Prevention of retinal injury and degeneration by specific factors

Abstract

Photoreceptor injury or cell death (retinal degeneration) is prevented by the introduction into the living mammalian eye of specific, survival-promoting factors. These specific factors prevent damage and degeneration of photoreceptors when introduced into the living eye prior to, during or after exposure to the damaging effects of light and delay photoreceptor damage caused by inherited disease.

We claim:  
     
         1 . A method of reducing or preventing degeneration of retinal neurons in a mammal caused by exposure to light or other environmental trauma comprising administering to the mammal, prior to, during or following such exposure, a therapeutically effective dose of neurotrophic factor.  
     
     
         2 . The method of  claim 1  wherein said neurotrophic factor is brain derived neurotrophic factor, ciliary neurotrophic factor, neurotrophin-3 or a combination thereof.  
     
     
         3 . The method of  claim 2  wherein said retinal neurons are photoreceptors.  
     
     
         4 . The method of  claim 3  wherein said administration is intraocular.  
     
     
         5 . The method of  claim 4  wherein said administration is into the vitreous or into the subretinal (interphotoreceptor) space.  
     
     
         6 . The method of  claim 3  wherein said administration is systemic delivery.  
     
     
         7 . The method of  claim 6  wherein said neurotrophic factor has been modified in such a way as to increase its ability to be transported across the blood-retinal barrier.  
     
     
         8 . The method of  claim 7  wherein said modification comprises increasing the lipophilicity of the factor.  
     
     
         9 . The method of  claim 7  wherein said modification comprises glycosylation of the factor.  
     
     
         10 . The method of  claim 7  wherein said modification comprises increasing the net positive charge on said factor.  
     
     
         11 . The method of  claim 6  wherein said systemic delivery is by an oral route.  
     
     
         12 . The method of  claim 7  wherein said systemic delivery is by subcutaneous, intravenous or intramuscular injection.  
     
     
         13 . A method of preventing or reducing degeneration of retinal neurons in a mammal caused by exposure to light or other environmental trauma comprising administering to the mammal, prior to, during or following said exposure, a therapeutically effective dose of one or more factors selected from the group consisting of acidic fibroblast growth factor (aFGF), bFGF plus heparin, aFGF plus heparin, interleukin-1 beta (IL-1β) and tumor necrosis factor-alpha (TNF-α).  
     
     
         14 . The method of  claim 13  wherein said retinal neurons are photoreceptors.  
     
     
         15 . The method of  claim 14  wherein said administration is intraocular.  
     
     
         16 . The method of  claim 15  wherein said administration is into the vitreous or into the subretinal (interphotoreceptor) space.  
     
     
         17 . The method of  claim 14  wherein said administration is delivered systemically.  
     
     
         18 . The method of  claim 17  wherein said systemic delivery is by an oral route.  
     
     
         19 . The method of  claim 18  wherein said systemic delivery is by subcutaneous, intravenous or intramuscular injection.  
     
     
         20 . A method of reducing or preventing degeneration of retinal neurons in a mammal having a pathological condition wherein retinal degeneration occurs, comprising administering to said mammal a therapeutically effective dose of a neurotrophic factor.  
     
     
         21 . The method of  claim 20  wherein said pathological condition is retinal detachment, age-related or other maculopathies, photic retinopathies, surgery-induced retinopathies (either mechanically or light-induced), toxic retinopathies, diabetic retinopathies, retinopathy of prematurity, viral retinopathies such as CMV or HIV retinopathy related to AIDS; uveitis; ischemic retinopathies due to venous or arterial occlusion or other vascular disorder, retinopathies due to trauma or penetrating lesions of the eye, peripheral vitreoretinopathy or inherited retinal degenerations.  
     
     
         22 . The method of  claim 21  wherein said neurotrophic factor is brainderived neurotrophic factor, ciliary neurotrophic factor, neurotrophin-3 or a combination thereof.  
     
     
         23 . The method of  claim 22  wherein said retinal neurons are photoreceptors.  
     
     
         24 . The method of  claim 23  wherein said administration is intraocular.  
     
     
         25 . The method of  claim 24  wherein said administration is into the vitreous or into the subretinal (interphotoreceptor) space.  
     
     
         26 . The method of  claim 23  wherein said administration is by systemic delivery.  
     
     
         27 . The method of  claim 26  wherein said systemic delivery is by an oral route.  
     
     
         28 . The method of  claim 27  wherein said systemic delivery is by subcutaneous, intravenous or intramuscular injection.  
     
     
         29 . A method of reducing or preventing degeneration of retinal neurons in a mammal having a pathological condition wherein retinal degeneration occurs, comprising administering to said mammal a therapeutically effective dose of one or more factors selected from the group consisting of acidic fibroblast growth factor (aFGF), bFGF plus heparin, aFGF plus heparin, IL-1β, TNF-α and IGF-2.  
     
     
         30 . The method of  claim 29  wherein said retinal neurons are photoreceptors.  
     
     
         31 . The method of  claim 30  wherein said administration is intraocular.  
     
     
         32 . The method of  claim 31  wherein said administration is into the vitreous or into the subretinal (interphotoreceptor) space.  
     
     
         33 . The method of  claim 30  wherein said administration is systemic delivery.  
     
     
         34 . The method of  claim 33  wherein said systemic delivery is by an oral route.  
     
     
         35 . The method of  claim 34  wherein said systemic delivery is by subcutaneous, intravenous or intramuscular injection.  
     
     
         36 . A method of assessing the survival-promoting ability of an agent on retinal neurons or photoreceptors comprising 
 (i) injecting the agent intravitreally into an albino mammal eye, prior to, during, or after exposure of the mammal to continuous light,    (ii) evaluating the injected eye for degeneration of retinal neurons or photoreceptors as compared to a control eye exposed to the same light in the absence of injection of the agent;    wherein decreased retinal degeneration as compared to the control eye correlates positively with survival-promoting ability of the agent.    
     
     
         37 . The method of  claim 36  wherein said mammal is a rat.  
     
     
         38 . The method of  claim 36  wherein said control eye is in the same mammal as the intravitreally injected eye.