2016
DOI: 10.1089/hum.2015.130
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Cone-Specific Promoters for Gene Therapy of Achromatopsia and Other Retinal Diseases

Abstract: Adeno-associated viral (AAV) vectors containing cone-specific promoters have rescued cone photoreceptor function in mouse and dog models of achromatopsia, but cone-specific promoters have not been optimized for use in primates. Using AAV vectors administered by subretinal injection, we evaluated a series of promoters based on the human L-opsin promoter, or a chimeric human cone transducin promoter, for their ability to drive gene expression of green fluorescent protein (GFP) in mice and nonhuman primates. Each… Show more

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Cited by 70 publications
(63 citation statements)
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“…Three weeks after subretinal injections, retinal cross-sections were stained with cone arrestin, and GFP expression was examined ( Figure 1, A-C). We found GFP expression in both rod and cone photoreceptors with mCAR promoter, while PR2.1 and PR1.7 led to strong expression mostly in cones, as reported previously (18,19). Using the same vectors, we obtained strikingly different expression patterns after intravitreal delivery (Figure 1, D-F).…”
Section: Resultssupporting
confidence: 83%
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“…Three weeks after subretinal injections, retinal cross-sections were stained with cone arrestin, and GFP expression was examined ( Figure 1, A-C). We found GFP expression in both rod and cone photoreceptors with mCAR promoter, while PR2.1 and PR1.7 led to strong expression mostly in cones, as reported previously (18,19). Using the same vectors, we obtained strikingly different expression patterns after intravitreal delivery (Figure 1, D-F).…”
Section: Resultssupporting
confidence: 83%
“…Interestingly, we found a chicken ovalbumin upstream promoter-transcription factor I (COUP-TFI) binding site within this 337-bp sequence (Supplemental Table 1). COUP-TFI has been shown to suppress green opsin gene (Opn1mw) expression in the mouse retina (22) and might thus be accountable for lower expression with the PR2.1 promoter in macaque cones when AAV is delivered subretinally as previously shown (18). Within the same specific 337-bp region, we also found multiple binding sites for generic, ubiquitous activator TFs ( Figure 2B and Supplemental Table 1), such as CCAAT/enhancer binding protein β (CEBPB) and general transcription factor II-I (GTF2I).…”
Section: Resultsmentioning
confidence: 77%
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“…[6][7][8] Studies in mouse, sheep, and dog models of achromatopsia caused by mutations in the CNGA3 and CNGB3 genes indicate that gene augmentation therapy using a recombinant adeno-associated virus (AAV) vector expressing a normal CNGA3 or CNGB3 gene can produce the functional CNGA3 or CNGB3 proteins and restore cone photoreceptor function. [9][10][11][12][13] As part of the efforts to develop a product candidate for treatment of humans with ACHM caused by mutations in the CNGA3 gene, an Investigational New Drug (IND)-enabling safety and efficacy study of AGTC-402, an AAV vector containing a conespecific promotor (PR1.7), 14 a codon-optimized human CNGA3 cDNA, and a SV40 polyadenylation sequence packaged in an AAV2 capsid containing three tyrosine to phenylalanine (YF) mutations, was conducted in CNGA3-deficient sheep.…”
Section: Introductionmentioning
confidence: 99%