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

Journal article

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.

Authors: Botta, S; de Prisco, N; Marrocco, E; Renda, M; Sofia, M

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: American Society for Clinical Investigation
• Journal: JCI Insight
• Volume: 2
• Issue: 24
• Article number: e96560
• Publication date: 2017-12-21
• Acceptance date: 2017-11-15
• DOI: 10.1172/jci.insight.96560
• ISSN: 2379-3708
• Pmid: 29263295
• Language: English
• Keywords: therapeutics; ophthalmology; neurodegeneration; transcription