Recombinant manganese peroxidase reduces A2E burden in age-related and stargardt's macular degeneration models

Kelsey J. Moody, Jay Tinklepaugh, Elisabeth Obert, Kris Grohn, Jennifer R. Derosa, Ellie Lumen, Brandon S. Moyer, Scott Campbell, Aaron J. Wolfe, Meegan B. Sleeper, Anthony H. Bianchi, Cheyanne Fisher, Justin Applegate, Emily Leary, Nicholas Leclair, Danique Wortel, Robert Patrick Doyle, Baerbel Rohrer, Adam R. Blanden

Research output: Contribution to journalArticle

2 Scopus citations

Abstract

Macular degeneration is hallmarked by retinal accumulation of toxic retinoid species (e.g., A2E) for which there is no endogenous mechanism to eliminate it. This ultimately results in progressive dysfunction and loss of vision either in advanced age for genetically normal patients (age-related macular degeneration) or in adolescence for those with inherited genetic mutations (Stargardt's disease). In this article, we present a proof-of-concept study for an enzyme-based therapy to remove these retinoids, modeled on traditional enzyme replacement therapy. Recombinant manganese peroxidase (rMnP) is produced in Pichia pastoris. In vitro, we demonstrate that rMnP breaks down A2E and other lipofuscin fluorophores with limited cellular toxicity, and as this enzyme is mannosylated, it can be taken up into cells through mannose receptor-dependent endocytosis. In vivo, we demonstrate that rMnP can significantly reduce the A2E burden when administered by intravitreal injections. Together, these data provide encouraging results toward the development of an enzyme-based therapy for macular degeneration and indicate the need for additional work to characterize the molecular mechanism of A2E breakdown and to improve the pharmacological parameters of the enzyme.

Original languageEnglish (US)
Pages (from-to)560-571
Number of pages12
JournalRejuvenation Research
Volume21
Issue number6
DOIs
StatePublished - Dec 1 2018

Keywords

  • A2E
  • enzyme replacement therapy
  • macular degeneration
  • ophthalmology
  • Stargardt's disease

ASJC Scopus subject areas

  • Aging
  • Geriatrics and Gerontology

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    Moody, K. J., Tinklepaugh, J., Obert, E., Grohn, K., Derosa, J. R., Lumen, E., Moyer, B. S., Campbell, S., Wolfe, A. J., Sleeper, M. B., Bianchi, A. H., Fisher, C., Applegate, J., Leary, E., Leclair, N., Wortel, D., Doyle, R. P., Rohrer, B., & Blanden, A. R. (2018). Recombinant manganese peroxidase reduces A2E burden in age-related and stargardt's macular degeneration models. Rejuvenation Research, 21(6), 560-571. https://doi.org/10.1089/rej.2018.2146