Advanced

Intravitreal delivery of AAV8 retinoschisin results in cell type-specific gene expression and retinal rescue in the Rs1-KO mouse

Park, T K; Wu, Z; Kjellstrom, S LU ; Zeng, Yong; Bush, Ronald A; Sieving, P A and Colosi, Peter (2009) In Gene Therapy 16(7). p.26-916
Abstract

X-linked juvenile retinoschisis (XLRS) is a neurodevelopmental abnormality caused by retinoschisin gene mutations. XLRS is characterized by splitting through the retinal layers and impaired synaptic transmission of visual signals resulting in impaired acuity and a propensity to retinal detachment. Several groups have treated murine retinoschisis models successfully using adeno-associated virus (AAV) vectors. Owing to the fragile nature of XLRS retina, translating this therapy to the clinic may require an alternative to invasive subretinal vector administration. Here we show that all layers of the retinoschisin knockout (Rs1-KO) mouse retina can be transduced efficiently with AAV vectors administered by simple vitreous injection.... (More)

X-linked juvenile retinoschisis (XLRS) is a neurodevelopmental abnormality caused by retinoschisin gene mutations. XLRS is characterized by splitting through the retinal layers and impaired synaptic transmission of visual signals resulting in impaired acuity and a propensity to retinal detachment. Several groups have treated murine retinoschisis models successfully using adeno-associated virus (AAV) vectors. Owing to the fragile nature of XLRS retina, translating this therapy to the clinic may require an alternative to invasive subretinal vector administration. Here we show that all layers of the retinoschisin knockout (Rs1-KO) mouse retina can be transduced efficiently with AAV vectors administered by simple vitreous injection. Retinoschisin expression was restricted to the neuroretina using a new vector that uses a 3.5-kb human retinoschisin promoter and an AAV type 8 capsid. Intravitreal administration to Rs1-KO mice resulted in robust retinoschisin expression with a retinal distribution similar to that observed in wild-type retina, including the expression by the photoreceptors lying deep in the retina. No off-target expression was observed. Rs1-KO mice treated with this vector showed a decrease in the schisis cavities and had improved retinal signaling evaluated by recording the electroretinogram 11-15 weeks after the application.

(Less)
Please use this url to cite or link to this publication:
author
publishing date
type
Contribution to journal
publication status
published
keywords
Animals, Dependovirus, Disease Models, Animal, Electroretinography, Eye Proteins, Fluorescent Antibody Technique, Gene Expression, Gene Transfer Techniques, Genetic Therapy, Genetic Vectors, Green Fluorescent Proteins, Humans, Injections, Intraocular, Male, Mice, Mice, Knockout, Promoter Regions, Genetic, Retina, Retinoschisis, Transfection, Evaluation Studies, Journal Article
in
Gene Therapy
volume
16
issue
7
pages
11 pages
publisher
Nature Publishing Group
external identifiers
  • scopus:67749111389
ISSN
0969-7128
DOI
10.1038/gt.2009.61
language
English
LU publication?
no
id
3d149304-3e20-43e2-b4c9-f85abd03e4c5
date added to LUP
2017-04-14 08:29:16
date last changed
2017-10-08 05:01:00
@article{3d149304-3e20-43e2-b4c9-f85abd03e4c5,
  abstract     = {<p>X-linked juvenile retinoschisis (XLRS) is a neurodevelopmental abnormality caused by retinoschisin gene mutations. XLRS is characterized by splitting through the retinal layers and impaired synaptic transmission of visual signals resulting in impaired acuity and a propensity to retinal detachment. Several groups have treated murine retinoschisis models successfully using adeno-associated virus (AAV) vectors. Owing to the fragile nature of XLRS retina, translating this therapy to the clinic may require an alternative to invasive subretinal vector administration. Here we show that all layers of the retinoschisin knockout (Rs1-KO) mouse retina can be transduced efficiently with AAV vectors administered by simple vitreous injection. Retinoschisin expression was restricted to the neuroretina using a new vector that uses a 3.5-kb human retinoschisin promoter and an AAV type 8 capsid. Intravitreal administration to Rs1-KO mice resulted in robust retinoschisin expression with a retinal distribution similar to that observed in wild-type retina, including the expression by the photoreceptors lying deep in the retina. No off-target expression was observed. Rs1-KO mice treated with this vector showed a decrease in the schisis cavities and had improved retinal signaling evaluated by recording the electroretinogram 11-15 weeks after the application.</p>},
  author       = {Park, T K and Wu, Z and Kjellstrom, S and Zeng, Yong and Bush, Ronald A and Sieving, P A and Colosi, Peter},
  issn         = {0969-7128},
  keyword      = {Animals,Dependovirus,Disease Models, Animal,Electroretinography,Eye Proteins,Fluorescent Antibody Technique,Gene Expression,Gene Transfer Techniques,Genetic Therapy,Genetic Vectors,Green Fluorescent Proteins,Humans,Injections, Intraocular,Male,Mice,Mice, Knockout,Promoter Regions, Genetic,Retina,Retinoschisis,Transfection,Evaluation Studies,Journal Article},
  language     = {eng},
  number       = {7},
  pages        = {26--916},
  publisher    = {Nature Publishing Group},
  series       = {Gene Therapy},
  title        = {Intravitreal delivery of AAV8 retinoschisin results in cell type-specific gene expression and retinal rescue in the Rs1-KO mouse},
  url          = {http://dx.doi.org/10.1038/gt.2009.61},
  volume       = {16},
  year         = {2009},
}