Retinitis pigmentosa (RP) is a group of diseases in which one of hundreds of different mutations leads to death of rods resulting in night blindness followed by gradual death of cones causing constriction of visual fields and eventual blindness. The loss of rods results in elevated levels of oxygen in the outer retina and during the current grant period, we demonstrated that this is accompanied by progressive oxidative damage in cones causing reduced function and cell death. Using a transgenic approach, we demonstrated that over-expression of components of the endogenous antioxidant defense system in mouse models of RP can reduce oxidative damage and promote cone function and survival, but only if there is co- expression of a superoxide dismutase (SOD) and a H2O2-detoxifying enzyme in mitochondria or in the cytosol. This suggests that in the setting of RP, there are excessive reactive oxygen species (ROS) in both the cytosol and mitochondria and also indicates that in order to utilize ROS-detoxifying enzymes to treat RP, multi- gene transfer will be needed. We began translating our findings into a gene-based therapy for RP by identifying a viral vector/promoter combination that transduces photoreceptors after subretinal or intravitreous injections in mice or pigs and we initiated studies with therapeutic transgenes in mouse and pig models of RP. During the next grant period we use quantitative techniques to assess the effect of multi- gene transfer on the expression of individual component transgenes. We will continue our current experiments in both mouse and pig models of RP that will answer whether targeting the mitochondria or cytosol with multi-gene transfer provides greater cone rescue. Finally we will determine whether targeting both the mitochondrial and cytosolic compartments provides better outcomes than targeting either alone. The potential impact of this proposal is high because it will provide important new information regarding multi-gene transfer that will interest all investigator in the gene therapy field, and most importantly will provide critical efficacy data in a large animl model of RP that could lead to clinical trials.

Public Health Relevance

This project seeks to develop a gene-based treatment to prevent cone cell death in patients with retinitis pigmentosa (RP) by augmenting the endogenous antioxidant defense system. RP is a group of diseases in which hundreds of different mutations lead to rod cell death followed by progressive oxidative damage to cones and eventual blindness. This treatment which targets cones will apply to all patients with RP regardless of the underlying mutation and therefore could remedy a large unmet medical need providing major public health impact.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
2R01EY005951-26
Application #
8297476
Study Section
Special Emphasis Panel (ZRG1-BDPE-N (09))
Program Officer
Shen, Grace L
Project Start
1985-09-30
Project End
2015-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
26
Fiscal Year
2012
Total Cost
$616,356
Indirect Cost
$197,055
Name
Johns Hopkins University
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
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Usui, Shinichi; Oveson, Brian C; Iwase, Takeshi et al. (2011) Overexpression of SOD in retina: need for increase in H2O2-detoxifying enzyme in same cellular compartment. Free Radic Biol Med 51:1347-54
Usui, Shinichi; Komeima, Keiichi; Lee, Sun Young et al. (2009) Increased expression of catalase and superoxide dismutase 2 reduces cone cell death in retinitis pigmentosa. Mol Ther 17:778-86
Usui, Shinichi; Oveson, Brian C; Lee, Sun Young et al. (2009) NADPH oxidase plays a central role in cone cell death in retinitis pigmentosa. J Neurochem 110:1028-37
Lu, Lili; Oveson, Brain C; Jo, Young-Joon et al. (2009) Increased expression of glutathione peroxidase 4 strongly protects retina from oxidative damage. Antioxid Redox Signal 11:715-24
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