Mining Retrospective Data for Virtual Prospective Drug Repurposing: L-DOPA and Age-related Macular Degeneration

Murray H Brilliant, Kamyar Vaziri, Thomas B Connor Jr, Stephen G Schwartz, Joseph J Carroll, Catherine A McCarty, Steven J Schrodi, Scott J Hebbring, Krishna S Kishor, Harry W Flynn Jr, Andrew A Moshfeghi, Darius M Moshfeghi, M Elizabeth Fini, Brian S McKay, Murray H Brilliant, Kamyar Vaziri, Thomas B Connor Jr, Stephen G Schwartz, Joseph J Carroll, Catherine A McCarty, Steven J Schrodi, Scott J Hebbring, Krishna S Kishor, Harry W Flynn Jr, Andrew A Moshfeghi, Darius M Moshfeghi, M Elizabeth Fini, Brian S McKay

Abstract

Background: Age-related macular degeneration (AMD) is a leading cause of visual loss among the elderly. A key cell type involved in AMD, the retinal pigment epithelium, expresses a G protein-coupled receptor that, in response to its ligand, L-DOPA, up-regulates pigment epithelia-derived factor, while down-regulating vascular endothelial growth factor. In this study we investigated the potential relationship between L-DOPA and AMD.

Methods: We used retrospective analysis to compare the incidence of AMD between patients taking vs not taking L-DOPA. We analyzed 2 separate cohorts of patients with extensive medical records from the Marshfield Clinic (approximately 17,000 and approximately 20,000) and the Truven MarketScan outpatient and databases (approximately 87 million) patients. We used International Classification of Diseases, 9th Revision codes to identify AMD diagnoses and L-DOPA prescriptions to determine the relative risk of developing AMD and age of onset with or without an L-DOPA prescription.

Results: In the retrospective analysis of patients without an L-DOPA prescription, AMD age of onset was 71.2, 71.3, and 71.3 in 3 independent retrospective cohorts. Age-related macular degeneration occurred significantly later in patients with an L-DOPA prescription, 79.4 in all cohorts. The odds ratio of developing AMD was also significantly negatively correlated by L-DOPA (odds ratio 0.78; confidence interval, 0.76-0.80; P <.001). Similar results were observed for neovascular AMD (P <.001).

Conclusions: Exogenous L-DOPA was protective against AMD. L-DOPA is normally produced in pigmented tissues, such as the retinal pigment epithelium, as a byproduct of melanin synthesis by tyrosinase. GPR143 is the only known L-DOPA receptor; it is therefore plausible that GPR143 may be a fruitful target to combat this devastating disease.

Keywords: Age-related macular degeneration (AMD); GPR143; L-DOPA; Movement disorder; Parkinson's disease; Retinal pigment epithelium (RPE); Retrospective study.

Conflict of interest statement

Conflict of Interest: BSM is an inventor on an approved patent for the use of L-DOPA to treat or delay age-related macular degeneration, and has received no income from this patent.

Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Figures

Figure 1
Figure 1
Age distribution of subjects in the Marshfield Clinic Cohorts. The data summarize the age distributions for a first prescription (Rx) for L-DOPA (n = 314), diagnosis (Dx) of age-related macular degeneration (AMD) (n = 1795), or a record of L-DOPA before a diagnosis of AMD (n = 10). Errors bars represent the 95% confidence interval. *P <.01 by t test analysis.
Figure 2
Figure 2
Data from the Truven MarketScan database illustrates that L-DOPA both delays age-related macular degeneration (AMD) onset and reduces the risk of developing AMD. (A) Data represent the age of AMD onset in several groups, with error bars representing the 95% confidence interval. The AMD group represents our control individuals that had no record of movement disorder prescription history. The L-DOPA AMD group represents all individuals with an International Classification of Diseases, 9th Revision (ICD-9) code for AMD that also had a prescription history for L-DOPA. Neovascular (NV) AMD represents individuals with the specific ICD-9 code 362.52 but no history of L-DOPA prescriptions. The L-DOPA and NV AMD group is similar except that the individuals had a history of L-DOPA prescriptions. The dopamine agonist group represents individuals who had a prescription history for various movement disorder drugs, largely dopamine agonists. All groups were significantly different from the AMD control. *P <.001. (B) Odds ratio analysis to determine whether the drugs alter the probability of developing AMD. All values below 1, representing the control, AMD with no L-DOPA or movement disorder prescription history, indicating a reduction in the probability risk of developing AMD, either in general or specifically NV AMD. Each reduction in risk was significant. *P <.001.

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