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  • Targeting channelrhodopsin-2 to ON-bipolar cells with vitreally administered AAV Restores ON and OFF visual responses in blind mice.

Targeting channelrhodopsin-2 to ON-bipolar cells with vitreally administered AAV Restores ON and OFF visual responses in blind mice.

Molecular therapy : the journal of the American Society of Gene Therapy (2014-08-07)
Emilie Macé, Romain Caplette, Olivier Marre, Abhishek Sengupta, Antoine Chaffiol, Peggy Barbe, Mélissa Desrosiers, Ernst Bamberg, Jose-Alain Sahel, Serge Picaud, Jens Duebel, Deniz Dalkara
ABSTRACT

Most inherited retinal dystrophies display progressive photoreceptor cell degeneration leading to severe visual impairment. Optogenetic reactivation of retinal neurons mediated by adeno-associated virus (AAV) gene therapy has the potential to restore vision regardless of patient-specific mutations. The challenge for clinical translatability is to restore a vision as close to natural vision as possible, while using a surgically safe delivery route for the fragile degenerated retina. To preserve the visual processing of the inner retina, we targeted ON bipolar cells, which are still present at late stages of disease. For safe gene delivery, we used a recently engineered AAV variant that can transduce the bipolar cells after injection into the eye's easily accessible vitreous humor. We show that AAV encoding channelrhodopsin under the ON bipolar cell-specific promoter mediates long-term gene delivery restricted to ON-bipolar cells after intravitreal administration. Channelrhodopsin expression in ON bipolar cells leads to restoration of ON and OFF responses at the retinal and cortical levels. Moreover, light-induced locomotory behavior is restored in treated blind mice. Our results support the clinical relevance of a minimally invasive AAV-mediated optogenetic therapy for visual restoration.

MATERIALS
Product Number
Brand
Product Description

Supelco
Glycine hydrochloride solution, 100 mM amino acid in 0.1 M HCl, analytical standard
Sigma-Aldrich
Glycine hydrochloride, ≥99% (HPLC)
Sigma-Aldrich
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