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Diana Cepeda, Jim Ver Hoeve, Ming Ni, Annahita Keravala, Angelica Phillips, Mehdi Gasmi; Long-term functional delivery of the human L-opsin cDNA via intravitreal administration of an AAV vector in Mongolian gerbils.. Invest. Ophthalmol. Vis. Sci. 2018;59(9):5696. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
Adverum is developing ADVM-042 as an intravitreal gene therapy vector to treat blue cone monochromacy (BCM), an X-linked visual disorder resulting from the deficiency in the long-wave (L) and medium-wave (M) opsin pigments. ADVM-042 is an AAV.7m8 capsid vector which allows efficient intravitreal transgene delivery to the retina. It carries the human L-opsin cDNA under the control of pMNTC, an L and M cone photoreceptors specific expression cassette. The purpose of this study is to evaluate the long-term human L-Opsin expression in monochromatic Mongolian gerbil eyes after intravitreal dosing of ADVM-042 with function evaluated using full-field color electroretinogram (cERG).
Mongolian gerbils were used as a model for BCM because their retina contains 11-14% cone cells with peak light absorbance in the short and medium wave (UV-blue/green) spectral regions. Animals were injected intravitreally with 3E11 vg of ADVM-042 or formulation buffer in both eyes (n=4 animals). Functional expression of human L-opsin was evaluated using full-field color electroretinogram (cERG) with light emitting diodes of different colors: blue (440 nm), green (513 nm), red (630 nm) and far-red (660 nm), at different intensities and temporal frequencies, every 4 weeks up to week 22, and thereafter at 32, 39, 54, 67, 86, and 90 weeks.
General safety assessment (body weight) and color fundus imaging showed that the vector was well tolerated. Functional expression of human L-opsin was evidenced by increased cERG response to the long wavelength red and far-red light sources in dosed animals in comparison to controls, for over one year. No changes were noted in the blue, green or white light cERGs in dosed animals when compared to controls up to 90 weeks post-dosing. Histopathology, immunofluorescence staining and mRNA expression were performed on eye tissues and brain.
Tolerability and functionality of human L-opsin warrant further exploration of visual responses to long wavelength light sources in gerbils treated with ADVM-042 in parallel to IND-enabling development studies.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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