8.

Retinitis Pigmentosa: Novel Therapeutic Targets and Drug Development.

Wu K, Kulbay M, Toameh D, Xu A, Kalevar A, Tran S Pharmaceutics. 2023; 15(2).

PMID: 36840007 PMC: 9963330. DOI: 10.3390/pharmaceutics15020685.

Gene regulatory and gene editing tools and their applications for retinal diseases and neuroprotection: From proof-of-concept to clinical trial.

Altay H, Ozdemir F, Afghah F, Kilinc Z, Ahmadian M, Tschopp M Front Neurosci. 2022; 16:924917.

PMID: 36340792 PMC: 9630553. DOI: 10.3389/fnins.2022.924917.

miR-181a/b downregulation: a mutation-independent therapeutic approach for inherited retinal diseases.

Carrella S, Di Guida M, Brillante S, Piccolo D, Ciampi L, Guadagnino I EMBO Mol Med. 2022; 14(11):e15941.

PMID: 36194668 PMC: 9641422. DOI: 10.15252/emmm.202215941.

Gene Therapy for Rhodopsin Mutations.

Lewin A, Smith W Cold Spring Harb Perspect Med. 2022; .

PMID: 35940643 PMC: 9435570. DOI: 10.1101/cshperspect.a041283.

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