Novel anti-angiogenic PEDF-derived small peptides mitigate choroidal neovascularization

Nader Sheibani, Shoujian Wang, Soesiawati R. Darjatmoko, Debra L. Fisk, Pawan K. Shahi, Bikash R. Pattnaik, Christine M. Sorenson, Reshma Bhowmick, Olga V. Volpert, Daniel Albert, Ignacio Melgar-Asensio, Jack Henkin

Research output: Contribution to journalArticle

Abstract

Abnormal migration and proliferation of endothelial cells (EC) drive neovascular retinopathies. While anti-VEGF treatment slows progression, pathology is often supported by decrease in intraocular pigment epithelium-derived factor (PEDF), an endogenous inhibitor of angiogenesis. A surface helical 34-mer peptide of PEDF, comprising this activity, is efficacious in animal models of neovascular retina disease but remains impractically large for therapeutic use. We sought smaller fragments within this sequence that mitigate choroidal neovascularization (CNV). Expecting rapid intravitreal (IVT) clearance, we also developed a method to reversibly attach peptides to nano-carriers for extended delivery. Synthetic fragments of 34-mer yielded smaller anti-angiogenic peptides, and N-terminal capping with dicarboxylic acids did not diminish activity. Charge restoration via substitution of an internal aspartate by asparagine improved potency, achieving low nM apoptotic response in VEGF-activated EC. Two optimized peptides (PEDF 335, 8-mer and PEDF 336, 9-mer) were tested in a mouse model of laser-induced CNV. IVT injection of either peptide, 2–5 days before laser treatment, gave significant CNV decrease at day +14 post laser treatment. The 8-mer also decreased CNV, when administered as eye drops. Also examined was a nanoparticle-conjugate (NPC) prodrug of the 9-mer, having positive zeta potential, expected to display longer intraocular residence. This NPC showed extended efficacy, even when injected 14 days before laser treatment. Neither inflammatory cells nor other histopathologic abnormalities were seen in rabbit eyes harvested 14 days following IVT injection of PEDF 336 (>200 μg). No rabbit or mouse eye irritation was observed over 12–17 days of PEDF 335 eye drops (10 mM). Viability was unaffected in 3 retinal and 2 choroidal cell types by PEDF 335 up to 100 μM, PEDF 336 (100 μM) gave slight growth inhibition only in choroidal EC. A small anti-angiogenic PEDF epitope (G-Y-D-L-Y-R-V) was identified, variants (adipic-Sar-Y-N-L-Y-R-V) mitigate CNV, with clinical potential in treating neovascular retinopathy. Their shared active motif, Y - - - R, is found in laminin (Ln) peptide YIGSR, which binds Ln receptor 67LR, a known high-affinity ligand of PEDF 34-mer.

Original languageEnglish (US)
Article number107798
JournalExperimental Eye Research
Volume188
DOIs
StatePublished - Nov 1 2019

Fingerprint

Choroidal Neovascularization
Peptides
Lasers
Intravitreal Injections
Endothelial Cells
Ophthalmic Solutions
tyrosyl-isoleucyl-glycyl-seryl-arginine
Nanoparticles
Vascular Endothelial Growth Factor A
Angiogenic Proteins
pigment epithelium-derived factor
Laminin Receptors
Rabbits
Dicarboxylic Acids
Angiogenesis Inhibitors
Asparagine
Prodrugs
Laminin
Therapeutic Uses
Therapeutics

Keywords

  • Angiogenesis
  • Choroidal neovascularization
  • Laminin receptor
  • Macular degeneration
  • PEDF
  • Peptides
  • Retinopathy
  • YIGSR

ASJC Scopus subject areas

  • Ophthalmology
  • Sensory Systems
  • Cellular and Molecular Neuroscience

Cite this

Sheibani, N., Wang, S., Darjatmoko, S. R., Fisk, D. L., Shahi, P. K., Pattnaik, B. R., ... Henkin, J. (2019). Novel anti-angiogenic PEDF-derived small peptides mitigate choroidal neovascularization. Experimental Eye Research, 188, [107798]. https://doi.org/10.1016/j.exer.2019.107798

Novel anti-angiogenic PEDF-derived small peptides mitigate choroidal neovascularization. / Sheibani, Nader; Wang, Shoujian; Darjatmoko, Soesiawati R.; Fisk, Debra L.; Shahi, Pawan K.; Pattnaik, Bikash R.; Sorenson, Christine M.; Bhowmick, Reshma; Volpert, Olga V.; Albert, Daniel; Melgar-Asensio, Ignacio; Henkin, Jack.

In: Experimental Eye Research, Vol. 188, 107798, 01.11.2019.

