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Hope for Patients at Risk for Macular Degeneration

Dry Age-Related Macular Degeneration is an untreatable condition that causes blindness.  in millions because of the death of retinal pigmented epithelial cells (RPE).[3] Currently, there is no FDA-approved therapy for the more than 1 million Americans with GA[4]. Now, researchers at the University of Kentucky, led by Jayakrishna Ambati, MD, have made a finding that could eventually help patients. The work identifies a new therapeutic target for the dry form of AMD. 

Age-related macular degeneration (AMD) is a disorder in which one’s sharp central vision becomes blurry, and thus “straight ahead” activities such as reading, driving, and sewing grow increasingly difficult. People with AMD have vision loss due to damage in the eye’s macula, and there are two forms of the disease. In wet AMD, abnormal blood vessels growing beneath the retina can leak fluid and blood, which can lead to both damage and swelling of the macula. In dry AMD, also called geographic atrophy (GA), the light-sensitive cells in the macula that transmit visual information to the brain, as well as the supporting tissue beneath the macula, break down gradually. These changes within the eye are what cause the loss of vision. An individual can have both forms of AMD in the same eye, and either wet or dry AMD can appear first[2].

Dr. Ambati, a professor of ophthalmology at the University of Virginia School of Medicine, previously had published research in the journal, Nature, that showed that the eyes of individuals with GA have a deficiency of an enzyme called DICER1[5]. This deficiency leads to an accumulation of toxic Alu RNA molecules within the eye. In another paper published in the journal Cell, researchers showed that when these RNAs build up, they cause an immune complex known as the NLRP3 inflammasome to be activated, which leads to production of IL-18, a molecule that causes vision loss by activating a protein known as MyD88[6]. In the eyes of individuals with GA, activity of inflammasome, IL-18, and MyD88 are all increased, Dr. Ambati and his team discovered. They also were able to demonstrate that blocking any of these could stave off retinal degeneration in multiple disease models. In short, blocking these pathways could one day initiate a new potential therapy to treat GA, they found.

In the more recent paper, “ERK1/2 Activation is a Therapeutic Target in Age-Related Macular Degeneration,” which appeared online in the Proceedings of the National Academy of Science, Dr. Ambati and his colleagues have demonstrated that Alu RNA (which increases when there is a deficit of DICER1, activates a family of enzymes called extracellular-signal-regulated kinases (ERK)1/2. Known as classical mitogen-activated protein kinases (MAPKs), these were noted to be increased in the RPE of the eyes of individuals with GA. These MAPKs also were shown to be key mediators of RPE cell death. 

“Collectively, our findings – that there is an increased activation of ERK1/2 in the RPE of human eyes with GA and that ERK1/2 inhibition blocks RPE degeneration in an in vivo model that recapitulates the DICER1/Alu RNA imbalance existing in the human disease state – provide a molecular rationale for exploring ERK1/2 inhibition strategies in atrophic AMD,” the authors wrote. 

The paper written by Dr. Ambati and his colleagues more extensively describes the mechanisms of cell death in individuals with GA and identifies a new therapeutic target for the disorder. 

Last updated on 9/26/19.

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