June 2022
Volume 63, Issue 7
Open Access
ARVO Annual Meeting Abstract  |   June 2022
Protein-like polymers containing a thrombospondin-1 agonist are potent, biosafe inhibitors of choroidal angiogenesis
Author Affiliations & Notes
  • Steven Droho
    Ophthalmology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • Wonmin Choi
    Chemistry, Northwestern University, Evanston, Illinois, United States
  • Mara Fattah
    Chemistry, Northwestern University, Evanston, Illinois, United States
  • Spencer Burton
    Chemistry, Northwestern University, Evanston, Illinois, United States
  • Ashley Nensel
    Chemistry, Northwestern University, Evanston, Illinois, United States
  • Soumitra Punekar
    Chemistry, Northwestern University, Evanston, Illinois, United States
  • David Swygart
    Ophthalmology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • Greg Schwartz
    Ophthalmology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • Nathan C Gianneschi
    Chemistry, Northwestern University, Evanston, Illinois, United States
    Materials Science & Engineering, Northwestern University, Evanston, Illinois, United States
  • Jeremy Lavine
    Ophthalmology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • Footnotes
    Commercial Relationships   Steven Droho None; Wonmin Choi None; Mara Fattah None; Spencer Burton None; Ashley Nensel None; Soumitra Punekar None; David Swygart None; Greg Schwartz None; Nathan Gianneschi Grove Biopharma, Code P (Patent); Jeremy Lavine Grove Biopharma, Code P (Patent)
  • Footnotes
    Support  None
Investigative Ophthalmology & Visual Science June 2022, Vol.63, 289 – F0092. doi:
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    • Get Citation

      Steven Droho, Wonmin Choi, Mara Fattah, Spencer Burton, Ashley Nensel, Soumitra Punekar, David Swygart, Greg Schwartz, Nathan C Gianneschi, Jeremy Lavine; Protein-like polymers containing a thrombospondin-1 agonist are potent, biosafe inhibitors of choroidal angiogenesis. Invest. Ophthalmol. Vis. Sci. 2022;63(7):289 – F0092.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : Thrombospondin1 (TSP1) is a highly potent anti-angiogenic protein that could be a potential therapy for neovascular age-related macular degeneration (nAMD). Proteins and peptides, however, are poor therapeutics because of rapid degradation and clearance. Our group has pioneered a novel platform wherein therapeutic peptides are packaged as high-density brush polymers called protein-like polymers (PLPs). PLPs display active, functional amino acids, are resistant to proteolysis, and have a high molecular weight, improving pharmacokinetics. ABT898 is an 8 mer bioactive TSP1 peptide that binds the CD36 receptor to inhibit angiogenesis. We created a biostable, nontoxic PLP containing the ABT898 peptide, and tested its ability to inhibit choroidal angiogenesis.

Methods : PLP-ABT898 and PLP-Scramble control were synthesized. PLPs were characterized by size exclusion chromatography-multi-angle light scattering to ensure the molecular weight. PLP binding affinity to CD36 was tested using biolayer interferometry and inhibition of fatty acid uptake in CD36-expressing cells. Toxicity was tested using cell viability assays and by intravitreal injection of PLPs followed by hematoxylin and eosin analysis of retinal morphology. PLP effects upon choroidal angiogenesis were measured using the choroidal sprouting assay and the laser-induced choroidal neovascularization (CNV) model in 10-12 week-old male C57BL6/J mice.

Results : PLP-ABT898 bound CD36 with a KD of 12 nM and inhibited fatty acid update with an IC50 of 184 nM. PLP-ABT898 showed mildly reduced viability at 50 mM in ARPE19 cells. PLP-ABT898 intravitreal injection at 40 μM showed no change in retinal or outer nuclear layer thickness compared to PBS or PLP-Scramble control (N=7-10 per group). In the choroidal sprouting assay, PLP-ABT898 inhibited choroidal angiogenesis by 35% at 5 μM, 68% at 10 μM, and 92% at 20 μM (N=15-22, p<0.001 for all) compared to PLP-Scramble. PLP-ABT898 reduced laser-induced CNV area by 2.0-fold (N=19-21, p<0.05) on fluorescein angiography and 2.8-fold (N=18-20, p<0.05) on immunofluorescence analysis.

Conclusions : PLP-ABT898 was nontoxic and effectively inhibited choroidal angiogenesis. PLP-ABT898 is a potential new therapeutic for nAMD. Additionally, PLP technology is translatable to different peptides or combinations of anti-angiogenic peptides for therapeutic targeting of multiple angiogenesis pathways.

This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.

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