Novel compstatin family peptides inhibit complement activation by drusen-like deposits in human retinal pigmented epithelial cell cultures

Gorham, Ronald D.; Forest, David L.; Tamamis, Phanourios; Victoria, Aliana López de; Kraszni, Márta; Kieslich, Chris A.; Banna, Christopher D.; Bellows-Peterson, Meghan L.; Larive, Cynthia K.; Floudas, Christodoulos A.; Archontis, Georgios; Johnson, Lincoln V.; Morikis, Dimitrios

doi:10.1016/j.exer.2013.07.023

Cited by 24 publications

(65 citation statements)

References 55 publications

(156 reference statements)

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“…Activation of the classical complement pathway has also been shown to be necessary for drusen formation in hfRPE cultures (15). Furthermore, broad suppression of the complement response using the C3 inhibitor compstatin has previously been shown to regress drusen in a cellular and nonhuman primate model of macular degeneration (47,48). These data together support a link between complement pathway alteration/activation at the local level of RPE cells and drusen formation in multiple macular degeneration models.…”

Section: Col4 Levels Are Higher In Ecm Isolated From Sfd and Dhrd Hipsupporting

confidence: 61%

Drusen in patient-derived hiPSC-RPE models of macular dystrophies

Galloway

Dalvi

Hung

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

122

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Age-related macular degeneration (AMD) and related macular dystrophies (MDs) are a major cause of vision loss. However, the mechanisms underlying their progression remain ill-defined. This is partly due to the lack of disease models recapitulating the human pathology. Furthermore, in vivo studies have yielded limited understanding of the role of specific cell types in the eye vs. systemic influences (e.g., serum) on the disease pathology. Here, we use human induced pluripotent stem cell-retinal pigment epithelium (hiPSC-RPE) derived from patients with three dominant MDs, Sorsby's fundus dystrophy (SFD), Doyne honeycomb retinal dystrophy/malattia Leventinese (DHRD), and autosomal dominant radial drusen (ADRD), and demonstrate that dysfunction of RPE cells alone is sufficient for the initiation of sub-RPE lipoproteinaceous deposit (drusen) formation and extracellular matrix (ECM) alteration in these diseases. Consistent with clinical studies, sub-RPE basal deposits were present beneath both control (unaffected) and patient hiPSC-RPE cells. Importantly basal deposits in patient hiPSC-RPE cultures were more abundant and displayed a lipid-and protein-rich "drusen-like" composition. Furthermore, increased accumulation of COL4 was observed in ECM isolated from control vs. patient hiPSC-RPE cultures. Interestingly, RPE-specific up-regulation in the expression of several complement genes was also seen in patient hiPSC-RPE cultures of all three MDs (SFD, DHRD, and ADRD). Finally, although serum exposure was not necessary for drusen formation, COL4 accumulation in ECM, and complement pathway gene alteration, it impacted the composition of drusen-like deposits in patient hiPSC-RPE cultures. Together, the drusen model(s) of MDs described here provide fundamental insights into the unique biology of maculopathies affecting the RPE-ECM interface.human induced pluripotent stem cells | retinal pigment epithelium | macular dystrophies | drusen | sub-RPE deposits M aculopathies are a major cause of blindness, with agerelated macular degeneration (AMD) being the leading cause of irreversible vision loss in adults in the United States. Histopathological and clinical studies have shown that AMD and a subset of inherited macular dystrophies (MDs) share extensive phenotypic and clinical similarities (1-4). Specifically, AMD and related MDs have a cumulative etiology with adult onset of signs and symptoms and similar disease presentation including drusen formation, extracellular matrix (ECM) protein accumulation, thickening of Bruch's membrane, development of choroidal neovascularization, retinal pigment epithelium (RPE) atrophy, and ultimately the loss of vision (1-5). Although, the major pathological manifestations in these maculopathies are localized to the RPE-ECM interface in the retina, the multifactorial nature of these diseases, including the involvement of multiple retinal cell layers (photoreceptors, RPE, and choriocapillaris) (3, 6-9) and environmental risk factors (e.g., cigarette smoke) (10), has complicated the pursuit of t...

