AAV-mediated gene therapy in Dystrophin-Dp71 deficient mouse leads to blood-retinal barrier restoration and oedema reabsorption.
Dystrophin-Dp71 being a key membrane cytoskeletal protein, expressed mainly in Müller cells that provide a mechanical link at the Müller cell membrane by direct binding to actin and a transmembrane protein complex. Its absence has been related to blood-retinal barrier (BRB) permeability through delocalization and down-regulation of the AQP4 and Kir4.1 channels (1). We have previously shown that the adeno-associated virus (AAV) variant, ShH10, transduces Müller cells in the Dp71-null mouse retina efficiently and specifically (2,3). Here, we use ShH10 to restore Dp71 expression in Müller cells of Dp71 deficient mouse to study molecular and functional effects of this restoration in an adult mouse displaying retinal permeability. We show that strong and specific expression of exogenous Dp71 in Müller cells leads to correct localization of Dp71 protein restoring all protein interactions in order to re-establish a proper functional BRB and retina homeostasis thus preventing retina from oedema. This study is the basis for the development of new therapeutic strategies in dealing with diseases with BRB breakdown and macular oedema such as diabetic retinopathy (DR).
Sorbonne Universités, UPMC Univ Paris 06, INSERM, CNRS, Institut de la Vision, 75012 Paris, France ophelie.vacca@gmail.com.|Neuroscience Paris-Saclay Institute (NeuroPSI)-CNRS UMR 9197-Université Paris-Sud, Cognition & Behavior, 91405 Orsay cedex, France.
Ophélie
O
Vacca
Sorbonne Universités, UPMC Univ Paris 06, INSERM, CNRS, Institut de la Vision, 75012 Paris, France.
Hugo
H
Charles-Messance
Sorbonne Universités, UPMC Univ Paris 06, INSERM, CNRS, Institut de la Vision, 75012 Paris, France.
Brahim
B
El Mathari
Department of Ophthalmology, Therapeutic, Saint Louis, MO 63103, USA.
Abdoulaye
A
Sene
Sorbonne Universités, UPMC Univ Paris 06, INSERM, CNRS, Institut de la Vision, 75012 Paris, France.
Peggy
P
Barbe
Sorbonne Universités, UPMC Univ Paris 06, INSERM, CNRS, Institut de la Vision, 75012 Paris, France.
Stéphane
S
Fouquet
Sorbonne Universités, UPMC Univ Paris 06, INSERM, CNRS, Institut de la Vision, 75012 Paris, France.|Department of Genetics & Molecular Biology, CINVESTAV: Research Centre for Advanced Studies, IPN, C.P. 07360 México.
Jorge
J
Aragón
Sorbonne Universités, UPMC Univ Paris 06, INSERM, CNRS, Institut de la Vision, 75012 Paris, France.
Marie
M
Darche
Sorbonne Universités, UPMC Univ Paris 06, INSERM, CNRS, Institut de la Vision, 75012 Paris, France.|Ophthalmology Department, Avicenne Hospital, 93000 Bobigny, France.
Audrey
A
Giocanti-Aurégan
Sorbonne Universités, UPMC Univ Paris 06, INSERM, CNRS, Institut de la Vision, 75012 Paris, France.|CHNO des Quinze-Vingts, DHU Sight Restore, INSERM-DHOS CIC, 75012 Paris, France.
Michel
M
Paques
Sorbonne Universités, UPMC Univ Paris 06, INSERM, CNRS, Institut de la Vision, 75012 Paris, France.|CHNO des Quinze-Vingts, DHU Sight Restore, INSERM-DHOS CIC, 75012 Paris, France.
José-Alain
JA
Sahel
Sorbonne Universités, UPMC Univ Paris 06, INSERM, CNRS, Institut de la Vision, 75012 Paris, France.|Ophthalmology Dept, Hôpital Lariboisière, AP-HP, Univ Paris Diderot, 75010 Paris, France.
Ramin
R
Tadayoni
Department of Genetics & Molecular Biology, CINVESTAV: Research Centre for Advanced Studies, IPN, C.P. 07360 México.
Cecilia
C
Montañez
Sorbonne Universités, UPMC Univ Paris 06, INSERM, CNRS, Institut de la Vision, 75012 Paris, France.
Deniz
D
Dalkara
Sorbonne Universités, UPMC Univ Paris 06, INSERM, CNRS, Institut de la Vision, 75012 Paris, France.
Alvaro
A
Rendon
D000818:Animals; D001813:Blood-Retinal Barrier / Q000187:drug effects*; D000229:Dependovirus / Q000235:genetics; D016189:Dystrophin / Q000172:deficiency / Q000235:genetics* / Q000627:therapeutic use; D004487:Edema / Q000235:genetics / Q000628:therapy*; D063928:Ependymoglial Cells / Q000187:drug effects / Q000378:metabolism; D015316:Genetic Therapy; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D012160:Retina / Q000254:growth & development / Q000473:pathology
D016189:Dystrophin; C085339:apo-dystrophin 1