Recombinant Manganese Peroxidase Reduces A2E Burden in Age-Related and Stargardt's Macular Degeneration Models

Rejuvenation Res. 2018 Dec;21(6):560-571. doi: 10.1089/rej.2018.2146.


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.

Keywords: A2E; Stargardt's disease; enzyme replacement therapy; macular degeneration; ophthalmology.

MeSH terms

  • ATP-Binding Cassette Transporters / physiology
  • Animals
  • Cells, Cultured
  • Disease Models, Animal*
  • Humans
  • Lipofuscin / metabolism
  • Macular Degeneration / congenital*
  • Macular Degeneration / metabolism
  • Macular Degeneration / pathology
  • Macular Degeneration / therapy*
  • Mice
  • Mice, Knockout
  • Peroxidases / administration & dosage*
  • Recombinant Proteins / administration & dosage*
  • Retinal Pigment Epithelium / drug effects
  • Retinal Pigment Epithelium / metabolism
  • Retinal Pigment Epithelium / pathology
  • Retinoids / metabolism*
  • Stargardt Disease


  • A2-E (N-retinylidene-N-retinylethanolamine)
  • ATP-Binding Cassette Transporters
  • Abca4 protein, mouse
  • Lipofuscin
  • Recombinant Proteins
  • Retinoids
  • Peroxidases
  • manganese peroxidase