RPE-Directed Gene Therapy Improves Mitochondrial Function in Murine Dry AMD Models
![Thumbnail](/themes/Mirage2/images/white_rectangle.jpeg)
File Type:
PDFItem Type:
Journal ArticleDate:
2023Access:
openAccessCitation:
Millington-Ward S, Chadderton N, Finnegan LK, Post IJM, Carrigan M, Nixon R, Humphries MM, Humphries P, Kenna PF, Palfi A, Farrar GJ. RPE-Directed Gene Therapy Improves Mitochondrial Function in Murine Dry AMD Models, International Journal of Molecular Sciences; 2023 Feb 14;24(4):3847Download Item:
Abstract:
Age-related macular degeneration (AMD) is the most common cause of blindness in the
aged population. However, to date there is no effective treatment for the dry form of the disease,
representing 85–90% of cases. AMD is an immensely complex disease which affects, amongst others,
both retinal pigment epithelium (RPE) and photoreceptor cells and leads to the progressive loss of
central vision. Mitochondrial dysfunction in both RPE and photoreceptor cells is emerging as a key
player in the disease. There are indications that during disease progression, the RPE is first impaired
and RPE dysfunction in turn leads to subsequent photoreceptor cell degeneration; however, the exact
sequence of events has not as yet been fully determined. We recently showed that AAV delivery of an
optimised NADH-ubiquinone oxidoreductase (NDI1) gene, a nuclear-encoded complex 1 equivalent
from S. cerevisiae, expressed from a general promoter, provided robust benefit in a variety of murine
and cellular models of dry AMD; this was the first study employing a gene therapy to directly
boost mitochondrial function, providing functional benefit in vivo. However, use of a restricted RPE specific promoter to drive expression of the gene therapy enables exploration of the optimal target
retinal cell type for dry AMD therapies. Furthermore, such restricted transgene expression could
reduce potential off-target effects, possibly improving the safety profile of the therapy. Therefore,
in the current study, we interrogate whether expression of the gene therapy from the RPE-specific
promoter, Vitelliform macular dystrophy 2 (VMD2), might be sufficient to rescue dry AMD models
Sponsor
Grant Number
Science Foundation Ireland
16/IA/4452
Author's Homepage:
http://people.tcd.ie/gjfarrarhttp://people.tcd.ie/phumphrs
http://people.tcd.ie/pfkenna
http://people.tcd.ie/mhumphri
Type of material:
Journal ArticleCollections
Series/Report no:
International Journal of Molecular Sciences;24;
4;
Availability:
Full text availableKeywords:
AMD models, gene therapy, retina, BEST1, Mitochondria, Promoter, Age-related macular degeneration, Retina, AAV, RPE, VMD2DOI:
http://dx.doi.org/10.3390/ijms24043847Metadata
Show full item recordLicences: