In vivo genome editing as a potential treatment strategy for inherited retinal dystrophies.
In vivo genome editing represents an emerging field in the treatment of monogenic disorders, as it may constitute a solution to the current hurdles in classic gene addition therapy, which are the low levels and limited duration of transgene expression. Following the introduction of a double strand break (DSB) at the mutational site by highly specific endonucleases, such as TALENs (transcription activator like effector nucleases) or RNA based nucleases (clustered regulatory interspaced short palindromic repeats - CRISPR-Cas), the cell's own DNA repair machinery restores integrity to the DNA strand and corrects the mutant sequence, thus allowing the cell to produce protein levels as needed. The DNA repair happens either through the error prone non-homologous end-joining (NHEJ) pathway or with high fidelity through homology directed repair (HDR) in the presence of a DNA donor template. A third pathway called microhomology mediated endjoining (MMEJ) has been recently discovered. In this review, the authors focus on the different DNA repair mechanisms, the current state of the art tools for genome editing and the particularities of the retina and photoreceptors with regard to in vivo therapeutic approaches. Finally, current attempts in the field of retinal in vivo genome editing are discussed and future directions of research identified.
Department of Ophthalmology, Faculty of Medicine, Justus-Liebig-University Giessen, Germany.
Mert
M
Yanik
Department of Ophthalmology, Faculty of Medicine, Justus-Liebig-University Giessen, Germany.
Brigitte
B
Müller
Department of Ophthalmology, Faculty of Medicine, Justus-Liebig-University Giessen, Germany.
Fei
F
Song
Department of Ophthalmology, Faculty of Medicine, Justus-Liebig-University Giessen, Germany.
Jacqueline
J
Gall
Department of Ophthalmology, Faculty of Medicine, Justus-Liebig-University Giessen, Germany.
Franziska
F
Wagner
Institute of Biochemistry, Faculty of Biology and Chemistry, Justus-Liebig-University Giessen, Germany.
Wolfgang
W
Wende
Department of Ophthalmology, Faculty of Medicine, Justus-Liebig-University Giessen, Germany.
Birgit
B
Lorenz
Department of Ophthalmology, Faculty of Medicine, Justus-Liebig-University Giessen, Germany. Electronic address: knut.stieger@uniklinikum-giessen.de.
Knut
K
Stieger
D000818:Animals; D000072669:Gene Editing / Q000379:methods*; D015316:Genetic Therapy / Q000379:methods*; D016678:Genome; D006801:Humans; D017410:Practice Guidelines as Topic; D058499:Retinal Dystrophies / Q000235:genetics / Q000378:metabolism / Q000628:therapy
AAV; CRISPR-Cas; Endonucleases; Genome editing; HDR; In vivo; MMEJ; NHEJ; Retina; TALEN