Investigators have determined that treating patients with an advanced form of age-related macular degeneration (AMD) with levodopa, a safe and readily available drug commonly used to treat Parkinson's disease, stabilised and improved their vision. It reduced the number of treatments necessary to maintain vision, and as such, will potentially reduce the burden of treating the disease, financially and otherwise.
More than 15% of the US population over the age of 70 has AMD, a common cause of blindness in developed nations. Neovascular AMD (nAMD) is characterised by the abnormal growth of new blood vessels, triggered by vascular endothelial growth factor (VEGF), which can cause fluid and blood to leak in the sub-retinal space of the eye. While nAMD represents only 10%-15% of all AMD cases, it is responsible for 90% of the vision loss attributed to the disease. The standard treatment requires frequent injections of agents to block VEGF. While effective, the injections are expensive and painful.
Earlier research found that patients being treated with levodopa for movement disorders such as Parkinson's disease were significantly less likely to develop any type of AMD.
Lead investigator Dr Robert W Snyder, department of biomedical engineering, The University of Arizona-Tucson, and Snyder Biomedical Corporation, Tucson, Arizona, explained, "Levodopa has a receptor (GPR143) selectively expressed on pigmented cells. This receptor can be supportive of retinal health and survival, which led to the development of our hypothesis that it may prevent or treat AMD."
The investigators developed two proof-of-concept studies to test whether levodopa improves visual acuity and the anatomical changes caused by nAMD. They also evaluated the safety and tolerability of the drug in treating nAMD and whether treatment reduced or delayed the need for anti-VEGF therapy.
In the first study, 20 patients newly diagnosed with nAMD who had never had VEGF treatment were given a small daily dose of levodopa for one month and were evaluated weekly by their referring retina specialist, who determined whether anti-VEGF treatment was needed. In the second part of the study, the patients who completed the first study and a second group of 14 patients who had received anti-VEGF treatment for at least three months before the study received escalating doses of levodopa to test the tolerance and efficacy of the drug. The patients continued to be evaluated monthly by their referring retina specialist.
This trial demonstrated for the first time that levodopa is safe, well-tolerated, and delayed anti-VEGF injection therapy while improving visual outcomes. In the first month, retinal fluid decreased by 29%. After six months the decrease in retinal fluid was sustained and mean visual acuity improved enabling patients in the first and second group to read an additional line on the eye chart. This is the equivalent of improvement from 20/40 to 20/32. Side effects were limited.
The investigators noted that levodopa may be unlikely as a standalone treatment in patients with newly diagnosed nAMD since 11 of the patients did require anti-VEGF injections. However, they required fewer than the standard monthly treatments, and in the second group, monthly injections of anti-VEGF decreased by 52%.
According to Snyder, although this limited proof-of-concept study included a small sample size and limited patient diversity, its findings suggest efficacy and support the targeting of the GPR13 receptor with levodopa for the treatment of nAMD in future studies.
The concept had its genesis 20 years ago when Snyder began working with co-investigator Dr Brian S McKay, who had developed techniques to culture and examine retinal endothelial pigment cells. "We had a strong desire to make an impact in AMD, and I had a strong hunch that McKay could make a significant contribution," Snyder said. "Although this is nowhere near completed, I am happy to say, 20 years later, we have all persevered, and I believe the GPR143/levodopa story will make a significant impact on our treatment and prevention of AMD."
Abstract
Background: Age-related macular degeneration (AMD) is a common cause of blindness worldwide. Neovascular AMD (nAMD) is an advanced form of the disease, in which excess vascular endothelial growth factor (VEGF) induces growth of new blood vessels that leak fluid, accounting for 90% of vision loss in AMD. Dysfunction of the retinal pigment epithelium likely initiates AMD. Retinal pigment epithelial cells express a G protein-coupled receptor, GPR143, which downregulates VEGF in response to levodopa. Anti-VEGF therapy effectively treats nAMD, suggesting that excessive VEGF activity drives the pathology.
Methods: In an open-label pilot study, in patients with newly diagnosed nAMD and naïve to anti-VEGF injections (Cohort-1), the effects of carbidopa-levodopa on vision and anatomic outcomes were evaluated for 4 weeks. Then patients were followed 5 months further with ascending levodopa doses. Patients previously treated with anti-VEGF injection therapy (Cohort-2) were also treated with ascending levodopa doses and evaluated for 6 months.
Results: Levodopa was safe, well tolerated, and delayed anti-VEGF injection therapy while improving visual outcomes. In the first month, retinal fluid decreased by 29% (P = .02, n = 12) without anti-VEGF treatment. Through 6 months the decrease in retinal fluid was sustained, with a mean frequency of 0.38 injections/month. At month 6, mean visual acuity improved by 4.7 letters in Cohort-1 (P = .004, n = 15) and by 4.8 letters in Cohort-2 (P = .02, n = 11). Additionally, there was a 52% reduction in the need for anti-VEGF injections in Cohort-2 (P = .002).
Conclusions: Our findings suggest efficacy and support the pharmacological targeting of GPR143 with levodopa for the treatment of nAMD in future studies.
Authors
Anna G Figueroa, Brennan M Boyd, Cory A Christensen, Cameron G Javid, Brian S McKay, Timothy C Fagan, Robert W Snyder
[link url="https://www.elsevier.com/about/press-releases/research-and-journals/levodopa-may-improve-vision-in-patients-with-macular-degeneration"]Elsevier material[/link]
[link url="https://www.amjmed.com/article/S0002-9343(20)30539-8/fulltext"]The American Journal of Medicine abstract[/link]