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Karina Guziewicz, Andras Komaromy, Simone Iwabe, Artur Cideciyan, Emily Dutrow, Barbara Zangerl, William Beltran, Samuel Jacobson, William Hauswirth, Gustavo Aguirre; Sustained Therapeutic Reversal of Canine Bestrophinopathy with Gene Therapy using Recombinant AAV2. Invest. Ophthalmol. Vis. Sci. 2013;54(15):5965.
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© ARVO (1962-2015); The Authors (2016-present)
Canine multifocal retinopathy (cmr), a spontaneous animal model of BEST1-associated retinopathies in man, recapitulates the spectrum of clinical and molecular features observed in human bestrophinopathies, and is an important translational model for the development and testing of therapeutic strategies. We have previously shown that rAAV2-mediated BEST1 gene delivery controlled by human VMD2 promoter (hVMD2) specifically targets RPE cells, and is well tolerated in the wild-type canine retina. The aim of these studies was to assess the safety, efficiency and therapeutic potential of rAAV2-mediated BEST1 transgene expression in cmr-affected dogs.
Thirteen cmr-affected dogs carrying R25X, R25X/P463fs or P463fs mutations in BEST1 and exhibiting bilateral focal or multifocal lesions were subretinally injected with rAAV2 expressing either canine (0.136-1.59x1011vg/ml) or human (7.64-8.82x1011vg/ml) BEST1 regulated by the hVMD2 promoter. Each treated and control (non-injected or BSS-injected) eye was monitored clinically and imaged serially in vivo using cSLO/SD-OCT. For morphological studies, treated and control tissue samples were collected at 1 - 15 months post injection (p.i.).
In all cases, the transient retinal detachment associated with vector delivery completely resolved within 24h p.i. Based on the SD-OCT analyses, some lesions within the treated regions disappeared as early as 8 weeks and all resolved within 3 months after gene therapy, and the treated areas remained asymptomatic thereafter. In cases with advanced disease, hyperfluorescent FAF signals were still detectable and likely localized to RPE. The untreated regions of the treated eye or the contralateral control eye remained unchanged or developed lesions. Specific Best1 immunolabeling was detected only within the treated area, and comparable efficacy was noted with canine and human cDNAs. Both the in vivo imaging and immunohistochemical evaluation revealed no apparent adverse effects in RPE or retina secondary to the BEST1 gene augmentation therapy.
rAAV2-mediated BEST1 gene augmentation therapy shows great potential to reverse characteristic BEST1 lesions and reverse pathology in cmr models up to 15 months p.i., and carries a large translational promise as a first specific-treatment for human bestrophinopathies.
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