WO2023192935A1

WO2023192935A1 - Methods and compositions for the treatment for inflammation and fibrosis in retinal neovascular diseases

Info

Publication number: WO2023192935A1
Application number: PCT/US2023/065141
Authority: WO
Inventors: Akiyoshi Uemura; Udo RUDLOFF; Juan Jose Marugan; Rushikesh Vilas SABLE; Mark James HENDERSON; Raul Ronaldo CALVO; Noel Terrence Southall
Original assignee: The United States Of America, As Represented By The Secretary, Department Of Health And Human Services
Priority date: 2022-03-30
Filing date: 2023-03-30
Publication date: 2023-10-05

Abstract

Methods for treating diabetic retinopathy and age-related macular degeneration (AMD), as well as pharmaceutical compositions relevant thereto are disclosed.

Description

METHODS AND COMPOSITIONS FOR THE TREATMENT FOR INFLAMMATION AND FIBROSIS IN RETINAL NEO VASCULAR DISEASES

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority of U.S. Provisional Patent Application no. 63/325453, filed March 30, 2022, which is hereby incorporated herein by reference in its entirety.

FIELD OF THE INVENTION

[0002] This disclosure relates to methods for treating inflammation and fibrosis in retinal neovascular diseases including diabetic retinopathy and age-related macular degeneration, as well as pharmaceutical compositions relevant thereto.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

[0003] This invention was made with Government support under Federal Grant no. ZIA BC 011267 awarded by the Intramural Research Program of the NIH, NCI, C6nter for Cancer Research and Federal Grant no. ZIA TR000302-02 awarded by the Intramural Research Program of the NIH, National C6nter for Advancing Translational Sciences (NCATS). The Federal Government has certain rights to this invention.

BACKGROUND

[0004] Diabetic retinopathy (DR) and age-related macular degeneration (AMD) are major causes of vision loss in the developed world. In the advanced stage of DR, pre-retinal neovascularization often associates with the formation of fibrovascular membranes, which leads to tractional retinal detachment and blindness. In AMD, choroidal neovascularization causes retinal edema, hemorrhage, and detachment at the macula, resulting in central vision loss. At the end-stage of AMD, subretinal fibrosis irreversibly deteriorates visual acuity. Clinically, inflammation involving macrophage infiltration is implicated in the onset and progression of both DR and AMD. While agents antagonizing vascular endothelial growth factor (VEGF) are employed for the treatment of DR and AMD, pharmacologic modalities are unavailable for the fibrosis in these retinal neovascular diseases. As the numbers of patients with DR and AMD are increasing worldwide, there is therefore a need for more effective treatments for vision loss and the symptoms of DR, AMD, and associated syndromes.

SUMMARY OF THE DISCLOSURE

[0005] In various aspects, the present disclosure relates to methods and compositions for the treatment of DR and AMD.

[0006] One aspect of the disclosure provides a method of treating DR and AMD in a subject, including administering to the subject in need thereof a CD206 (checkpoint) modulator.

[0007] An aspect of the disclosure provides a method of reducing production of CD206 (mannose receptor C-type 1) protein in an eye of a subject, including administering to the subject in need thereof a CD206 modulator.

[0008] An aspect of the disclosure provides a method for reducing the expression of gene MRC1 (mannose receptor C-type 1), which encodes CD206 protein, in an eye of a subject, including administering to the subject in need thereof a CD206 modulator.

[0009] An aspect of the disclosure provides a method for reducing oxidative stress in endothelial cells and/or pericytes in an eye of a subject, including administering to the subject in need thereof a CD206 modulator.

[0010] An aspect of the disclosure provides a method for reducing the concentration of one or more of peroxides, superoxides, nitric oxide, and oxygen free radicals in an eye of a subject, including administering to the subject in need thereof a CD206 modulator.

[0011] An aspect of the disclosure provides a method for reducing production of VEGF protein in an eye of a subject, including administering to the subject in need thereof a CD206 modulator.

[0012] An aspect of the disclosure provides a method for reducing the expression of gene VEGF, which encodes VEGF protein, in an eye of a subject, including administering to the subject in need thereof a CD206 modulator. In embodiments, the VEGF gene is one or more selected from the group consisting of one or more of VEGF-A, VEGF-B, VEGF-C and VEGF-D., and in some embodiments, the VEGF gene is VEGF-A. [0013] An aspect of the disclosure provides a method for reducing the amount of inflammatory and/or fibrotic proteins in an eye of a subject, including administering to the subject in need thereof a CD206 modulator.

[0014] An aspect of the disclosure provides a method for reducing the production of a protein that promotes inflammation and/or fibrosis in an eye of a subject, including administering to the subject in need thereof a CD206 modulator. In embodiments, the protein that promotes inflammation and/or fibrosis is selected from the group consisting of IL-ip, CSF-1, IL-4, IFNy, ANGPT2, TGFp-2, IL-6, CCL2, IL- 10, TNF-a, or IL-13.

[0015] An aspect of the disclosure provides a method for reducing the expression of a gene that encodes a protein that promotes inflammation and/or fibrosis in an eye of a subject, including administering to the subject in need thereof a CD206 modulator.

[0016] In embodiments, the gene that encodes a protein that promotes inflammation and/or fibrosis is selected from the group consisting of ILB1, CSF1, IL4, INFG, ANGPT2, TGFB2, IL6, CCL2, IL10, TNF and IL13.

[0017] An aspect of the disclosure provides a method for reducing aberrant blood vessel growth in an eye of a subject, including administering to the subject in need thereof a CD206 modulator.

[0018] In some embodiments, the blood vessel growth comprises NVE (new vessels everywhere) growth, and in some embodiments the blood vessel growth comprises NVD (new vessels at disk) growth

[0019] An aspect of the disclosure provides a method for reducing vitreous hemorrhages in an eye of a subject, including administering to the subject in need thereof a CD206 modulator.

[0020] An aspect of the disclosure provides a method for reducing epiretinal fibrovascular membrane formation in an eye of a subject, including administering to the subject in need thereof a CD206 modulator.

[0021] An aspect of the disclosure provides a method for reducing tractional retinal detachment in an eye of a subject, including administering to the subject in need thereof a CD206 modulator.

[0022] An aspect of the disclosure provides a method for reducing subretinal fibrosis in an eye of a subject, including administering to the subject in need thereof a CD206 modulator. [0023] An aspect of the disclosure provides a method for reducing production of α -SMA (alpha-smooth muscle actin; ACTA2) in an eye of a subject, including administering to the subject in need thereof a CD206 modulator.

[0024] An aspect of the disclosure provides a method for reducing expression of gene ACTA2, which encodes α -SMA, in an eye of a subject, including administering to the subject in need thereof a CD206 modulator.

[0025] An aspect of the disclosure provides a method for reducing chronic inflammation in an eye of a subject, including administering to the subject in need thereof a CD206 modulator.