Research output: Contribution to journalArticle

Sheibani, N, Wang, S, Darjatmoko, SR, Fisk, DL, Shahi, PK, Pattnaik, BR, Sorenson, CM, Bhowmick, R, Volpert, OV, Albert, D, Melgar-Asensio, I & Henkin, J 2019, 'Novel anti-angiogenic PEDF-derived small peptides mitigate choroidal neovascularization', Experimental Eye Research, vol. 188, 107798. https://doi.org/10.1016/j.exer.2019.107798
Sheibani, Nader ; Wang, Shoujian ; Darjatmoko, Soesiawati R. ; Fisk, Debra L. ; Shahi, Pawan K. ; Pattnaik, Bikash R. ; Sorenson, Christine M. ; Bhowmick, Reshma ; Volpert, Olga V. ; Albert, Daniel ; Melgar-Asensio, Ignacio ; Henkin, Jack. / Novel anti-angiogenic PEDF-derived small peptides mitigate choroidal neovascularization. In: Experimental Eye Research. 2019 ; Vol. 188.
@article{903fdf0ce74f492b90314cd0eceb2ccb,
title = "Novel anti-angiogenic PEDF-derived small peptides mitigate choroidal neovascularization",
abstract = "Abnormal migration and proliferation of endothelial cells (EC) drive neovascular retinopathies. While anti-VEGF treatment slows progression, pathology is often supported by decrease in intraocular pigment epithelium-derived factor (PEDF), an endogenous inhibitor of angiogenesis. A surface helical 34-mer peptide of PEDF, comprising this activity, is efficacious in animal models of neovascular retina disease but remains impractically large for therapeutic use. We sought smaller fragments within this sequence that mitigate choroidal neovascularization (CNV). Expecting rapid intravitreal (IVT) clearance, we also developed a method to reversibly attach peptides to nano-carriers for extended delivery. Synthetic fragments of 34-mer yielded smaller anti-angiogenic peptides, and N-terminal capping with dicarboxylic acids did not diminish activity. Charge restoration via substitution of an internal aspartate by asparagine improved potency, achieving low nM apoptotic response in VEGF-activated EC. Two optimized peptides (PEDF 335, 8-mer and PEDF 336, 9-mer) were tested in a mouse model of laser-induced CNV. IVT injection of either peptide, 2–5 days before laser treatment, gave significant CNV decrease at day +14 post laser treatment. The 8-mer also decreased CNV, when administered as eye drops. Also examined was a nanoparticle-conjugate (NPC) prodrug of the 9-mer, having positive zeta potential, expected to display longer intraocular residence. This NPC showed extended efficacy, even when injected 14 days before laser treatment. Neither inflammatory cells nor other histopathologic abnormalities were seen in rabbit eyes harvested 14 days following IVT injection of PEDF 336 (>200 μg). No rabbit or mouse eye irritation was observed over 12–17 days of PEDF 335 eye drops (10 mM). Viability was unaffected in 3 retinal and 2 choroidal cell types by PEDF 335 up to 100 μM, PEDF 336 (100 μM) gave slight growth inhibition only in choroidal EC. A small anti-angiogenic PEDF epitope (G-Y-D-L-Y-R-V) was identified, variants (adipic-Sar-Y-N-L-Y-R-V) mitigate CNV, with clinical potential in treating neovascular retinopathy. Their shared active motif, Y - - - R, is found in laminin (Ln) peptide YIGSR, which binds Ln receptor 67LR, a known high-affinity ligand of PEDF 34-mer.",
keywords = "Angiogenesis, Choroidal neovascularization, Laminin receptor, Macular degeneration, PEDF, Peptides, Retinopathy, YIGSR",
author = "Nader Sheibani and Shoujian Wang and Darjatmoko, {Soesiawati R.} and Fisk, {Debra L.} and Shahi, {Pawan K.} and Pattnaik, {Bikash R.} and Sorenson, {Christine M.} and Reshma Bhowmick and Volpert, {Olga V.} and Daniel Albert and Ignacio Melgar-Asensio and Jack Henkin",
year = "2019",
month = "11",
day = "1",
doi = "10.1016/j.exer.2019.107798",
language = "English (US)",
volume = "188",
journal = "Experimental Eye Research",
issn = "0014-4835",
publisher = "Academic Press Inc.",

}

TY - JOUR

T1 - Novel anti-angiogenic PEDF-derived small peptides mitigate choroidal neovascularization

AU - Sheibani, Nader

AU - Wang, Shoujian

AU - Darjatmoko, Soesiawati R.

AU - Fisk, Debra L.

AU - Shahi, Pawan K.

AU - Pattnaik, Bikash R.

AU - Sorenson, Christine M.

AU - Bhowmick, Reshma

AU - Volpert, Olga V.

