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Bin Lin, Ke Wang, Moussa B. Youdim; Long-term Preservation Of Cone Photoreceptors By A Novel Multifunctional Drug In A Mouse Model Of Human Retinitis Pigmentosa. Invest. Ophthalmol. Vis. Sci. 2012;53(14):6461.
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Degeneration of retinal photoreceptors is a leading cause of untreatable blindness, affecting more than two million people worldwide every year. One of the most common causes of inherited photoreceptor degeneration is retinitis pigmentosa (RP). This disorder typically is characterized by an initial loss of rod photoreceptors. Cone photoreceptors, however, die progressively, even though cones do not express a mutated protein. This secondary event leads to central vision loss and potentially complete blindness. There are currently no clinically effective treatments for RP. Therapies aimed to preserve the cone function may thus be a very effective alternative for improving the quality of life of many RP patients. Here, we apply an innovative ‘one-drug-multiple-targets’ therapeutic approach to prevent the secondary cone death by targeting multiple pathological pathways that eventually lead to photoreceptor death.
A multifunctional compound M30 [5-(N-methyl-Npropargyaminomethyl)-8-hydroxyquinoline], a nontoxic brain-permeable iron chelator, exerts multiple pharmacological activities against Parkinson’s and Alzhermer’s diseases. We hypothesized that M30 might provide significant preservation of retinal photoreceptor function by blocking multiple pathways of photoreceptor death in rd1 mice, an animal model of RP. The delivery of M30 into eyes was achieved either by a single injection of the drug into subretinal space of the eye, or by systemic administration, starting from P7, the time point at which rod degeneration begins. The anatomical and physiological measurements were designed to evaluate the long-term survival of the cones promoted by M30.
After one week treatment, the ONL was largely maintained in M30 treated eyes relative to that seen in the WT. Only a half of nuclei remained in the ONL of untreated eyes indicating loss of rods. Cones appeared to have normal outer segment (OS) and inner segment (IS) in M30 treated eyes compared to WT, while cones in PBS treated eyes lost both OS and IS. By P49, M30-treated eyes appeared to have greater cone density compared to PBS-treated mice. M30 also helped to preserve mRNA synthesis in rods and cones. Electroretinogram (ERG) and optomotor behavior tests showed M30 treatment preserved not only retinal structure but also retinal function.
M30 treatment provides long-term benefit to the retina by significantly reducing rod and cone cell death, and slowing loss of rod-specific and cone-specific mRNAs in the retina of rd1 mice.
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