Effectiveness of gene therapy for retinal degeneration verified

Effectiveness of gene therapy for retinal degeneration verified

Jan 16, 2013

Under the leadership of FURUKAWA Takahisa , Professor, Institute for Protein Research, Osaka University, a group of researchers have verified the effectiveness of gene therapy in experiments using mice with retinal pigment epithelium (RPE) degeneration.
Photoreceptor degeneration is one of the causes of blindness in the world, including Japan. It occurs in one in 3 ~ 4,000 people and is an incurable condition without effective treatment. The effectiveness of gene therapy for severe RPE degeneration has not been known. This group has identified the serum type of virus vector that is best for gene therapy. Using Crx KO mice with severe retinal degeneration, this group verified the effectiveness of the gene therapy. This group succeeded in the improvement of situations that had been observed in mice such as developmental, morphological, structural abnormalities of photoreceptor cells, retinal degeneration (apoptosis) and retinal dysfunction and mice were able to recognize light.
This group's achievements heighten the possibility of gene therapy for retinal degeneration.

Abstract

Background
Adeno-associated virus (AAV) is well established as a vehicle for in vivo gene transfer into the mammalian retina. This virus is promising not only for gene therapy of retinal diseases, but also for in vivo functional analysis of retinal genes. Previous reports have shown that AAV can infect various cell types in the developing mouse retina. However, AAV tropism in the developing retina has not yet been examined in detail.
Methodology/Principal Findings
We subretinally delivered seven AAV serotypes (AAV2/1, 2/2, 2/5, 2/8, 2/9, 2/10, and 2/11) of AAV-CAG-mCherry into P0 mouse retinas, and quantitatively evaluated the tropisms of each serotype by its infecting degree in retinal cells. After subretinal injection of AAV into postnatal day 0 (P0) mouse retinas, various retinal cell types were efficiently transduced with different AAVs. Photoreceptor cells were efficiently transduced with AAV2/5. Retinal cells, except for bipolar and Müller glial cells, were efficiently transduced with AAV2/9. Horizontal and/or ganglion cells were efficiently transduced with AAV2/1, AAV2/2, AAV2/8, AAV2/9 and AAV2/10. To confirm the usefulness of AAV-mediated gene transfer into the P0 mouse retina, we performed AAV-mediated rescue of the Cone-rod homeobox gene knockout (Crx KO) mouse, which exhibits an outer segment formation defect, flat electroretinogram (ERG) responses, and photoreceptor degeneration. We injected an AAV expressing Crx under the control of the Crx 2kb promoter into the neonatal Crx KO retina. We showed that AAV mediated-Crx expression significantly decreased the abnormalities of the Crx KO retina.
Conclusion/Significance
In the current study, we report suitable AAV tropisms for delivery into the developing mouse retina. Using AAV2/5 in photoreceptor cells, we demonstrated the possibility of gene replacement for the developmental disorder and subsequent degeneration of retinal photoreceptors caused by the absence of Crx.

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To learn more about this research, please read the full research report entitled "Tropisms of AAV for Subretinal Delivery to the Neonatal Mouse Retina and Its Application for In Vivo Rescue of Developmental Photoreceptor Disorders" at this page of the PLOS ONE website.

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