AU - Albert, Daniel

AU - Melgar-Asensio, Ignacio

AU - Henkin, Jack

PY - 2019/11/1

Y1 - 2019/11/1

N2 - Abnormal migration and proliferation of endothelial cells (EC) drive neovascular retinopathies. While anti-VEGF treatment slows progression, pathology is often supported by decrease in intraocular pigment epithelium-derived factor (PEDF), an endogenous inhibitor of angiogenesis. A surface helical 34-mer peptide of PEDF, comprising this activity, is efficacious in animal models of neovascular retina disease but remains impractically large for therapeutic use. We sought smaller fragments within this sequence that mitigate choroidal neovascularization (CNV). Expecting rapid intravitreal (IVT) clearance, we also developed a method to reversibly attach peptides to nano-carriers for extended delivery. Synthetic fragments of 34-mer yielded smaller anti-angiogenic peptides, and N-terminal capping with dicarboxylic acids did not diminish activity. Charge restoration via substitution of an internal aspartate by asparagine improved potency, achieving low nM apoptotic response in VEGF-activated EC. Two optimized peptides (PEDF 335, 8-mer and PEDF 336, 9-mer) were tested in a mouse model of laser-induced CNV. IVT injection of either peptide, 2–5 days before laser treatment, gave significant CNV decrease at day +14 post laser treatment. The 8-mer also decreased CNV, when administered as eye drops. Also examined was a nanoparticle-conjugate (NPC) prodrug of the 9-mer, having positive zeta potential, expected to display longer intraocular residence. This NPC showed extended efficacy, even when injected 14 days before laser treatment. Neither inflammatory cells nor other histopathologic abnormalities were seen in rabbit eyes harvested 14 days following IVT injection of PEDF 336 (>200 μg). No rabbit or mouse eye irritation was observed over 12–17 days of PEDF 335 eye drops (10 mM). Viability was unaffected in 3 retinal and 2 choroidal cell types by PEDF 335 up to 100 μM, PEDF 336 (100 μM) gave slight growth inhibition only in choroidal EC. A small anti-angiogenic PEDF epitope (G-Y-D-L-Y-R-V) was identified, variants (adipic-Sar-Y-N-L-Y-R-V) mitigate CNV, with clinical potential in treating neovascular retinopathy. Their shared active motif, Y - - - R, is found in laminin (Ln) peptide YIGSR, which binds Ln receptor 67LR, a known high-affinity ligand of PEDF 34-mer.

AB - Abnormal migration and proliferation of endothelial cells (EC) drive neovascular retinopathies. While anti-VEGF treatment slows progression, pathology is often supported by decrease in intraocular pigment epithelium-derived factor (PEDF), an endogenous inhibitor of angiogenesis. A surface helical 34-mer peptide of PEDF, comprising this activity, is efficacious in animal models of neovascular retina disease but remains impractically large for therapeutic use. We sought smaller fragments within this sequence that mitigate choroidal neovascularization (CNV). Expecting rapid intravitreal (IVT) clearance, we also developed a method to reversibly attach peptides to nano-carriers for extended delivery. Synthetic fragments of 34-mer yielded smaller anti-angiogenic peptides, and N-terminal capping with dicarboxylic acids did not diminish activity. Charge restoration via substitution of an internal aspartate by asparagine improved potency, achieving low nM apoptotic response in VEGF-activated EC. Two optimized peptides (PEDF 335, 8-mer and PEDF 336, 9-mer) were tested in a mouse model of laser-induced CNV. IVT injection of either peptide, 2–5 days before laser treatment, gave significant CNV decrease at day +14 post laser treatment. The 8-mer also decreased CNV, when administered as eye drops. Also examined was a nanoparticle-conjugate (NPC) prodrug of the 9-mer, having positive zeta potential, expected to display longer intraocular residence. This NPC showed extended efficacy, even when injected 14 days before laser treatment. Neither inflammatory cells nor other histopathologic abnormalities were seen in rabbit eyes harvested 14 days following IVT injection of PEDF 336 (>200 μg). No rabbit or mouse eye irritation was observed over 12–17 days of PEDF 335 eye drops (10 mM). Viability was unaffected in 3 retinal and 2 choroidal cell types by PEDF 335 up to 100 μM, PEDF 336 (100 μM) gave slight growth inhibition only in choroidal EC. A small anti-angiogenic PEDF epitope (G-Y-D-L-Y-R-V) was identified, variants (adipic-Sar-Y-N-L-Y-R-V) mitigate CNV, with clinical potential in treating neovascular retinopathy. Their shared active motif, Y - - - R, is found in laminin (Ln) peptide YIGSR, which binds Ln receptor 67LR, a known high-affinity ligand of PEDF 34-mer.

KW - Angiogenesis

KW - Choroidal neovascularization

KW - Laminin receptor

KW - Macular degeneration

KW - PEDF

KW - Peptides

KW - Retinopathy

KW - YIGSR

UR - http://www.scopus.com/inward/record.url?scp=85072194310&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85072194310&partnerID=8YFLogxK

U2 - 10.1016/j.exer.2019.107798

DO - 10.1016/j.exer.2019.107798

M3 - Article

C2 - 31520600

AN - SCOPUS:85072194310

VL - 188

JO - Experimental Eye Research

JF - Experimental Eye Research

SN - 0014-4835

M1 - 107798

ER -