[0026] An aspect of the disclosure provides a method for reducing Ibal+ (ionized calcium binding adaptor molecule 1 positive) mononuclear phagocytes in a sub-retinal area of an eye of a subject, including administering to the subject in need thereof a CD206 modulator.

[0027] An aspect of the disclosure provides a method for reducing or eliminating CD206 positive cells in the subretinal space in an eye of a subject, including administering to the subject in need thereof a CD206 modulator.

[0028] An aspect of the disclosure provides a method for increasing production of CD86 in microglia cells in an eye of a subject, including administering to the subject in need thereof a CD206 modulator.

[0029] An aspect of the disclosure provides a method for reducing or eliminating M2- like macrophages in an eye of a subject, including administering to the subject in need thereof a CD206 modulator.

[0030] An aspect of the disclosure provides a method for increasing Ml -like macrophages in an eye of a subject, including administering to the subject in need thereof a CD206 modulator.

[0031] An aspect of the disclosure provides a method for preventing pericyte loss in an eye of a subject, including administering to the subject at risk for pericyte loss a CD206 modulator.

[0032] An aspect of the disclosure provides a method for reducing or eliminating pericyte loss in an eye of a subject, including administering to the subject in need thereof a CD206 modulator [0033] An aspect of the disclosure provides a method for preventing a proliferative phase of diabetic retinopathy in an eye of a subject, including administering to the subject in need thereof a CD206 modulator.

[0034] An aspect of the disclosure provides a method for or delaying onset of a proliferative phase of diabetic retinopathy in an eye of a subject, including administering to the subject in need thereof a CD206 modulator.

[0035] An aspect of the disclosure provides a method for preventing onset of fibrosis and proliferative retinopathy in an eye of a subject, including administering to the subject in need thereof a CD206 modulator.

[0036] An aspect of the disclosure provides a method for delaying onset of fibrosis and proliferative retinopathy in an eye of a subject, including administering to the subject in need thereof a CD206 modulator.

[0037] An aspect of the disclosure provides a method for preventing the onset of early or intermediate AMD in an eye of a subject, including administering to the subject in need thereof a CD206 modulator.

[0038] An aspect of the disclosure provides a method for delaying the onset of early or intermediate AMD in an eye of a subject, including administering to the subject in need thereof a CD206 modulator. In some embodiments, the CD206 modulator is present in an amount sufficient to delay the onset of early or intermediate AMD in a treated eye of a subject by an average of at least about 1 day, 7 days, 14 days, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 18 months, 24 months, 30 months, 36 months, 42 months, 48 months, 54 months, 5 years, 6 years, 7 years, 8 years, 9 years, 10 years, or more than 10 year.

[0039] An aspect of the disclosure provides a method for preventing the onset of late AMD in an eye of a subject, comprising administering to the subject in need thereof a CD206 modulator.

[0040] An aspect of the disclosure provides a method for delaying the onset of late AMD in an eye of a subject, comprising administering to the subject in need thereof a CD206 modulator. In some embodiments, the CD206 modulator is present in an amount sufficient to delay the onset of late AMD in a treated eye of a subject by an average of at least about 1 day, 7 days, 14 days, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 18 months, 24 months, 30 months, 36 months, 42 months, 48 months, 54 months, 5 years, 6 years, 7 years, 8 years, 9 years, 10 years, or more than 10 year. [0041] An aspect of the disclosure provides a method for preventing the onset of nonexudative (dry) or exudative (wet) age-related macular degeneration (AMD) in an eye of a subject, comprising administering to the subject in need thereof a CD206 modulator.

[0042] An aspect of the disclosure provides a method for delaying the onset of nonexudative (dry) or exudative (wet) age-related macular degeneration (AMD) in an eye of a subject, comprising administering to the subject in need thereof a CD206 modulator. In some embodiments, the CD206 modulator is present in an amount sufficient to delay the onset of dry or wet AMD in a treated eye of a subject by an average of at least about 1 day, 7 days, 14 days, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 18 months, 24 months, 30 months, 36 months, 42 months, 48 months, 54 months, 5 years, 6 years, 7 years, 8 years, 9 years, 10 years, or more than 10 years.

[0043] An aspect of the disclosure provides a method for preventing onset of sub-retinal fibrosis of AMD in an eye of a subject, including administering to the subject in need thereof a CD206 modulator.

[0044] An aspect of the disclosure provides a method for delaying onset of sub-retinal fibrosis of AMD in an eye of a subject, including administering to the subject in need thereof a CD206 modulator. In some embodiments, the CD206 modulator is present in an amount sufficient to delay the onset of sub-retinal fibrosis of AMD in a treated eye of a subject by an average of at least about 1 day, 7 days, 14 days, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 18 months, 24 months, 30 months, 36 months, 42 months, 48 months, 54 months, 5 years, 6 years, 7 years, 8 years, 9 years, 10 years, or more than 10 years.

[0045] An aspect of the disclosure provides a method for reducing macular degeneration in a subject by an average of at least about 5, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, 90, more than 90%, or substantially eliminate macular degeneration.

[0046] An aspect of the disclosure provides a method for delaying onset of sub-retinal fibrosis of AMD in an eye of a subject, including administering to the subject in need thereof a CD206 modulator.

[0047] In embodiments of aspects of the disclosure, the CD206 modulator is NGCG00413972, and in embodiments of aspects of the disclosure, an effective amount of the CD206 modulator is a daily dose of about 1 x 10^-8, 1 MO^-7, 1 MO^-6, 1 MO^-5, 1 MO^-4, 1 MO^-3, I x lO^-2, or I x lO^-1 grams. [0048] In embodiments of various aspects of the disclosure, the CD206 modulator is administered topically, orally, periocularly, via an insert, via an implanted device, or via a drop.

[0049] In embodiments of various aspects of the disclosure, the CD206 modulator is administered in a carrier vehicle which is liquid drops, liquid wash, gel, ointment, polymer micro and nanoparticles, solution, suspension, solid, biodegradable matrix, powder, crystals, foam, or liposomes.

[0050] In embodiments, the CD206 modulator is administered orally, and in some embodiments, the CD206 modulator is administered topically, wherein the topical administration comprises infusion of the CD206 modulator to the eyes via a device selected from the group consisting of a pump-catheter system, an insert, a continuous or selective release device, a bioabsorbable implant, a continuous or sustained release formulation, and a contact lens.

[0051] In embodiments of various aspects of the disclosure, a therapeutically effective amount of the CD206 modulator is delivered to an eye of said subject via local or systemic delivery.

[0052] In embodiments of various aspects of the disclosure, the act of administering is accomplished by administering an intra-ocular instillation of a gel, cream, powder, foam, crystals, liposomes, polymer micro or nanoparticles, or liquid suspension form of the CD206 modulator.

