Abstract
Neovascular age-related macular degeneration (nAMD) is the leading cause of blindness in the developed world. Current therapy includes monthly intraocular injections of anti-VEGF antibodies, which are ineffective in up to one third of patients. Thrombospondin-1 (TSP1) inhibits angiogenesis via CD36 binding, and its down-regulated expression is negatively associated with the onset of nAMD. Here, we describe TSP1 mimetic protein-like polymers (TSP1 PLPs). TSP1 PLPs bind CD36 with high affinity, resist degradation, show prolonged intraocular half-lives (13.1 hours), have no toxicity at relevant concentrations in vivo (40 μM), and are more efficacious in ex vivo choroidal sprouting assays compared to the peptide sequence and Eylea (aflibercept), the current standard of care anti-VEGF treatment. Furthermore, PLPs exhibit superior in vivo efficacy in a mouse model for nAMD compared to control PLPs consisting of scrambled peptide sequences, using fluorescein angiography and immunofluorescence. Since TSP-1 inhibits angiogenesis by VEGF-dependent and independent mechanisms, TSP1 PLPs are a potential therapeutic for patients with anti-VEGF treatment–resistant nAMD.
Original language | English (US) |
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Article number | eadi8534 |
Journal | Science Advances |
Volume | 9 |
Issue number | 41 |
DOIs | |
State | Published - Oct 2023 |
Funding
This work was supported by the NSF, Division of Material Research grant 2004899 (N.C.G.), NIH grant K08 EY 030923 and R01 EY034486 (J.A.L.), Research to Prevent Blindness Sybil B. Harrington Career Development Award for Macular Degeneration (J.A.L.), Unrestricted Departmental Grant from Research to Prevent Blindness (J.A.L.), NIH and National Eye Institute grant R01EY031029 (G.W.S.), NIH and National Eye Institute grant R01EY031329 (G.W.S.), and National Defense Science and Engineering Graduate Fellowship (A.K.N.). Acknowledgments:W ethankthemembersoftheGianneschiLabforalltheinsightful discussionsandsupportandM.P .Thompsonfortheassistancewithpeptidesynthesis.This workmadeuseof:(i)theIMSERCMSfacilityattheNorthwesternUniversity,whichhasreceived supportfromtheSoftandHybridNanotechnologyExperimental(SHyNE)Resource(NSFECCS-2025633),theStateofIllinois,theInternationalInstituteforNanotechnology(IIN),and NorthwesternUniversity;(ii)theIMSERCNMRfacilityatNorthwesternUniversity,whichhas received support from the Soft and Hybrid Nanotechnology Experimental (SHyNE) Resource (NSFECCS-2025633),NSFCHE-1048773,andNorthwesternUniversity;(iii)theKeckBiophysics Facility,asharedresourceoftheRobertH.LurieComprehensiveCancerCenterofNorthwestern UniversitysupportedinpartbytheNCICancerCenterSupportGrant#P30CA060553;and(iv) theBiologicalImagingFa cility atNorthwesternUniversity(RRID:SCR_017767),supportedbythe ChemistryforLifeProcessesInstitute,theNUOfficeforResearch,theDepartmentofMolecular Biosciences.MicroscopywasperformedattheNorthwesternUniversityCenterforAdvanced MicroscopysupportedbyCCSGP30CA060553awardedtotheRobertHLurieComprehensive CancerCenter.Funding:ThisworkwassupportedbytheNSF ,DivisionofMaterialResearch grant2004899(N.C.G.),NIHgrantK08EY030923andR01EY034486(J.A.L.),ResearchtoPrevent BlindnessSybilB.HarringtonCareerDevelopmentA wardforMacularDegenera tion (J.A.L.), UnrestrictedDepartmentalGrantfromResearchtoPrev ent Blindness(J.A.L.),NIHandNational EyeInstitutegrantR01EY031029(G.W .S.), NIHandNationalEyeInstitutegrantR01EY031329 (G.W .S.), andNationalDefenseScienceandEngineeringGradua te Fellowship(A.K.N.).Author contributions:Conceptualization:W .C., S.M.-P ., G.W .S., J.A.L.,andN.C.G.Synthesisand characterizationofmaterials:W .C., S.M.-P ., A.K.N.,andM.A.F .Exvivosproutingandinvivo assays:S.D.andJ.A.L.Pharmacokineticassay:W .C., S.M.-P ., D.I.S.,A.K.N.,andM.A.F .LIVE/DEAD analysis:W .C. andM.F .Enzymedegradation:W .C., M.A.F ., andA.K.N.Blitzassay:W .C., S.M.-P ., and A.K.N.Fattyaciduptakeassay:S.T .B. Writing–originaldraft:A.K.N.,W .C., N.C.G.,G.W .S., andJ.A.L. Writing–reviewandediting:A.K.N.,W .C., M.A.F ., N.C.G.,G.W .S., andJ.A.L.Competinginterests: N.C.G is acofounderof Grov e Biopharmatowhom intellectual property related to this work is exclusivelylicensed.N.C.G,J.A.L.,andW .C. areallcoinventorsonpatentUS20220280625A1filed byNorthwesternUniversityon2022-06-15(AppNumUS17/634,497,pending)relatedinpartto theworkdescribedherein.Theotherauthorsdeclarethattheyhavenocompetinginterests. Dataandmaterialsavailability:Alldataneededtoevaluatetheconclusionsinthepaperare presentinthepaperand/ortheSupplementaryMaterials.
ASJC Scopus subject areas
- General