Open AccessNovel AAV capsids for intravitreal gene therapy of photoreceptor disorders
Author(s) -
Pavlou Marina,
Schön Christian,
Occelli Laurence M,
Rossi Axel,
Meumann Nadja,
Boyd Ryan F,
Bartoe Joshua T,
Siedlecki Jakob,
Gerhardt Maximilian J,
Babutzka Sabrina,
Bogedein Jacqueline,
Wagner Johanna E,
Priglinger Siegfried G,
Biel Martin,
PetersenJones Simon M,
Büning Hildegard,
Michalakis Stylianos
Publication year - 2021
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.15252/emmm.202013392
Subject(s) - transduction (biophysics) , genetic enhancement , achromatopsia , gene delivery , retinal , biology , viral vector , adeno associated virus , retina , retinal disorder , microbiology and biotechnology , vector (molecular biology) , neuroscience , recombinant dna , gene , genetics , biochemistry
Gene therapy using recombinant adeno‐associated virus (rAAV) vectors to treat blinding retinal dystrophies has become clinical reality. Therapeutically impactful targeting of photoreceptors still relies on subretinal vector delivery, which detaches the retina and harbours substantial risks of collateral damage, often without achieving widespread photoreceptor transduction. Herein, we report the development of novel engineered rAAV vectors that enable efficient targeting of photoreceptors via less invasive intravitreal administration. A unique in vivo selection procedure was performed, where an AAV2‐based peptide‐display library was intravenously administered in mice, followed by isolation of vector DNA from target cells after only 24 h. This stringent selection yielded novel vectors, termed AAV2.GL and AAV2.NN, which mediate widespread and high‐level retinal transduction after intravitreal injection in mice, dogs and non‐human primates. Importantly, both vectors efficiently transduce photoreceptors in human retinal explant cultures. As proof‐of‐concept, intravitreal Cnga3 delivery using AAV2.GL lead to cone‐specific expression of Cnga3 protein and rescued photopic cone responses in the Cnga3 −/− mouse model of achromatopsia. These novel rAAV vectors expand the clinical applicability of gene therapy for blinding human retinal dystrophies.