[0053] In embodiments of various aspects of the disclosure, the CD206 modulator is administered to the subject in an amount sufficient to achieve intraocular or retinal concentrations of from about 1 nM (nanomoles per liter) to about 1 mM (millimoles per liter). [0054] In embodiments of various aspects of the disclosure, the CD206 modulator and any co-administered therapeutic agent, in embodiments the co-administered therapeutic agent in the form of a pharmaceutical composition, are administered at least once a day, or at least once a week, or at least once a month, or at least once a year.

[0055] In embodiments of various aspects of the disclosure, the methods further include a step of determining that the subject is in need of treatment for diabetic retinopathy.

[0056] In embodiments of various aspects of the disclosure, the methods further include administering a second therapeutic agent, in embodiments the co-administered therapeutic agent in the form of a pharmaceutical composition, prior to, in combination with, at the same time, or after administration of the CD206 modulator. In embodiments, the second therapeutic agent is selected from the group consisting of anti-angiogenic agents, anti- oxidative agents (antioxidants), anti-apoptotic agents, each alone or in combinations thereof. [0057] An aspect of the disclosure provides a pharmaceutical composition formulated for ocular delivery including a CD206 modulator and a pharmaceutically acceptable carrier. In some embodiments, the CD206 modulator is NCGC00413972. In embodiments, the pharmaceutical compositions are suitable for periocular administration; and, in some embodiments, the pharmaceutical compositions are suitable for oral administration.

[0058] An aspect of the disclosure provides a method of treating diabetic retinopathy and AMD in a subject in need thereof including (1) identifying a subject in need of treatment for diabetic retinopathy and AMD; and (2) administering to the subject an effective amount of a composition including compound NCGC00413972, or a pharmaceutically acceptable salt thereof.

[0059] An aspect of the disclosure provides a method of treating age-related macular degeneration (AMD) in a subject in need thereof including (1) identifying a subject in need of treatment for diabetic retinopathy and AMD; and (2) administering to the subject an effective amount of a composition including compound NCGC00413972, or a pharmaceutically acceptable salt thereof. In embodiments, the subject also has diabetic retinopathy.

[0060] In embodiments of various aspects of the disclosure, the CD206 modulator is administered prior to or during the inflammatory phase of diabetic retinopathy.

[0061] In embodiments of various aspects of the disclosure, the CD206 modulator is administered prior to or during the non-proliferative phase of diabetic retinopathy.

[0062] In embodiments of various aspects of the disclosure, the CD206 modulator is administered prior to or during the proliferative phase of diabetic retinopathy.

[0063] In embodiments of various aspects of the disclosure, the CD206 modulator is administered prior to the formation of or onset of AMD.

[0064] In embodiments of various aspects of the disclosure, the CD206 modulator is administered after the onset of AMD.

[0065] In embodiments of various aspects of the disclosure, AMD is selected from the group consisting of early/intermediate AMD, late AMD, dry AMD and wet AMD.

[0066] In embodiments of various aspects of the disclosure, the CD206 modulator is administered prior to the formation of or onset of sub-retinal fibrosis of AMD

[0067] These and other aspects of the disclosure are set forth in more detail in the description of the disclosure below. BRIEF DESCRIPTION OF THE DRAWINGS

[0068] FIG. 1 is an electron micrograph showing an endothelial cell (EC) and associated pericyte (PC) of retinal vasculature. Diabetic retinopathy is linked to the loss of pericytes surrounding retinal vasculature.

[0069] FIG. 2 shows murine fixed eye sections at postnatal day ten (P10), fourteen (P14) and twenty-one (P21) after rat anti-mouse PDGFRP monoclonal antibody APB 5 was intraperitoneally injected into Pl mice, causing depletion of pericytes, elevated retinal vascular leakage, and retinal hemorrhage, edema, and detachment. Induction of subretinal fibrosis in the eye (visualized by smooth muscle actin (SMA) content; red staining) after anti- PDGFRβ inhibition progresses centripetally by P 14 in pericyte-deficient retinas, resulting in contraction of the initially round eyeball and disturbance of the histological retinal structure on P21.

[0070] FIG. 3A and Fig. 3B show gene expression levels of inflammatory cytokines measured by qRT-PCR and normalized to housekeeping genes in excised retinas including Il lb, 116, Tnfa, and Ccl2 (cytokines associated with inflammation; Ml phenotype promoting) peaked at P14, whereas those of 114, 1110, 1113, and Tgfb2 (cytokines associated with alternative macrophage activation and fibrosis; M2 phenotype promoting) peaked at P21, indicating a shift in cell-infiltrates in pericyte-deficient retinas from inflammatory to fibrotic phases between P14 and P21. Normal retinas are the represented by lower curve in each graph; pericyte-deficient retinas are represented by the upper curve in each graph.

[0071] FIG. 4A shows that after single IP injections of APB5 at Pl, Ibal-positive macrophages derived from activated microglia and circulating monocytes infiltrated around pericyte-deficient vessels in the superficial retinal area at P8. Fig. 4B shows that after the onset of retinal detachment around P10, macrophages migrated toward apoptotic neurons in the deep retinal area and accumulated in the subretinal spaces.

[0072] FIG. 5 shows the association of macrophages with myofibroblasts in subretinal fibrosis. In subretinal fibrosis, α-smooth muscle actin (αSMA)-positive myofibroblasts were intimately associated with the infiltration of Ibal-positive macrophages. Note the epithelial- mesenchymal transition in the underlying retinal pigment epithelial cells.

[0073] FIG. 6A and Fig. 6B are a flow cytometric analysis showing CD45hi (Ml-like) and CD45int (M2 -like) macrophages in pericyte-deficient retinas. Fig. 6A shows control and APB5-treated cells at postnatal days P7 and P14; whereas, FIG. 6B shows the control and APB5-treated cells at P21 and P28. In pericyte deficient retinas, CD45hiCDl lb+ (Ml-like) macrophages were decreased between P14 and P21, whereas CD45intCDl lb+ (M2-like) macrophages remained over months.

[0074] FIG. 7 shows histogram analyses of the flow cytometry data of Fig. 6A and Fig. 6B for postnatal days P8, P9, PIO, and P12.

[0075] FIG. 8 shows that in pericyte-deficient retinas (APB 5 -treated), CD206-positive macrophages migrate from the superficial to the deep retinal areas during the inflammatory phase. Postnatal days P8, P9, PIO and P12 shown.

[0076] FIG. 9A and Fig. 9B show flow cytometry histograms indication CD206 positive macrophage cell fractions (x axis). FIG. 9A shows control retinas; whereas, Fig. 9B shows pericyte-deficient retinas that, unlike controls, exhibit CD45int M2-like macrophages that continuously expressed CD206 during the fibrotic phase. FIG. 9C shows tissue immunofluorescence staining of normal and pericyte-deficient eyes at P21. In the fibrotic phase (P21), macrophages expressed CD206 only in the subretinal (fibrotic), but not intraretinal (neural retinal), areas. FIG. 9D shows quantification of the CD206 expression in intra-retinal (left) versus sub-retinal (right) areas compared to Ibal control.

