Safety and Biodistribution Evaluation in Cynomolgus Macaques of rAAV2tYF-PR1.7-hCNGB3, a Recombinant AAV Vector for Treatment of Achromatopsia

Ye, Guo-jie; Budzynski, Ewa; Sonnentag, Peter; Nork, T. Michael; Miller, Paul E.; Sharma, Alok; Hoeve, James N. Ver; Smith, Leia M.; Arndt, Tara; Calcedo, Roberto; Gaskin, Chantelle; Robinson, Paul; Knop, David R.; Hauswirth, William W.; Chulay, Jeffrey D.

doi:10.1089/humc.2015.164

Cited by 54 publications

(48 citation statements)

References 34 publications

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“…19 In the current study, the two animals treated with AGTC-402 that had an increase in NAb titer had either vitreal reflux of the drug product or considerable subconjunctival hemorrhage that occurred during or immediately after surgery. In the other sheep, the NAb titer increase in the current study was significantly lower than that in the NHP study, suggesting a possible species-dependent effect on the development of NAb to AAV capsid.…”

Section: Aav-cnga3 Vectors In Achm Sheepmentioning

confidence: 66%

“…No serum antibody to the transgene product hCNGA3 protein was detected in any vector treated sheep, which is consistent with the finding in the NHP study for the rAAV2tYF-PR1.7-hCNGB3 drug product. 19 …”

Section: Aav-cnga3 Vectors In Achm Sheepmentioning

confidence: 99%

“…The AGTC-402 vector was designed based on the rAAV2tYF-PR1.7-hCNGB3 vector 19 in which the CNGB3 cDNA was replaced by a codon-optimized CNGA3 cDNA. The vector was produced by AGTC using a recombinant herpes simplex virus (rHSV) complementation system in suspension-cultured baby hamster kidney (sBHK) cells.…”

Section: Vector Productionmentioning

confidence: 99%

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Safety and Efficacy Evaluation of rAAV2tYF-PR1.7-hCNGA3 Vector Delivered by Subretinal Injection in CNGA3 Mutant Achromatopsia Sheep

Gootwine

Ofri

Banin

et al. 2017

Human Gene Therapy Clinical Development

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{These authors contributed equally to this work.Applied Genetic Technologies Corporation (AGTC) is developing a recombinant adeno-associated virus (rAAV) vector expressing the human CNGA3 gene designated AGTC-402 (rAAV2tYF-PR1.7-hCNGA3) for the treatment of achromatopsia, an inherited retinal disorder characterized by markedly reduced visual acuity, extreme light sensitivity, and absence of color discrimination. The results are herein reported of a study evaluating safety and efficacy of AGTC-402 in CNGA3-deficient sheep. Thirteen day-blind sheep divided into three groups of four or five animals each received a subretinal injection of an AAV vector expressing a CNGA3 gene in a volume of 500 lL in the right eye. Two groups (n = 9) received either a lower or higher dose of the AGTC-402 vector, and one efficacy control group (n = 4) received a vector similar in design to one previously shown to rescue cone photoreceptor responses in the day-blind sheep model (rAAV5-PR2.1-hCNGA3). The left eye of each animal received a subretinal injection of 500 lL of vehicle (n = 4) or was untreated (n = 9). Subretinal injections were generally well tolerated and not associated with systemic toxicity. Most animals had mild to moderate conjunctival hyperemia, chemosis, and subconjunctival hemorrhage immediately after surgery that generally resolved by postoperative day 7. Two animals treated with the higher dose of AGTC-402 and three of the efficacy control group animals had microscopic findings of outer retinal atrophy with or without inflammatory cells in the retina and choroid that were procedural and/or test-article related. All vector-treated eyes showed improved cone-mediated electroretinography responses with no change in rod-mediated electroretinography responses. Behavioral maze testing under photopic conditions showed significantly improved navigation times and reduced numbers of obstacle collisions in all vector-treated eyes compared to their contralateral control eyes or predose results in the treated eyes. These results support the use of AGTC-402 in clinical studies in patients with achromatopsia caused by CNGA3 mutations, with careful evaluation for possible inflammatory and/ or toxic effects.

