Toxicity and Efficacy Evaluation of an Adeno-Associated Virus Vector Expressing Codon-Optimized RPGR Delivered by Subretinal Injection in a Canine Model of X-linked Retinitis Pigmentosa
Applied Genetic Technologies Corporation (AGTC) is developing a recombinant adeno-associated virus (rAAV) vector AGTC-501, also designated rAAV2tYF-GRK1-hRPGRco, to treat X-linked retinitis pigmentosa (XLRP) in patients with mutations in the retinitis pigmentosa GTPase regulator (RPGR) gene. The vector contains a codon-optimized human RPGR cDNA (hRPGRco) driven by a photoreceptor-specific promoter (G protein-coupled receptor kinase 1 [GRK1]), and is packaged in an AAV2 capsid variant with three surface tyrosine residues changed to phenylalanine (AAV2tYF). We conducted a toxicity and efficacy study of this vector administered by subretinal injection in the naturally occurring RPGR mutant (X-linked progressive retinal atrophy 2 [XLPRA2]) dog model. Sixteen RPGR mutant dogs divided into four groups of three to five animals each received either a subretinal injection of 0.07 mL of AGTC-501 at low (1.2 × 1011 vector genome [vg]/mL), mid (6 × 1011 vg/mL), or high dose (3 × 1012 vg/mL), or of vehicle control in the right eye at early-stage disease. The left eye remained untreated. Subretinal injections were well tolerated and were not associated with systemic toxicity. Electroretinography, in vivo retinal imaging, and histological analysis showed rescue of photoreceptor function and structure in the absence of ocular toxicity in the low- and mid-dose treatment groups when compared with the vehicle-treated group. The high-dose group showed evidence of both photoreceptor rescue and posterior segment toxicity. These results support the use of AGTC-501 in clinical studies with patients affected with XLRP caused by RPGR mutations and define the no-observed-adverse-effect level at 6 × 1011 vg/mL.
| Errataetall: | |
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| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2020 |
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| Erschienen: |
2020 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:31 |
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| Enthalten in: |
Human gene therapy - 31(2020), 3-4 vom: 01. Feb., Seite 253-267 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Dufour, Valérie L [VerfasserIn] |
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| Links: |
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| Themen: |
Biomarkers |
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| Anmerkungen: |
Date Completed 03.06.2021 Date Revised 03.06.2021 published: Print-Electronic ErratumIn: Hum Gene Ther. 2020 Jun 25;:. - PMID 32589471 Citation Status MEDLINE |
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| doi: |
10.1089/hum.2019.297 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM305094971 |
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| 100 | 1 | |a Dufour, Valérie L |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Toxicity and Efficacy Evaluation of an Adeno-Associated Virus Vector Expressing Codon-Optimized RPGR Delivered by Subretinal Injection in a Canine Model of X-linked Retinitis Pigmentosa |
| 264 | 1 | |c 2020 | |
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| 500 | |a Date Completed 03.06.2021 | ||
| 500 | |a Date Revised 03.06.2021 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a ErratumIn: Hum Gene Ther. 2020 Jun 25;:. - PMID 32589471 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Applied Genetic Technologies Corporation (AGTC) is developing a recombinant adeno-associated virus (rAAV) vector AGTC-501, also designated rAAV2tYF-GRK1-hRPGRco, to treat X-linked retinitis pigmentosa (XLRP) in patients with mutations in the retinitis pigmentosa GTPase regulator (RPGR) gene. The vector contains a codon-optimized human RPGR cDNA (hRPGRco) driven by a photoreceptor-specific promoter (G protein-coupled receptor kinase 1 [GRK1]), and is packaged in an AAV2 capsid variant with three surface tyrosine residues changed to phenylalanine (AAV2tYF). We conducted a toxicity and efficacy study of this vector administered by subretinal injection in the naturally occurring RPGR mutant (X-linked progressive retinal atrophy 2 [XLPRA2]) dog model. Sixteen RPGR mutant dogs divided into four groups of three to five animals each received either a subretinal injection of 0.07 mL of AGTC-501 at low (1.2 × 1011 vector genome [vg]/mL), mid (6 × 1011 vg/mL), or high dose (3 × 1012 vg/mL), or of vehicle control in the right eye at early-stage disease. The left eye remained untreated. Subretinal injections were well tolerated and were not associated with systemic toxicity. Electroretinography, in vivo retinal imaging, and histological analysis showed rescue of photoreceptor function and structure in the absence of ocular toxicity in the low- and mid-dose treatment groups when compared with the vehicle-treated group. The high-dose group showed evidence of both photoreceptor rescue and posterior segment toxicity. These results support the use of AGTC-501 in clinical studies with patients affected with XLRP caused by RPGR mutations and define the no-observed-adverse-effect level at 6 × 1011 vg/mL | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a RPGR | |
| 650 | 4 | |a XLRP | |
| 650 | 4 | |a gene therapy | |
| 650 | 4 | |a retinal degeneration | |
| 650 | 7 | |a Biomarkers |2 NLM | |
| 650 | 7 | |a Codon |2 NLM | |
| 650 | 7 | |a Eye Proteins |2 NLM | |
| 650 | 7 | |a RPGR protein, human |2 NLM | |
| 700 | 1 | |a Cideciyan, Artur V |e verfasserin |4 aut | |
| 700 | 1 | |a Ye, Guo-Jie |e verfasserin |4 aut | |
| 700 | 1 | |a Song, Chunjuan |e verfasserin |4 aut | |
| 700 | 1 | |a Timmers, Adrian |e verfasserin |4 aut | |
| 700 | 1 | |a Habecker, Perry L |e verfasserin |4 aut | |
| 700 | 1 | |a Pan, Wei |e verfasserin |4 aut | |
| 700 | 1 | |a Weinstein, Nicole M |e verfasserin |4 aut | |
| 700 | 1 | |a Swider, Malgorzata |e verfasserin |4 aut | |
| 700 | 1 | |a Durham, Amy C |e verfasserin |4 aut | |
| 700 | 1 | |a Ying, Gui-Shuang |e verfasserin |4 aut | |
| 700 | 1 | |a Robinson, Paulette M |e verfasserin |4 aut | |
| 700 | 1 | |a Jacobson, Samuel G |e verfasserin |4 aut | |
| 700 | 1 | |a Knop, David R |e verfasserin |4 aut | |
| 700 | 1 | |a Chulay, Jeffrey D |e verfasserin |4 aut | |
| 700 | 1 | |a Shearman, Mark S |e verfasserin |4 aut | |
| 700 | 1 | |a Aguirre, Gustavo D |e verfasserin |4 aut | |
| 700 | 1 | |a Beltran, William A |e verfasserin |4 aut | |
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