[0077] FIG. 10A is an experimental schematic to evaluate treatment efficacy of NCGC00413972 in pericyte-deficient retinas. Every-other-day IP injections of NCGC00413972 (10 mg/kg, 10 mice) versus vehicle (8 mice) were administered starting in the inflammatory phase (from P7) and administered for 2 weeks. Fig. 10B and Fig. 10C show retinal cryo-sections of right and left eyes of mice harvested at P21 that were immunostained for αSMA and Iba expression in conjunction with DAPI nuclear labeling. Because subretinal fibrosis occurred only in the eyes with retinal detachment, samples without retinal detachment were excluded from the analyses.

[0078] FIG. 11 A through Fig. 1 ID show retinal cryo-sections of right and left eyes of mice harvested at P21 that were immunostained for αSMA and Iba expression in conjunction with DAPI nuclear labeling. Subretinal and intraretinal sections are shown. Because subretinal fibrosis occurred only in the eyes with retinal detachment, samples without retinal detachment were excluded from the analyses. Fig. 11A shows vehicle-treated mice 1-5; Fig. 11B shows vehicle-treated mice 6-8; Fig. 11C shows NCGC00413972-treated mice 1-5 and Fig. 11D shows NCGC00413972-treated mice 6-10.

[0079] FIG. 12 shows quantification of the experiments shown in Fig. 11 A through Fig. 11D. Compared with the eyes from vehicle-treated mice, the eyes from NCGC00413972- treated mice showed significant reduction of subretinal fibrosis represented by the αSMA- positive areas (P = 0.0194) and subretinal, but not intraretinal, Ibal -positive macrophages (P = 0.001).

[0080] FIG. 13A and Fig. 13B show retinal cryo-sections of right and left eyes of mice harvested at P21 that were immunostained for αSMA and Iba expression in conjunction with DAPI nuclear labeling. Instead of vehicle, control mice were treated with NCGC00123051, an inactive analog of NCGC00413972. These experiments reproduced the anti-fibrotic effects of intraperitoneal NCGC00413972 injections. In addition, NCGC00413972 significantly increased the number of CD86/CD206-double positive macrophages, indicating reprogramming of M2-like macrophages into Ml -like macrophages. FIG. 13A shows mice 1-5 and Fig. 13B shows mice 6-9 for NCGC00413972-treated mice (or 6-10 for NCGC00123051-treaeted mice).

[0081] FIG. 14 shows quantification of the experiments shown in Fig. 13A and Fig. 13B. Compared with the eyes from NCGC00123051 -treated mice, the eyes from NCGC00413972-treated mice showed significant reduction of subretinal fibrosis represented by the αSMA-positive areas (P=0.0451) and subretinal, but not intraretinal, Ibal-positive macrophages (P=0.0035). NCGC00413972-treated mice also showed a significant decrease in (M2 marker) CD206+ in sub-retinal area and a significant increase in the number of CD86/CD206-double positive macrophages, indicating reprogramming of M2-like macrophages into Ml -like macrophages in the sub-retina.

[0082] FIG. 15 is a liquid chromatography mass spectroscopy (LCMS) chromatogram of a liquid formulation of NCGC00413972.

DETAILED DESCRIPTION

[0083] The present disclosure is explained in greater detail below. This description is not intended to be a detailed catalog of all the different ways in which the disclosure may be implemented, or all the features that may be added to the instant disclosure. For example, features illustrated with respect to one embodiment may be incorporated into other embodiments, and features illustrated with respect to a particular embodiment may be deleted from that embodiment. Numerous variations and additions to the various embodiments suggested herein will be apparent to those skilled in the art in light of the instant disclosure, which do not depart from the instant disclosure. Hence, the following specification is intended to illustrate some particular embodiments of the disclosure, and not to exhaustively specify all permutations, combinations, and variations thereof. [0084] Unless the context indicates otherwise, it is specifically intended that the various features of the disclosure described herein can be used in any combination. Moreover, the present disclosure also contemplates that in some embodiments of the disclosure, any feature or combination of features set forth herein can be excluded or omitted. To illustrate, if the specification states that a complex comprises components A, B and C, it is specifically intended that any of A, B or C, or a combination thereof, can be omitted and disclaimed singularly or in any combination.

[0085] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. The terminology used in the description of the disclosure herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the disclosure.

[0086] All publications, patent applications, patents, nucleotide sequences, amino acid sequences and other references mentioned herein are incorporated by reference in their entireties for all purposes.

[0087] Definitions

[0088] The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting. As used herein, the singular forms “a,” “an,” and “the” are intended to include the plural forms as well, unless the context clearly indicates otherwise. It will be further understood that the terms “comprises” and/or “comprising,” and/or “including” when used in this specification, specify the presence of stated features, elements, and/or components, but do not preclude the presence or addition of one or more other features, elements, components, and/or groups thereof. As used herein, the term “and/or” includes any and all combinations of one or more of the associated listed items. As used herein, phrases such as “between X and Y” and “between about X and Y” should be interpreted to include X and Y. As used herein, phrases such as “between about X and Y” mean “between about X and about Y.” As used herein, phrases such as “from about X to Y” mean “from about X to about Y.”

[0089] Moreover, the present disclosure also contemplates that in some embodiments, any feature or combination of features set forth herein can be excluded or omitted.

[0090] Furthermore, the term “about,” as used herein when referring to a measurable value such as an amount of a compound or agent of this disclosure, dose, time, temperature, and the like, is meant to encompass variations of ±10%, ±5%, ±1%, ±0.5%, or even ±0.1% of the specified amount.

[0091] As used herein, the transitional phrase “consisting essentially of’ is to be interpreted as encompassing the recited materials or steps and those that do not materially affect the basic and novel characteristic(s) of the disclosure. Thus, the term “consisting essentially of’ as used herein should not be interpreted as equivalent to “comprising.”

[0092] “Pharmaceutical compositions” means compositions comprising at least one active agent, such as a compound or salt of Formulae (I), (II), or (III), and at least one other substance, such as a carrier. Pharmaceutical compositions meet the U.S. FDA’s GMP (good manufacturing practice) standards for human or non-human drugs.

[0093] Carrier” means a diluent, excipient, or vehicle with which an active compound is administered. A “pharmaceutically acceptable carrier” means a substance, e.g., excipient, diluent, or vehicle, that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes a carrier that is acceptable for veterinary use as well as human pharmaceutical use. A “pharmaceutically acceptable carrier” includes both one and more than one such carrier.

[0094] “Patient”, “subject”, and “individual” mean a human or non-human animal in need of medical treatment. Medical treatment can include treatment of an existing condition, such as a disease or disorder or diagnostic treatment. In some embodiments the patient is a human patient.

[0095] “Providing” means giving, administering, selling, distributing, transferring (for profit or not), manufacturing, compounding, or dispensing.

