title: Solid lipid nanoparticle-based vectors intended for the treatment of X-linked juvenile retinoschisis by gene therapy: In vivo approaches in Rs1h-deficient mouse model.
abstract: X-linked juvenile retinoschisis (XLRS), which results from mutations in the gene RS1 that encodes the protein retinoschisin, is a retinal degenerative disease affecting between 1/5000 and 1/25,000 people worldwide. Currently, there is no cure for this disease and the treatment is based on the application of low-vision aids. The aim of the present work was the in vitro and in vivo evaluation of two different non-viral vectors based on solid lipid nanoparticles (SLNs), protamine and two anionic polysaccharides, hyaluronic acid (HA) or dextran (DX), for the treatment of XLRS. First, the vectors containing a plasmid which encodes both the reporter green fluorescent protein (GFP) and the therapeutic protein retinoschisin, under the control of CMV promoters, were characterized in vitro. Then, the vectors were subretinally or intravitreally administrated to C57BL/6 wild type mice. One week later, GFP was detected in all treated mice and in all retinal layers except in the Outer Nuclear Layer (ONL) and the Inner Nuclear Layer (INL), regardless of the administration route and the vector employed. Finally, two weeks after subretinal or intravitreal injection to Rs1h-deficient mice, GFP and retinoschisin expression was detected in all retinal layers, except in the ONL, which was maintained for at least two months after subretinal administration. The structural analysis of the treated Rs1h-deficient eyes showed a partial recovery of the retina related to the production of retinoschisin. This work shows for the first time a successful RS1 gene transfer to Rs1h-deficient animals using non-viral nanocarriers, with promising results that point to non-viral gene therapy as a feasible future therapeutic tool for retinal disorders.
authors.affiliation: Pharmacokinetic, Nanotechnology and Gene Therapy Group (PharmaNanoGene), Faculty of Pharmacy, Centro de investigación Lascaray ikergunea, University of the Basque Country UPV/EHU, Paseo de la Universidad 7, 01006 Vitoria-Gasteiz, Spain.
authors.forename: P S
authors.initials: PS
authors.lastname: Apaolaza
authors.affiliation: Pharmacokinetic, Nanotechnology and Gene Therapy Group (PharmaNanoGene), Faculty of Pharmacy, Centro de investigación Lascaray ikergunea, University of the Basque Country UPV/EHU, Paseo de la Universidad 7, 01006 Vitoria-Gasteiz, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Del Pozo-Rodríguez
authors.affiliation: Pharmacokinetic, Nanotechnology and Gene Therapy Group (PharmaNanoGene), Faculty of Pharmacy, Centro de investigación Lascaray ikergunea, University of the Basque Country UPV/EHU, Paseo de la Universidad 7, 01006 Vitoria-Gasteiz, Spain.
authors.forename: J
authors.initials: J
authors.lastname: Torrecilla
authors.affiliation: Pharmacokinetic, Nanotechnology and Gene Therapy Group (PharmaNanoGene), Faculty of Pharmacy, Centro de investigación Lascaray ikergunea, University of the Basque Country UPV/EHU, Paseo de la Universidad 7, 01006 Vitoria-Gasteiz, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Rodríguez-Gascón
authors.affiliation: Physiology Laboratory, Faculty of Pharmacy, University of the Basque Country UPV/EHU, Paseo de la Universidad 7, 01006 Vitoria-Gasteiz, Spain.
authors.forename: J M
authors.initials: JM
authors.lastname: Rodríguez
authors.affiliation: Institute of Human Genetics, University of Regensburg, Franz-Josef-Strauss-Allee 11, 93053 Regensburg, Germany.
authors.forename: U
authors.initials: U
authors.lastname: Friedrich
authors.affiliation: Institute of Human Genetics, University of Regensburg, Franz-Josef-Strauss-Allee 11, 93053 Regensburg, Germany.
authors.forename: B H F
authors.initials: BH
authors.lastname: Weber
authors.affiliation: Pharmacokinetic, Nanotechnology and Gene Therapy Group (PharmaNanoGene), Faculty of Pharmacy, Centro de investigación Lascaray ikergunea, University of the Basque Country UPV/EHU, Paseo de la Universidad 7, 01006 Vitoria-Gasteiz, Spain. Electronic address: marian.solinis@ehu.eus.
authors.forename: M A
authors.initials: MA
authors.lastname: Solinís
mesh_terms: D000818:Animals; D015815:Cell Adhesion Molecules / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D002460:Cell Line; D004247:DNA / Q000378:metabolism; D005136:Eye Proteins / Q000235:genetics* / Q000378:metabolism; D015316:Genetic Therapy / Q000379:methods*; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008055:Lipids / Q000008:administration & dosage / Q000737:chemistry; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D053758:Nanoparticles / Q000008:administration & dosage / Q000737:chemistry; D012160:Retina / Q000378:metabolism; D041441:Retinoschisis / Q000628:therapy*
chemical_list: D015815:Cell Adhesion Molecules; D005136:Eye Proteins; D008055:Lipids; C491843:RS1 protein, mouse; D049452:Green Fluorescent Proteins; D004247:DNA
keywords: Dextran; Gene therapy; Hyaluronic acid; Non-viral vector; Solid lipid nanoparticles; X-linked juvenile retinoschisis