Effect of CNTF on Retinal Ganglion Cell Survival in Experimental Glaucoma

Pease, Mary Ellen; Zack, Donald J.; Berlinicke, Cynthia; Bloom, Kristen; Cone, Frances E.; Wang, Yuxia; Klein, Ronald L.; Hauswirth, William W.; Quigley, Harry A.

doi:10.1167/iovs.08-3013

Cited by 197 publications

(135 citation statements)

References 70 publications

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“…67 Four weeks after laser-induced ocular hypertension, there was a 15% increase in the number of RGC axons in eyes treated with AAV.CNTF compared with eyes treated with a control vector. 66 Adenoviral-mediated CNTF gene transfer was reported to increase retinal CNTF and CNTF receptor-a levels, which correlated with a 7% increase in the survival of axotomized RGCs. 45 Lentiviral-mediated CNTF gene transfer was also reported to enhance survival of axotomized RGCs.…”

Section: Cracking the Case: Gene Therapy Strategies For Rgc Neuroprotmentioning

confidence: 98%

“…Exogenous or endogenous CNTF protein has been shown to stimulate RGC survival after optic nerve axotomy or crush 63,64 in experimental glaucoma 65,66 and acute autoimmune optic neuritis. 67 Four weeks after laser-induced ocular hypertension, there was a 15% increase in the number of RGC axons in eyes treated with AAV.CNTF compared with eyes treated with a control vector.…”

Section: Cracking the Case: Gene Therapy Strategies For Rgc Neuroprotmentioning

confidence: 99%

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Gene therapy for retinal ganglion cell neuroprotection in glaucoma

Wilson

Polo

2011

Gene Ther

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Glaucoma is the leading cause of irreversible blindness worldwide. The primary cause of glaucoma is not known, but several risk factors have been identified, including elevated intraocular pressure and age. Loss of vision in glaucoma is caused by the death of retinal ganglion cells (RGCs), the neurons that convey visual information from the retina to the brain. Therapeutic strategies aimed at delaying or halting RGC loss, known as neuroprotection, would be valuable to save vision in glaucoma. In this review, we discuss the significant progress that has been made in the use of gene therapy to understand mechanisms underlying RGC degeneration and to promote the survival of these neurons in experimental models of optic nerve injury. Gene Therapy (2012) 19, 127-136; doi:10.1038/gt.2011; published online 6 October 2011Keywords: retinal ganglion cell; neuroprotection; glaucoma NEUROPROTECTION IN GLAUCOMA: RATIONALE AND CURRENT LIMITATIONS Adult-onset glaucoma is an optic neuropathy that affects more than 50 million people around the world, with 47 million having bilateral (both eyes) blindness due to this disease. As more effective diagnostic tools become available, the number of cases is expected to rise, and a recent study predicts that there will be 70 million people with glaucoma in 2020. 1 Glaucoma is considered to be a group of diseases characterized by progressive optic nerve degeneration that results in visual field loss and irreversible blindness. The cause of glaucoma is unknown, but several risk factors have been identified, including high intraocular pressure, age and genetic predisposition. Open angle and angle-closure glaucoma, the most common forms of the disease, are often associated with high intraocular pressure. A crucial element in the pathophysiology of all forms of glaucoma is the death of retinal ganglion cells (RGCs; Figure 1) and, as these are central nervous system neurons, their loss is irreversible. At present, there is no cure for glaucoma, and the standard treatment is to lower intraocular pressure by medication or surgery. However, a significant proportion of patients continue to experience visual loss even when pharmacological treatments effectively reduce eye pressure. Therefore, novel therapeutic approaches are needed for its treatment and management.Early-onset glaucoma, comprising primary congenital glaucoma and juvenile open-angle glaucoma, has a clear genetic basis. Between 10 and 30% of individuals with juvenile open-angle glaucoma have mutations in the gene encoding myocilin, 2,3 and, on average, B40% of people with primary congenital glaucoma have mutations in the gene encoding cytochrome P450 protein. 4 Both genes are expressed in the trabecular meshwork and ciliary body, and defects in these genes may cause ocular hypertension. The elucidation of the genetic basis underlying adult-onset glaucoma is difficult because the late onset of disease limits the number of individuals available for linkage analysis. However, at least 29 genetic loci for various forms of glaucoma and 12...

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Section: Cracking the Case: Gene Therapy Strategies For Rgc Neuroprotmentioning

confidence: 98%

Section: Cracking the Case: Gene Therapy Strategies For Rgc Neuroprotmentioning

confidence: 99%

Gene therapy for retinal ganglion cell neuroprotection in glaucoma

Wilson

Polo

2011

Gene Ther

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“…Recent experiments suggest that combinations of growth factors, such as the combination of brain-derived neurotrophic factor and LINGO-1 fusion protein, can provide more complete rescue of ganglion cells for longer periods of time (106). In addition, delivery of ciliary-derived neurotrophic factor, using viral transfer and injections of nerve growth factor in the episcleral veins, has been shown to be neuroprotective in a rat model of glaucoma (107,108). Although current investigations are limited to animal models, these studies suggest that future clinical applications in human glaucoma patients could prevent ganglion cell damage and restore ganglion cell function.…”

Section: Figurementioning

confidence: 99%

Glaucoma: genes, phenotypes, and new directions for therapy

Fan

Wiggs²

2010

J. Clin. Invest.

121

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Glaucoma, a leading cause of blindness worldwide, is characterized by progressive optic nerve damage, usually associated with intraocular pressure. Although the clinical progression of the disease is well defined, the molecular events responsible for glaucoma are currently poorly understood and current therapeutic strategies are not curative. This review summarizes the human genetics and genomic approaches that have shed light on the complex inheritance of glaucoma genes and the potential for gene-based and cellular therapies that this research makes possible.

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“…These observations, coupled with promising results showing neuroprotection in models of CNS degenerative disease (Andrews et al, 2008;Karussis et al, 2008;Parr et al, 2007;Torrente and Polli, 2008), have led to this category of stem cells becoming a focus for the development of cell-based neuroprotective strategies to treat glaucoma. Disruption of the retrograde axonal transport of BDNF has been shown to be involved in the pathophysiology of glaucoma and attempts to upregulate expression of BDNF (Martin et al, 2003) and CNTF (Pease et al, 2009) using gene therapy have been shown to attenuate RGC loss in experimental models. A reduction in RGC loss has been observed in rodents with raised intraocular pressure following intravitreal transplantation of mesenchymal stem cells (Johnson et al, 2010a;Yu et al, 2006).…”

Section: Stem Cell Mediated Neuroprotection In Glaucomamentioning

confidence: 99%