[0096] Treat”, “Treatment”, or “treating” mean providing therapeutic agent(s) to a patient who has a disease, a symptom of disease or a predisposition to or risk for developing a disease, with the purpose to cure, heal, alleviate, relieve, alter, remedy, ameliorate, improve, affect, or prevent the disease and/or the symptoms of disease. In embodiments, therapeutic agent(s) are provided in an amount sufficient to measurably reduce any symptoms of diabetic retinopathy and/or AMD, slow progression or cause regression of diabetic retinopathy and/or AMD or prevent diabetic retinopathy and/or AMD. In various embodiments, treatment of diabetic retinopathy and/or AMD may be commenced for a subject who does not exhibit signs of diabetic retinopathy and/or AMD. In some embodiments, treatment may be administered to a subject who exhibits only early signs of diabetic retinopathy and/or AMD for the purpose of decreasing the risk of developing pathology associated with the disease, disorder, and/or condition.

[0097] A “therapeutically effective amount”, an “effective amount” and an “effective dose” of a pharmaceutical composition refer to an amount effective, at dosages and for periods of time necessary, that when administered to a patient provides a desired therapeutic or prophylactic benefit, such as measurably reducing any biological hallmark or symptom of diabetic retinopathy and/or AMD, slowing progression of diabetic retinopathy and/or AMD, causing regression of diabetic retinopathy and/or AMD, or preventing or delaying onset of diabetic retinopathy and/or AMD.

[0098] A significant change is any detectable change that is statistically significant in a standard parametric test of statistical significance such as Student’s t-test, where p < 0.05.

[0099] Reference herein to any numerical range (for example, a dosage range) expressly includes each numerical value (including fractional numbers and whole numbers) encompassed by that range. For example, but without limitation, reference herein to a range of 0.5 mg to 100 mg explicitly includes all whole numbers of and fractional numbers between the upper and lower limit of the range, inclusive of the upper and lower limit.

[00100] An individual referred to as “suffering from” diabetic retinopathy and/or AMD, as described herein, has been diagnosed with and/or displays one or more symptoms of diabetic retinopathy and/or AMD.

[00101] As used herein, the term “at risk” for diabetic retinopathy and/or AMD, refers to a subject (e.g., a human) that is predisposed to developing diabetic retinopathy and/or AMD, and/or expressing one or more symptoms of the diseases. This predisposition may be genetic or due to other factors, such as pre-diabetes. It is not intended that the present disclosure be limited to any particular signs or symptoms. Thus, it is intended that the present disclosure encompasses subjects that are experiencing any range of diabetic retinopathy and/or AMD, from sub-clinical to non-proliferative diabetic retinopathy to proliferative diabetic retinopathy, and from dry AMD to wet AMD, wherein the subject exhibits at least one of the indicia (e.g., signs and symptoms) associated with diabetic retinopathy and/or AMD.

[00102] The terms “peptide” and “polypeptide” are used synonymously herein to refer to polymers constructed from amino acid residues. [00103] Biology of Diabetic Retinopathy and Age-related Macular Degeneration

[00104] Ocular complications of diabetes are a leading cause of visual loss and blindness worldwide. One hallmark of diabetic retinopathy (DR) is the development of alterations in the retinal microvasculature that leads to loss of microcapillary autoregulation. Diabetic retinopathy exhibits a spectrum of symptoms and is often divided into two categories (1) nonproliferative DR and (2) proliferative DR.

[00105] In the quiescent state, including the early stage of DR, microglial cells help maintain tissue homeostasis in the retina through phagocytosis and control of low-grade inflammation. However, prolonged tissue stress due to hyperglycemia (thought to be oxidative stress in cells, in particular endothelial cells and pericytes surrounding endothelial cells) leads to the formation of an excess of toxic end-products of oxidation, including peroxides, superoxides, nitric oxide, and oxygen free radicals, which primes microglia to become reactive with a concomitant production of pro-inflammatory cytokines and chemokines, e.g., Vascular Endothelial Growth Factor (VEGF). Chronic inflammation and new blood vessel growth (including new vessels at disk, “NVD” and new vessels elsewhere; “NVE”) is promoted, as is vascular permeability. New, abnormal ‘fragile’ blood vessels can lead to bleeding, causing vitreous hemorrhages. NVD and NVE may cause epiretinal fibrovascular membrane formation (fibrosis contracting and distorting the macula), and tractional retinal detachment (TRD) causing loss of vision and blindness.

[00106] Adhering to diagnostic stage, non-proliferative diabetic retinopathy begins with abnormalities of the normal microvascular architecture characterized by degeneration of retinal capillaries, formation of saccular capillary microaneurysms, pericyte deficient capillaries, and capillary occlusion and obliteration. Mechanisms of action include diabetes-induced vascular inflammation leading to occlusion of the vascular lumen by leukocytes and platelets followed by the eventual death of both pericytes and endothelial cells. Attraction and adhesion of leukocytes to the vascular wall by the inflammatory process cause leukocytes to adhere temporarily to the endothelium (leukostasis), release cytotoxic factors, and injure or kill the endothelial cell. The damaged endothelial surface initiates platelet adherence, aggregation, microthrombus formation, vascular occlusion and ischemia. Retinal ganglion cells are eventually lost, leading to visual loss or blindness. Disrupted autoregulation and decreased retinal blood flow resulting from the changes in vasculature in endothelial cells, pericyte death, and capillary obliteration are markers for progression of DR, which leads to development of retinal ischemia, which in turn enables development of the more severe, proliferative stage of diabetic retinopathy.

[00107] Proliferative DR includes neovascularization or angiogenesis, induced by retinal ischemia of the disc or other locations of the retina. This new vasculature can cause hemorrhage of the vitreous humor and retinal detachments from accompanying contractile fibrous tissue.

[00108] Blood sugar control has not proved sufficient to end the progression from healthy retinal structure and function to non-proliferative DR, then to proliferative DR. Thus, the disclosure provides methods and compositions for treating diabetic retinopathy.

[00109] Age-related macular degeneration (AMD) is a chronic, progressive, multifactorial, late-onset disease characterized by the formation of lipid-rich extracellular deposits (“drusen”) that accumulate in the retina and block absorption of nutrients, localized inflammation, and ultimately neurodegeneration in the central part of the retina (macula). The etiology of AMD is complex, with advanced age and family history being major risk factors. [00110] Clinical examination of human retinas can reveal distinct hallmarks of AMD that can be broadly divided into early/intermediate and late (i.e., advanced) stages.

Early/intermediate AMD is the most common and least severe form, characterized by pigmentary abnormalities in the macula and accumulation of drusen. Late AMD is usually subdivided into nonexudative (“dry”; geographic atrophy) and wet (choroidal neovascularization) subtypes.

[00111] Nonexudative AMD and exudative AMD have been shown to not be significantly associated with diabetes alone; however, nonexudative and exudative AMD have been shown to be highly correlated to diabetes with DR.

[00112] CD206 Modulator Compounds and Pharmaceutical Compositions

[00113] Various methods and pharmaceutical compositions described herein include the use of a CD206 modulator compound.

