title: Preclinical safety evaluation of a recombinant AAV8 vector for X-linked retinoschisis after intravitreal administration in rabbits.
abstract: X-linked retinoschisis (XLRS) is a retinal disease caused by mutations in the gene encoding the protein retinoschisin (RS1) and one of the most common causes of macular degeneration in young men. Currently, no FDA-approved treatments are available for XLRS and a replacement gene therapy could provide a promising strategy. We have developed a novel gene therapy approach for XLRS, based on the administration of AAV8-scRS/IRBPhRS, an adeno-associated viral vector coding the human RS1 protein, via the intravitreal route. On the basis of our prior study in an Rs1-KO mouse, this construct transduces efficiently all the retinal layers, resulting in an RS1 expression similar to that observed in the wild-type and improving retinal structure and function. In support of a clinical trial, we carried out a study to evaluate the ocular safety of intravitreal administration of AAV8-scRS/IRBPhRS into 39 New Zealand White rabbits. Two dose levels of vector, 2e(10) and 2e(11) vector genomes per eye (vg/eye), were tested and ocular inflammation was monitored over a 12-week period by serial ophthalmological and histopathological analysis. A mild ocular inflammatory reaction, consisting mainly of vitreous infiltrates, was observed within 4 weeks from injection, in both 2e(10) and 2e(11) vg/eye groups and was likely driven by the AAV8 capsid. At 12-week follow-up, ophthalmological examination revealed no clinical signs of vitreitis in either of the dose groups. However, while vitreous inflammatory infiltrate was significantly reduced in the 2e(10) vg/eye group at 12 weeks, some rabbits in the higher dose group still showed persistence of inflammatory cells, histologically. In conclusion, intravitreal administration of AAV8-scRS/IRBPhRS into the rabbit eye produces a mild and transient intraocular inflammation that resolves, at a 2e(10) vg/eye dose, within 3 months, and does not cause irreversible tissue damages. These data support the initiation of a clinical trial of intravitreal administration of AAV8-scRS/IRBPhRS in XLRS patients.
authors.affiliation: 1 National Institute on Deafness and Other Communication Disorders, National Institutes of Health , Bethesda, MD 20892.
authors.forename: Dario
authors.initials: D
authors.lastname: Marangoni
authors.forename: Zhijian
authors.initials: Z
authors.lastname: Wu
authors.forename: Henry E
authors.initials: HE
authors.lastname: Wiley
authors.forename: Caroline J
authors.initials: CJ
authors.lastname: Zeiss
authors.forename: Camasamudram
authors.initials: C
authors.lastname: Vijayasarathy
authors.forename: Yong
authors.initials: Y
authors.lastname: Zeng
authors.forename: Suja
authors.initials: S
authors.lastname: Hiriyanna
authors.forename: Ronald A
authors.initials: RA
authors.lastname: Bush
authors.forename: Lisa L
authors.initials: LL
authors.lastname: Wei
authors.forename: Peter
authors.initials: P
authors.lastname: Colosi
authors.forename: Paul A
authors.initials: PA
authors.lastname: Sieving
mesh_terms: D000818:Animals; D004274:DNA, Recombinant / Q000008:administration & dosage / Q000009:adverse effects* / Q000235:genetics; D000229:Dependovirus / Q000235:genetics* / Q000378:metabolism; D005136:Eye Proteins / Q000235:genetics* / Q000378:metabolism; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage / Q000009:adverse effects* / Q000235:genetics; D058449:Intravitreal Injections; D011817:Rabbits; D041441:Retinoschisis / Q000628:therapy*
chemical_list: D004274:DNA, Recombinant; D005136:Eye Proteins; C108726:RS1 protein, human