Reduced MMP2 activity from RPE contributes to drusen formation and RPE atrophy in AMD and MDs.
Dysfunction involves DAMP-mediated RAGE activation and increased sPLA2-IIA levels, leading to inflammation and lipid imbalance.
Potential therapies include MMP2 supplementation, RAGE-antagonistic peptides, and sPLA2-IIA inhibitors in iPSC-derived RPE models.

Related macular dystrophies include Sorsby’s fundus dystrophy, Doyne honeycomb macular dystrophy, and autosomal dominant radial drusen.

(Image Credit: AdobeStock/adam121)

A new study¹described the underlying defect responsible for the development of age-related macular degeneration (AMD) and related macular dystrophies (MDs), such as Sorsby’s fundus dystrophy, Doyne honeycomb macular dystrophy, and autosomal dominant radial drusen.

The investigators, led by Sonal Dalvi, PhD, showed that reduced activity of matrix metalloproteinase 2 (MMPs) secreted from the retinal pigment epithelium (RPE) promotes drusen formation in AMD and MDs. She is from the Department of Ophthalmology, Department of Biomedical Genetics, and the Center for Visual Science, University of Rochester, and the University of Rochester Stem Cell and Regenerative Medicine Center, Rochester, NY.

The researchers explained, “The primary disease manifestations of AMD/MDs are localized to the RPE-choriocapillaris complex in the eye.² Furthermore, alterations of Bruch’s membrane, the extracellular matrix underlying the RPE, is central to AMD/MD development.³ Bruch’s membrane undergoes regulated turnover that involves protease-mediated degradation by MMPs, and consistently several MMPs (eg, MMP2, MMP3, and MMP9) have been linked to AMD/MD pathophysiology.^4-7

Davli and colleagues used human induced pluripotent stem cell (iPSC)-derived RPE from patients with AMD and 3 MDs to show that the reduced activity of RPE-secreted MMP2 contributes to drusen formation, impaired RPE barrier integrity, and RPE atrophy in MDs by inducing sterile inflammation and impaired lipid homeostasis. The mechanism of this dysfunction is damage-associated molecular pattern molecule (DAMP)-mediated activation of receptor for advanced glycation end-products (RAGE) and increased secretory phospholipase 2-IIA (sPLA2-IIA) levels, Dalvi and colleagues found.

They also reported that drusen accumulation was abated by a potential therapy for AMD, Sorsby’s fundus dystrophy, Doyne honeycomb macular dystrophy, and autosomal dominant radial drusen that included RPE-specific MMP2 supplementation, RAGE-antagonistic peptide, and a small molecule inhibitor of sPLA2-IIA in AMD/MD iPSC-RPE.

The take-aways from the study are as follows according to the authors:

Identification of a shared mechanistic defect in AMD and MDs
Reduced activity of RPE-secreted MMP2 instigates pro-maculopathy cellular events
Perturbation of the MMP2-DAMP-RAGE-sPLA2-IIA axis contributes to AMD/MD pathology
Pharmacologic targeting in a human iPSC model of AMD and 3 distinct MDs

References:

Dalvi S, Roll M, Chatterjee A, et al. Human iPSC-based disease modeling studies identify a common mechanistic defect and potential therapies for AMD and related macular dystrophies. Dev Cell. 2024; https://doi.org/10.1016/j.devcel.2024.09.006
Engel AL, Wang Y, Khuu TH, et al. Extracellular matrix dysfunction in Sorsby patient-derived retinal pigment epithelium. Exp Eye Res. 2022;215:https://doi.org/10.1016/j.exer.2021.108899
LeuST, Batni S, Radee MJ, et al. Drusen are cold spots for proteolysis: expression of matrix metalloproteinases and their tissue inhibitor proteins in age-related macular degeneration. Exp Eye Res. 2002;74:141-54; doi: 10.1006/exer.2001.1112.
Lambert V,Munaut C, Jost M, et al. Matrix metalloproteinase-9 contributes to choroidal neovascularization. Am J Pathol. 2002:161:1247-1253.
Manian KV, Galloway CA, Dalvi S, et al. 3D iPSC modeling of the retinal pigment epithelium-choriocapillaris complex identifies factors involved in the pathology of macular degeneration. Cell Stem Cell. 2021;28:846-862.e8; doi: 10.1016/j.stem.2021.02.006.
Berton A, Rigot V, Huet E, et al. Involvement of fibronectin type II repeats in the efficient inhibition of gelatinases A and B by long-chain unsaturated fatty acids. J Biol Chem. 2001;276:20458-65; doi: 10.1074/jbc.M011664200.
J. Liu J, Xiong W, Baca-Regen L, et al.Mechanism of inhibition of matrix metalloproteinase-2 expression by doxycycline in human aortic smooth muscle cells. J Vasc Surg. 2003;38:1376-83; doi: 10.1016/s0741-5214(03)01022-x.

Dalvi S, Roll M, Chatterjee A, et al. Human iPSC-based disease modeling studies identify a common mechanistic defect and potential therapies for AMD and related macular dystrophies. Dev Cell. 2024; https://doi.org/10.1016/j.devcel.2024.09.006

Engel AL, Wang Y, Khuu TH, et al. Extracellular matrix dysfunction in Sorsby patient-derived retinal pigment epithelium. Exp Eye Res. 2022;215:https://doi.org/10.1016/j.exer.2021.108899

LeuST, Batni S, Radee MJ, et al. Drusen are cold spots for proteolysis: expression of matrix metalloproteinases and their tissue inhibitor proteins in age-related macular degeneration. Exp Eye Res. 2002;74:141-54; doi: 10.1006/exer.2001.1112.

Lambert V,Munaut C, Jost M, et al. Matrix metalloproteinase-9 contributes to choroidal neovascularization. Am J Pathol. 2002:161:1247-1253.

Manian KV, Galloway CA, Dalvi S, et al. 3D iPSC modeling of the retinal pigment epithelium-choriocapillaris complex identifies factors involved in the pathology of macular degeneration. Cell Stem Cell. 2021;28:846-862.e8; doi: 10.1016/j.stem.2021.02.006.

Berton A, Rigot V, Huet E, et al. Involvement of fibronectin type II repeats in the efficient inhibition of gelatinases A and B by long-chain unsaturated fatty acids. J Biol Chem. 2001;276:20458-65; doi: 10.1074/jbc.M011664200.

J. Liu J, Xiong W, Baca-Regen L, et al.Mechanism of inhibition of matrix metalloproteinase-2 expression by doxycycline in human aortic smooth muscle cells. J Vasc Surg. 2003;38:1376-83; doi: 10.1016/s0741-5214(03)01022-x.