[00114] In various aspects of the methods and pharmaceutical compositions as otherwise described herein, the CD206 modulator is a compound of Formula I or a pharmaceutically- acceptable salt thereof:

[00115] Wherein for Formula I the following conditions are met:

[00116] Each bond shown as a solid line and a dashed line together, , can be a single bond, double, or aromatic bond.

[00117] R¹ is hydrogen, halogen, hydroxyl, cyano, -CO2H, C₁-C₆alkyl, C2-C6alkenyl, C2- C6alkynyl, C₁-C₆alkoxy, -(Co-C6alkyl)cycloalkyl, C₁-C₆haloalkyl, -(Co-C6alkyl)phenyl, - (Co-C6alkyl)aryl, -(Co-C₆alkyl)heteroaryl, -C(O)Ci-C₆alkyl, -C(O)NR⁸R⁹, -(Co- C6alkyl)NR⁵R⁶, -CO2R⁶, -C6Hi-R⁷, and a monocyclic or bicyclic heterocycle of 4 to 10 ring atoms having 1, 2, or 3 ring atoms independently chosen from N, S and O.

[00118] R², R³, and R⁴ are each independently chosen at each occurrence from hydrogen, halogen, hydroxyl, cyano, -CO2H, C₁-C₆alkyl, C2-C6alkenyl, C2-C6alkynyl, C₁-C₆alkoxy, -(Co-C6alkyl)cycloalkyl, C₁-C₆haloalkyl, -(Co-C6alkyl)phenyl, -(Co-C6alkyl)aryl, -(Co- C₆alkyl)heteroaryl, -C(O)Ci-C₆alkyl, -C(O)NR⁵R⁶, (Co-C₆alkyl)NR⁸R⁹ -CO2R⁶, and - C₆H₄-R⁷.

[00119] a, b, c, d, and X are each independently chosen at each occurrence from N, C, and CH.

[00120] R⁵, and R⁶ are each independently chosen at each occurrence from hydrogen, halogen, hydroxy, Cl-C6alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆alkoxy, a substituted or unsubstituted -(Co-C6alkyl)cycloalkyl, -(Co-C6alkyl)phenyl, -(Co- C6alkyl)aryl, -(Co-C6alkyl)heteroaryl, -C(O)C₁-C₆alkyl, -C(0)(Co-C6alkyl)phenyl, -(Co- C6alkyl)NR⁸R⁹, - C(0)(Co-C6alkyl)aryl, -C(0)(Co-C6alkyl)heteroaryl, and a 4- to 7- membered heterocycloalkyl ring having 1, 2, or 3 ring atoms independently chosen from N, O, and S.

[00121] Any R⁵ and R⁶ bound to the same nitrogen atom may be taken together to form a 4- to 7-membered monocyclic heterocycloalkyl ring or 6- to 11 -membered bridged bicyclic heterocycloalkyl ring, which heterocycloalkyl ring contains 0, 1, or 2 additional heteroatoms chosen from N, O, S, S(O), and SO2 which heterocycloalkyl ring is optionally substituted at any carbon or hetero ring atom with halogen, hydroxyl, cyano, oxo, dioxo, C₁-C₆alkyl, C₁-C₆alkoxy, C₁-C₆haloalkyl, -(Co-C6alkyl)cycloalkyl, -(Co- C₆alkyl)phenyl, -(Co-C₆alkyl)aryl, -(Co-C6alkyl)C0₂R⁸, -(Co-C₆alkyl)C(0)NR⁸R⁹, -(Ci- C6alkyl)OR⁸, -C(O)Ci-C₆alkyl, -(Co-C₆alkyl)NR⁸R⁹, or -C(0)(Co-C₆alkyl)NR⁸R⁹.

[00122] R⁷ is hydrogen, halogen, hydroxyl, cyano, -CO2H, C₁-C₆alkyl, C2-C6alkenyl, C2- C6alkynyl, C₁-C₆alkoxy, C₁-C₆haloalkyl, -(Co-C6alkyl)cycloalkyl, -(Co-C6alkyl)phenyl, - (Co-C6alkyl)aryl, -(Co-C₆alkyl)heteroaryl, -CO2R⁸, -C(O)Ci-C₆alkyl, -C(O)C2-C₆alkenyl, - C(O)C₂-C₆alkynyl, -C(O)Ci-C₆alkoxy, -C(O)Ci-C₆hydroxyalkyl, -C(0)-(Co- C6alkyl)cycloalkyl, -C(0)-(Co-C6alkyl)phenyl, -C(0)-(Co-C6alkyl)aryl, -C(0)-(Co- C₆alkyl)heteroaryl, -C(O)NR⁸R⁹, -C(O)NR⁵R⁶, -C(0)-(Co-C₆alkyl)NR⁵R⁶, -C(O)-NR⁸- (Co-C₆alkyl)NR⁵R⁶, or (Co-C₆alkyl)NR⁵R⁶.

[00123] R⁸ and R⁹ are each independently chosen at each occurrence from hydrogen, halogen, C₁-C₆ alkyl, C₁-C₆alkoxy, C₁-C₆haloalkyl, -(Co-C6alkyl)phenyl, -(Co- C₆alkyl)aryl, -(Co-C₆alkyl)NR⁵R⁶, -CO2R⁶, -C(O)Ci-C₆alkyl, and -(Co- C6alkyl)cycloalkyl.

[00124] In various such methods and pharmaceutical compositions in which the CD206 modulator is a compound of Formula I or a pharmaceutically-acceptable salt thereof:

[00125] R¹ is -C6H4-R⁷.

[00126] R² and R⁴ are H.

[00127] R³ is -(Co-C6alkyl)phenyl, -(Co-C6alkyl)aryl, or -(Co-C6alkyl)heteroaryl.

[00128] a, c, and X are N.

[00129] b is C.

[00130] d is CH.

[00131] R⁷ is -C(O)NR⁵R⁶ or -C(O)-NR⁸-(C0-C₆alkyl)NR⁵R⁶.

[00132] R⁵ and R⁶ are each independently chosen at each occurrence from hydrogen, a substituted or unsubstituted -(Co-C6alkyl)cycloalkyl, -(Co-C6alkyl)heteroaryl, Ci- C6hydroxyalkyl, C₁-C₆alkoxy, -(Co-C6alkyl)NR⁸R⁹, and a 4- to 7-membered heterocycloalkyl ring having 1, 2, or 3 ring atoms independently chosen from N, O, and S.

