Gene therapy for glaucoma: treating a multifaceted, chronic disease.

Glaucoma is a progressive optic neuropathy. It is characterized by a particular pattern of optic nerve head and visual field damage resulting from a number of different diseases that affect the eye. Many of these are associated with elevated intraocular pressure (IOP), which is the most common known associated risk factor, but not the only risk factor, for the development and/or progression of glaucomatous damage. The final common pathologic event is retinal ganglion cell (RGC) death. As such, glaucoma offers a variety of potential targets for gene therapy. In the anterior segment, these include various causes of trabecular dysfunction and alterations in aqueous production. Mutations in the myocilin gene cause autosomal dominant juvenile primary open-angle glaucoma and approximately 3% of cases of adult-onset open-angle glaucomas. Several other hereditary disorders are also associated with glaucoma. Elucidation of non-IOP–dependent risk factors for glaucomatous damage has become an area of increasingly active investigation. These risk factors are thought to be responsible for approximately 30% of open-angle glaucoma in the United States and up to 70% in Japan. They include systemic hypotension, including positional or nocturnal hypotension, cardiovascular disease, vasospasm (migraine, Raynaud’s disease), defective vascular autoregulation, endothelin abnormalities, sleep apnea, autoimmune disease, hemorheologic abnormalities, and cerebral microvascular ischemia. All these risk factors and their underlying causes are potentially susceptible to modulation by gene transfer. Events leading to RGC damage and death are targets for genetic modulation. A recently described causative gene for normal-tension glaucoma, optineurin (optic neuropathy-inducing protein) is another potential target and as genetic studies continue, additional targets are likely to be identified. Hauswirth and Beaufrere have delineated four basic prerequisites that should be met for any genetic therapy targeted to an ocular disease: an efficient and nontoxic gene delivery technique, sufficient characterization of the genetic basis of the disease to select an appropriately matched therapeutic approach, proper control of the expression of the therapeutic gene, and the availability of an animal model of the disease for preclinical testing. Glaucoma is a disease in which some of these conditions can be met. Strategies now exist that use gene therapy to modulate aqueous production and outflow and prevent RGC death.