Macular Degeneration Research - Completed Award

Summary:

The goal of this proposal is to determine whether the iron binding drugs SIH and BSIH, which are very effective in protecting cultured retinal cells, will be similarly protective in living animals. To this end, we will test the drugs in our Cp/Heph iron overload-induced model of AMD, which is a mouse that possesses a number of eye features in common with human AMD.

Details:

Potential benefit for AMD patients: This line of research represents a novel therapeutic area for AMD. Patients with AMD have elevated retinal iron levels, which may increase oxidative damage. We have found recently that the cell-permeable iron binding drugs SIH and BSIH protect cultured retinal cells against oxidant induced cell death. We now propose to test SIH and BSIH for their ability to decrease retinal iron overload and protect against retinal degeneration in our Cp/Heph double gene knockout mouse model.

Specific Aim1: To determine whether SIH and BSIH can decrease retinal iron levels when administered systemically or by eye drops in mice.

Specific Aim2: To determine whether SIH and BSIH will protect the Cp/Heph mice from retinal degeneration.

If SIH and/or BSIH prove non-toxic and effective for prevention of retinal degeneration, this will provide proof-of-principle for the possibility that SIH or similar iron binding drugs could, after further testing, be used to reduce the risk of vision loss in patients with early AMD.

Publications:

Hadziahmetovic M, Song Y, Wolkow N, Iacovelli J, Kautz L, Roth MP, Dunaief JL. Am J Pathol. Bmp6 regulates retinal iron homeostasis and has altered expression in age-related macular degeneration. 2011 Jul;179(1):335-48. Epub 2011 May 3.

Iacovelli J, Zhao C, Wolkow N, Veldman P, Gollomp K, Ojha P, Lukinova N, King A, Feiner L, Esumi N, Zack DJ, Pierce EA, Vollrath D, Dunaief JL. Generation of Cre transgenic mice with postnatal RPE-specific ocular expression. Invest Ophthalmol Vis Sci. 2011 Mar 14;52(3):1378-83. Print 2011 Mar.

Hadziahmetovic M, Song Y, Wolkow N, Iacovelli J, Grieco S, Lee J, Lyubarsky A, Pratico D, Connelly J, Spino M, Harris ZL, Dunaief JL. The oral iron chelator deferiprone protects against iron overload-induced retinal degeneration. Invest Ophthalmol Vis Sci. 2011 Feb 16;52(2):959-68. Print 2011 Feb.

Hadziahmetovic M, Song Y, Ponnuru P, Iacovelli J, Hunter A, Haddad N, Beard J, Connor JR, Vaulont S, Dunaief JL. Age-dependent retinal iron accumulation and degeneration in hepcidin knockout mice. Invest Ophthalmol Vis Sci. 2011 Jan 5;52(1):109-18. Print 2011 Jan.

Progress Updates:

Patients with age-related macular degeneration (AMD) have elevated retinal iron levels, which may increase oxidative damage. This type of damage is common to aging cells, and may be prevented by “nutritional antioxidants.” Therefore, this line of research represents a novel therapeutic area for AMD.

Dr. Joshua Dunaief and collaborators have found that two iron-binding drugs, called SIH and BSIH, are able to cross the cell membrane and protect cultured retinal cells from oxidant-induced death. These researchers tested SIH and BSIH for their ability to decrease retinal iron overload and protect against retinal degeneration in a genetically modified line of mice which have features of AMD. BSIH reduced the iron buildup in the eyes of these mice. However, both BSIH and SIH did not protect against retinal degeneration. In contrast, a third iron-binding drug markedly protected against retinal degeneration. This provides proof-of-principle that iron-binding drugs could, after further testing, be used to reduce the risk of vision loss in patients with AMD. Dr. Dunaief will now be able to focus his retina-protective therapeutic research on this third iron‐binding drug.