[00133] Any R⁵ and R⁶ bound to the same nitrogen atom may be taken together to form a 4- to 7-membered monocyclic heterocycloalkyl ring or 6- to 11 -membered bridged bicyclic heterocycloalkyl ring, which heterocycloalkyl ring contains 0, 1, or 2 additional heteroatoms chosen from N, O, S, S(O), and SO2 which heterocycloalkyl ring is optionally substituted at any carbon or hetero ring atom with halogen, hydroxyl, cyano, oxo, dioxo, C₁-C₆alkyl, C₁-C₆alkoxy, C₁-C₆haloalkyl, -(Co-C6alkyl)cycloalkyl, -(Co- C₆alkyl)phenyl, -(Co-C₆alkyl)aryl, -(Co-C6alkyl)C0₂R⁸, -(Co-C₆alkyl)C(0)NR⁸R⁹, -(Ci- C6alkyl)OR⁸, -CO2R⁸, -C(O)Ci-C₆alkyl, -(Co-C₆alkyl)NR⁸R⁹, or -C(0)(Co- C₆alkyl)NR⁸R⁹.

[00134] R⁸ and R⁹ are each independently chosen at each occurrence from hydrogen, halogen, C₁-C₆ alkyl, C₁-C₆alkoxy, C₁-C₆haloalkyl, -(Co-C6alkyl)phenyl, -(Co- C₆alkyl)aryl, -(Co-C₆alkyl)NR⁵R⁶, -CO2R⁶, -C(O)Ci-C₆alkyl, and -(Co- C6alkyl)cycloalkyl.

[00135] In various such methods and pharmaceutical compositions in which the CD206 modulator is a compound of Formula I or a pharmaceutically-acceptable salt thereof:

[00136] R¹ is -C6H4-R⁷.

[00137] R² and R⁴ are hydrogen.

[00138] R³ is -(Co-C6alkyl)phenyl, -(Co-C6alkyl)aryl, or -(Co-C6alkyl)heteroaryl.

[00139] a, c, d, and X are N.

[00140] b is C.

[00141] R⁷ is -C(0)-NR⁸-(Co-C₆alkyl)NR⁵R⁶.

[00142] R⁵ and R⁶ bound to the same nitrogen atom may be taken together to form a 4- to 7-membered monocyclic heterocycloalkyl ring or 6- to 11 -membered bridged bicyclic heterocycloalkyl ring, which heterocycloalkyl ring contains 0, 1, or 2 additional heteroatoms chosen from N, O, S, S(O), and SO2 which heterocycloalkyl ring is optionally substituted at any carbon or hetero ring atom with halogen, hydroxyl, cyano, oxo, dioxo, C₁-C₆alkyl, C₁-C₆alkoxy, C₁-C₆haloalkyl, -(Co-C6alkyl)cycloalkyl, -(Co- C6alkyl)phenyl, or -(Co-C6alkyl)aryl.

[00143] R⁸ is hydrogen.

[00144] In various such methods and pharmaceutical compositions in which the CD206 modulator is a compound of Formula I or a pharmaceutically-acceptable salt thereof:

[00145] R¹ is -C6H4-R⁷.

[00146] R² and R⁴ are hydrogen.

[00147] R³ is -(Co-C6alkyl)phenyl, -(Co-C6alkyl)aryl, or -(Co-C6alkyl)heteroaryl.

[00148] a is C.

[00149] b, d, and X are N.

[00150] c is CH.

[00151] R⁷ is -C(0)-NR⁸-(Co-C₆alkyl)NR⁵R⁶,

[00152] R⁵ and R⁶ bound to the same nitrogen atom may be taken together to form a 4- to 7-membered monocyclic heterocycloalkyl ring or 6- to 11 -membered bridged bicyclic heterocycloalkyl ring, which heterocycloalkyl ring contains 0, 1, or 2 additional heteroatoms chosen from N, O, S, S(O), and SO2 which heterocycloalkyl ring is optionally substituted at any carbon or hetero ring atom with halogen, hydroxyl, cyano, oxo, dioxo, C₁-C₆alkyl, C₁-C₆alkoxy, C₁-C₆haloalkyl, -(Co-C6alkyl)cycloalkyl, -(Co- C6alkyl)phenyl, or -(Co-C6alkyl)aryl.

[00153] R⁸ is hydrogen.

[00154] In various such methods and pharmaceutical compositions in which the CD206 modulator is a compound of Formula I or a pharmaceutically-acceptable salt thereof:

[00155] R² and R⁴ are hydrogen.

[00156] R³ is -(Co-C6alkyl)phenyl, -(Co-C6alkyl)aryl, or -(Co-C6alkyl)heteroaryl.

[00157] a is C.

[00158] b and X are N.

[00159] c and d are CH.

[00160] R⁷ is -C(0)-NR⁸-(Co-C₆alkyl)NR⁵R⁶

[00161] R⁵ and R⁶ bound to the same nitrogen atom may be taken together to form a 4- to 7-membered monocyclic heterocycloalkyl ring or 6- to 11 -membered bridged bicyclic heterocycloalkyl ring, which heterocycloalkyl ring contains 0, 1, or 2 additional heteroatoms chosen from N, O, S, S(O), and SO2 which heterocycloalkyl ring is optionally substituted at any carbon or hetero ring atom with halogen, hydroxyl, cyano, oxo, dioxo, C₁-C₆alkyl, C₁-C₆alkoxy, C₁-C₆haloalkyl, -(Co-C6alkyl)cycloalkyl, -(Co- C6alkyl)phenyl, or -(Co-C6alkyl)aryl.

[00162] R⁸ is hydrogen.

[00163] In various aspects of the methods and pharmaceutical compositions as otherwise described herein, the CD206 modulator is a compound of Formula II or a pharmaceutically- acceptable salt thereof:

Formula II

[00164] Wherein for Formula II the following conditions are met:

[00165] Each bond shown as a solid line and a dashed line together, , can be a single or double bond.

[00166] R¹⁰, R¹¹, and R¹³ are each independently chosen at each occurrence from hydrogen, hydroxyl, -CO2H, C₁-C₆alkyl, C2-C6alkenyl, C2-C6alkynyl, C₁-C₆alkoxy, -(Co- C6alkyl)cycloalkyl, C₁-C₆haloalkyl, -(Co-C6alkyl)phenyl, -(Co-C6alkyl)aryl, -(Co- C6alkyl)heteroaryl, -C(O)C₁-C₆alkyl, -C(O)heteroaryl, and -CO2R¹⁶.

[00167] R¹², R¹⁴, and R¹⁵ are each independently chosen at each occurrence from hydrogen, halogen, hydroxyl, and cyano.

[00168] X is O or S.

[00169] R¹⁶ is hydrogen, halogen, hydroxy, an amino group, C₁-C₆alkyl, C2-C6alkenyl, C2-C6alkynyl, C₁-C₆alkoxy, -(Co-C6alkyl)cycloalkyl, -C(O)C₁-C₆alkyl, -(Co- C6alkyl)aryl, -(Co-C6alkyl)heteroaryl, -(Co-C6alkyl)phenyl, or a monocyclic or bicyclic heterocycle of 4 to 10 ring atoms having 1, 2, or 3 ring atoms independently chosen from N, S and O.

[00170] In various such methods and pharmaceutical compositions in which the CD206 modulator is a compound of Formula II or a pharmaceutically-acceptable salt thereof, the compound of Formula II is a compound of Formula IIA

Formula IIA.

