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JCI Insight. 2017 Dec 21;2(24). pii: 96560. doi: 10.1172/jci.insight.96560.

Targeting and silencing of rhodopsin by ectopic expression of the transcription factor KLF15.

Author information

1
Telethon Institute of Genetics and Medicine, Napoli, Italy.
2
Department of Veterinary Medical Sciences, University of Bologna, Bologna, Italy.
3
Multidisciplinary Department of Medical, Surgical and Dental Sciences, Eye Clinic, Second University of Naples, Naples, Italy.
4
Department of Translational Medicine, University of Naples Federico II, Naples, Italy.

Abstract

The genome-wide activity of transcription factors (TFs) on multiple regulatory elements precludes their use as gene-specific regulators. Here we show that ectopic expression of a TF in a cell-specific context can be used to silence the expression of a specific gene as a therapeutic approach to regulate gene expression in human disease. We selected the TF Krüppel-like factor 15 (KLF15) based on its putative ability to recognize a specific DNA sequence motif present in the rhodopsin (RHO) promoter and its lack of expression in terminally differentiated rod photoreceptors (the RHO-expressing cells). Adeno-associated virus (AAV) vector-mediated ectopic expression of KLF15 in rod photoreceptors of pigs enables Rho silencing with limited genome-wide transcriptional perturbations. Suppression of a RHO mutant allele by KLF15 corrects the phenotype of a mouse model of retinitis pigmentosa with no observed toxicity. Cell-specific-context conditioning of TF activity may prove a novel mode for somatic gene-targeted manipulation.

KEYWORDS:

Neurodegeneration; Ophthalmology; Therapeutics; Transcription

PMID:
29263295
PMCID:
PMC5752276
DOI:
10.1172/jci.insight.96560
[Indexed for MEDLINE]
Free PMC Article

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