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Human iPSC-based disease modeling studies identify a common mechanistic defect and potential therapies for AMD and

Sonal Dalvi1, Michael Roll1, Amit Chatterjee1

  • 1Department of Ophthalmology, University of Rochester, Rochester, NY 14620, USA; Department of Biomedical Genetics, University of Rochester, Rochester, NY 14620, USA; Center for Visual Science, University of Rochester, Rochester, NY 14620, USA; UR Stem Cell and Regenerative Medicine Center, Rochester, NY 14620, USA.

Developmental Cell
|October 3, 2024
PubMed

Insights

Reduced matrix metalloproteinase 2 (MMP2) activity in retinal cells drives drusen in macular diseases. Targeting the MMP2-RAGE-sPLA2-IIA pathway therapeutically reduced drusen accumulation in patient-derived cells.

Area of Science:

  • Ophthalmology
  • Cell Biology
  • Molecular Medicine

Background:

  • Age-related macular degeneration (AMD) and macular dystrophies (MDs) impact the retinal pigment epithelium (RPE).
  • Drusen, extracellular deposits under the RPE, are a key feature driving AMD/MD pathology.
  • The formation and accumulation mechanisms of drusen remain largely unknown.

Purpose of the Study:

  • To investigate the role of RPE-secreted matrix metalloproteinase 2 (MMP2) in drusen formation across different maculopathies.
  • To elucidate the molecular pathways involved in drusen pathogenesis, including sterile inflammation and lipid homeostasis.
  • To evaluate potential therapeutic strategies targeting identified pathways for AMD/MD treatment.

Main Methods:

  • Utilized human induced pluripotent stem cell (iPSC)-derived RPE from AMD and MD patients.
  • Assessed MMP2 activity, sterile inflammation markers, lipid homeostasis, and receptor for advanced glycation end-products (RAGE) and secretory phospholipase 2-IIA (sPLA2-IIA) signaling.
  • Tested therapeutic interventions including MMP2 supplementation, RAGE antagonism, and sPLA2-IIA inhibition in iPSC-RPE models.

Main Results:

  • Reduced MMP2 activity was identified as a common factor contributing to drusen in multiple maculopathies, independent of genotype.
  • This reduction instigated sterile inflammation and impaired lipid homeostasis via DAMP-mediated RAGE activation and elevated sPLA2-IIA.
  • RPE-specific MMP2 supplementation, RAGE-antagonistic peptide, and sPLA2-IIA inhibition significantly reduced drusen accumulation in patient-derived RPE cells.

Conclusions:

  • Establishes a causal link between MMP2 deficiency and drusen formation in AMD/MDs.
  • Defines the MMP2-DAMP-RAGE-sPLA2-IIA axis as a critical pathway in the pathogenesis of maculopathies.
  • Highlights potential therapeutic targets for mitigating drusen accumulation in AMD and related macular dystrophies.
Keywords:
ADRDDHRDDoyne honeycomb macular dystrophySFDSorsby’s fundus dystrophyage-related macular degenerationautosomal dominant radial drusendrusenmacular dystrophymatrix metalloproteinase 2retinal pigment epitheliumsterile inflammationtissue inhibitor of metalloproteinase 3

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