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Section: Col4 Levels Are Higher In Ecm Isolated From Sfd and Dhrd Hipsupporting

confidence: 61%

Drusen in patient-derived hiPSC-RPE models of macular dystrophies

Galloway

Dalvi

Hung

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

122

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“… 52 During the simulations of analog W4(OMW)A9, the methyl group of Trp4 is frequently found to lay upon the Cys2-Cys12 disulfide bridge, and this leads to increased intramolecular nonpolar interactions between Trp4 and Cys2-Cys12. Similar behavior was observed in recently published MD computational studies 53 investigating two novel analogs, R1W4(OMW)A9 and R-1S0W4(OMW)A9, which also contain 1-methyltryptophan in position 4 and using the CHARMM forcefield. 54 W4(OMW) forms increased intra- and intermolecular interactions compared with the less potent analogs containing Trp4 and Val4.…”

Section: Resultssupporting

confidence: 85%

Forcefield_NCAA: Ab Initio Charge Parameters to Aid in the Discovery and Design of Therapeutic Proteins and Peptides with Unnatural Amino Acids and Their Application to Complement Inhibitors of the Compstatin Family

et al. 2014

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We describe the development and testing of ab initio derived, AMBER ff03 compatible charge parameters for a large library of 147 noncanonical amino acids including β- and N-methylated amino acids for use in applications such as protein structure prediction and de novo protein design. The charge parameter derivation was performed using the RESP fitting approach. Studies were performed assessing the suitability of the derived charge parameters in discriminating the activity/inactivity between 63 analogs of the complement inhibitor Compstatin on the basis of previously published experimental IC50 data and a screening procedure involving short simulations and binding free energy calculations. We found that both the approximate binding affinity (K*) and the binding free energy calculated through MM-GBSA are capable of discriminating between active and inactive Compstatin analogs, with MM-GBSA performing significantly better. Key interactions between the most potent Compstatin analog that contains a noncanonical amino acid are presented and compared to the most potent analog containing only natural amino acids and native Compstatin. We make the derived parameters and an associated web interface that is capable of performing modifications on proteins using Forcefield_NCAA and outputting AMBER-ready topology and parameter files freely available for academic use at . The forcefield allows one to incorporate these customized amino acids into design applications with control over size, van der Waals, and electrostatic interactions.

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“…Novel compstatin family of peptides, inhibitors of complement activation have also has also been investigated in a cell culture model of human retinal pigmented epithelial cells where it was demonstrated to inhibit complement activation by drusen-like deposits (Gorham et al, 2013) and in cynomolgus monkeys with early-onset macular degeneration (2010).…”

Section: Evidence From the Retina Degeneration Models Demonstrating Tmentioning

confidence: 98%

Exploring the potential benefits of vaccinia virus complement control protein in controlling complement activation in pathogenesis of the central nervous system diseases

Kotwal

Fernando²,

Zhou³

et al. 2014

Molecular Immunology

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Aging is a major risk factor for the development of diseases related to the central nervous system (CNS), such as Alzheimer's disease (AD) and age-related macular degeneration (AMD). In both cases, linkage studies and genome-wide association studies found strong links with complement regulatory genes and disease risk. In AD, both CLU and CR1 genes were implicated in the late-onset form of the disease. In AMD, polymorphisms in CFH, CFB and C2 were similarly implicated. The cost of caring for patients with AD or AMD is approaching billions of dollars, and with the baby boomers reaching their 60's, this amount is likely to increase further. Intervention using complement inhibitors for individuals in their early 50s who are at a higher risk of disease development, (testing positive for genetic risk factors), could slow the progression of AD or AMD and possibly prevent the severity of late stage symptoms. Although we have used the vaccinia virus complement control protein (VCP) to elucidate the role of complement in CNS diseases, it has merely been an investigational tool but not the only possible potential therapeutic agent.

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Novel compstatin family peptides inhibit complement activation by drusen-like deposits in human retinal pigmented epithelial cell cultures

Cited by 24 publications

References 55 publications

Drusen in patient-derived hiPSC-RPE models of macular dystrophies

Drusen in patient-derived hiPSC-RPE models of macular dystrophies

Forcefield_NCAA: Ab Initio Charge Parameters to Aid in the Discovery and Design of Therapeutic Proteins and Peptides with Unnatural Amino Acids and Their Application to Complement Inhibitors of the Compstatin Family

Exploring the potential benefits of vaccinia virus complement control protein in controlling complement activation in pathogenesis of the central nervous system diseases

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