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Section: Aav-cnga3 Vectors In Achm Sheepmentioning

confidence: 66%

Section: Aav-cnga3 Vectors In Achm Sheepmentioning

confidence: 99%

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Safety and Efficacy Evaluation of rAAV2tYF-PR1.7-hCNGA3 Vector Delivered by Subretinal Injection in CNGA3 Mutant Achromatopsia Sheep

Gootwine

Ofri

Banin

et al. 2017

Human Gene Therapy Clinical Development

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“…We selected 3 previously described promoters in view of their utility in driving gene expression in cones (4,18,19,42,43) and tested them for specificity and strength of cone transduction side by side. All promoters tested in vivo in mouse retinas led to transgene expression in the photoreceptor layer when delivered subretinally.…”

Section: Discussionmentioning

confidence: 99%

Noninvasive gene delivery to foveal cones for vision restoration

Khabou¹,

Garita-Hernández²,

Chaffiol³

et al. 2018

JCI Insight

102

105

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“…15 The vector was produced using a recombinant herpes simplex virus (rHSV) complementation system in suspensioncultured baby hamster kidney (sBHK) cells 16 and characterized as described in the companion article published in this issue of the journal. 15 …”

Section: Vector Description Production and Characterizationmentioning

confidence: 99%

Safety and Biodistribution Evaluation in CNGB3-Deficient Mice of rAAV2tYF-PR1.7-hCNGB3, a Recombinant AAV Vector for Treatment of Achromatopsia

Budzynski

Sonnentag

et al. 2016

Human Gene Therapy Clinical Development

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Applied Genetic Technologies Corporation (AGTC) is developing rAAV2tYF-PR1.7-hCNGB3, a recombi-nant adeno-associated virus (rAAV) vector expressing the human CNGB3 gene, for treatment of achro-matopsia, an inherited retinal disorder characterized by markedly reduced visual acuity, extreme light sensitivity, and absence of color discrimination. We report here results of a study evaluating safety and biodistribution of rAAV2tYF-PR1.7-hCNGB3 in CNGB3-deficient mice. Three groups of animals (n = 35 males and 35 females per group) received a subretinal injection in one eye of 1 ll containing either vehicle or rAAV2tYF-PR1.7-hCNGB3 at one of two dose concentrations (1 · 10 12 or 4.2 · 10 12 vg/ml) and were euthanized 4 or 13 weeks later. There were no test-article-related changes in clinical observations, body weights, food consumption, ocular examinations, clinical pathology parameters, organ weights, or mac-roscopic observations at necropsy. Cone-mediated electroretinography (ERG) responses were detected after vector administration in the treated eyes in 90% of animals in the higher dose group and 31% of animals in the lower dose group. Rod-mediated ERG responses were reduced in the treated eye for all groups, with the greatest reduction in males given the higher dose of vector, but returned to normal by the end of the study. Microscopic pathology results demonstrated minimal mononuclear cell infiltrates in the retina and vitreous of some animals at the interim euthanasia and in the vitreous of some animals at the terminal euthanasia. Serum anti-AAV antibodies developed in most vector-injected animals. No animals developed antibodies to hCNGB3. Biodistribution studies demonstrated high levels of vector DNA in vector-injected eyes but little or no vector DNA in nonocular tissue. These results support the use of rAAV2tYF-PR1.7-hCNGB3 in clinical studies in patients with achromatopsia caused by CNGB3 mutations.

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Safety and Biodistribution Evaluation in Cynomolgus Macaques of rAAV2tYF-PR1.7-hCNGB3, a Recombinant AAV Vector for Treatment of Achromatopsia

Cited by 54 publications

References 34 publications

Safety and Efficacy Evaluation of rAAV2tYF-PR1.7-hCNGA3 Vector Delivered by Subretinal Injection in CNGA3 Mutant Achromatopsia Sheep

Safety and Efficacy Evaluation of rAAV2tYF-PR1.7-hCNGA3 Vector Delivered by Subretinal Injection in CNGA3 Mutant Achromatopsia Sheep

Noninvasive gene delivery to foveal cones for vision restoration

Safety and Biodistribution Evaluation in CNGB3-Deficient Mice of rAAV2tYF-PR1.7-hCNGB3, a Recombinant AAV Vector for Treatment of Achromatopsia

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