[00171] In various such methods and pharmaceutical compositions in which the CD206 modulator is a compound of Formula IIA or a pharmaceutically-acceptable salt thereof:

[00172] R¹⁰ and R¹¹ are each independently chosen at each occurrence from -(Co- C6alkyl)phenyl, -(Co-C6alkyl)aryl, and -(Co-C6alkyl)heteroaryl.

[00173] R¹², R¹⁴ and R¹⁵ are hydrogen.

[00174] R¹³ is -C(O)heteroaryl.

[00175] In various such methods and pharmaceutical compositions in which the CD206 modulator is a compound of Formula IIA or a pharmaceutically-acceptable salt thereof:

[00176] R¹⁰ is -(Co-C6alkyl)phenyl.

[00177] R¹¹ is -(Co-C6alkyl)heteroaryl.

[00178] R¹², R¹⁴ and R¹⁵ are hydrogen.

[00179] R¹³ is -C(O)heteroaryl.

[00180] In various aspects of the methods and pharmaceutical compositions as otherwise described herein, the CD206 modulator is a compound of Formula III or a pharmaceutically- acceptable salt thereof:

Formula III

[00181] Within Formula III the following conditions are met:

[00182] R¹⁷, R¹⁸, and R²¹ are each independently chosen at each occurrence from hydrogen, halogen, hydroxyl, cyano, an amidino group, -NR²³R²⁴ a sulfonic acid group or a salt thereof, a phosphoric acid group or a salt thereof, -CO2H, C₁-C₆alkyl, C2-C6alkenyl, C2- C6alkynyl, C₁-C₆alkoxy, -(Co-C6alkyl)cycloalkyl, C₁-C₆haloalkyl, -(Co-C6alkyl)phenyl, -(Co- C6alkyl)aryl, -(Co-C6alkyl)heteroaryl, -C(O)C₁-C₆alkyl, -C(0)(Co-C6alkyl)phenyl, -C(0)(Co- C₆alkyl)aryl, -C(0)(Co-C₆alkyl)heteroaryl, -C(O)NR²³R²⁴, -(Co-C₆alkyl)NR²³R²⁴ -CO2R²³, and a monocyclic or bicyclic heterocycle of 4 to 10 ring atoms having 1, 2, or 3 ring atoms independently chosen from N, S and O.

[00183] X is chosen at each occurrence from O and S.

[00184] R¹⁹, R²⁰, and R²² are each independently chosen at each occurrence from hydrogen, halogen, hydroxy, cyano, and an amino group.

[00185] R²³ and R²⁴ are each independently chosen at each occurrence from hydrogen, halogen, C₁-C₆ alkyl, C₁-C₆alkoxy, C₁-C₆haloalkyl, C₁-C₆haloalkoxy, C₁-C₆alkoxy, -(Co- C6alkyl)phenyl, -(Co-C6alkyl)aryl, -(Co-C6alkyl)heteroaryl, -C(0)(Co-C6alkyl)phenyl, - C(0)(Co-C6alkyl)aryl, -C(0)(Co-C6alkyl)heteroaryl, -S(O)phenyl, -S(O)aryl, -S(O)heteroaryl, -SO₂phenyl, -SO₂aryl, -SO₂heteroaryl, -(Co-C6alkyl)cycloalkyl, and -CO2R²⁵.

[00186] R²⁵ is hydrogen, halogen, hydroxy, an amino group, C₁-C₆alkyl, C2-C6alkenyl,

C2-C6alkynyl, C₁-C₆alkoxy, -(Co-C6alkyl)cycloalkyl, -C(O)C₁-C₆alkyl, -(Co-C6alkyl)aryl, - (Co-C6alkyl)heteroaryl, -(Co-C6alkyl)phenyl, or a monocyclic or bicyclic heterocycle of 4 to 10 ring atoms having 1, 2, or 3 ring atoms independently chosen from N, S and O.

[00187] In various such methods and pharmaceutical compositions in which the CD206 modulator is a compound of Formula III or a pharmaceutically-acceptable salt thereof:

[00188] R¹⁷ is -C(O)Ci-C₆alkyl, -C(0)(Co-C₆alkyl)phenyl, -C(0)(Co-C₆alkyl)aryl, or - C(0)(Co-C6alkyl)heteroaryl .

[00189] R¹⁸ is C₁-C₆alkyl, C2-C6alkenyl, C2-C6alkynyl, C₁-C₆alkoxy, -(Co-

C6alkyl)cycloalkyl, C₁-C₆haloalkyl, -(Co-C6alkyl)phenyl, -(Co-C6alkyl)aryl, or -(Co- C6alkyl)heteroaryl .

[00190] R¹⁹, R²⁰ and R²² are hydrogen. [00191] R²¹ is -NR²³R²⁴.

[00192] X is chosen at each occurrence from O and S.

[00193] R²³ and R²⁴ are each independently chosen at each occurrence from -S(O)phenyl,

-S(O)aryl, -S(O)heteroaryl, -SO₂phenyl, -SO₂aryl, -SO₂heteroaryl, -(Co- C6alkyl)cycloalkyl, and -CO2R²⁵.

[00194] R²⁵ is C₁-C₆alkyl, -(Co-C6alkyl)cycloalkyl, -(Co-C6alkyl)aryl, or -(Co- C6alkyl)phenyl.

[00195] In various such methods and pharmaceutical compositions in which the CD206 modulator is a compound of Formula III or a pharmaceutically-acceptable salt thereof:

[00196] R¹⁷ is -C(O)Ci-C₆alkyl.

[00197] R¹⁸ is C₁-C₆alkyl.

[00198] R¹⁹, R²⁰ and R²² are hydrogen.

[00199] R²¹ is -NR²³R²⁴

[00200] X is oxygen.

[00201] R²³ and R²⁴ are each independently chosen at each occurrence from a substituted or unsubstituted aryl sulfonyl, -CO2R²⁵, -SO₂phenyl, -SO₂aryl, and -SO2R²⁵.

[00202] R²⁵ is phenyl.

[00203] In various aspects of the methods and pharmaceutical compositions as otherwise described herein, the CD206 modulator is a compound of a structure labeled Compound 1 through Compound 33 below, or a pharmaceutically-acceptable salt thereof:

Compound 25;

[00204] In various aspects of the methods and pharmaceutical compositions as otherwise described herein, the CD206 modulator is Compound 28, or a pharmaceutically-acceptable salt thereof. Compound 28 is also referred to herein as “NCGC00413972” and “NCGC72”. [00205] Various CD206 modulators of the disclosure, as well as synthetic preparations therefor, are described in International Patent Application no. 2021/126923, which is hereby incorporated herein by reference in its entirety.

[00206] In the compounds described herein, suitable groups that may be present on an "optionally substituted" position include, but are not limited to, e.g., halogen, cyano, hydroxyl, amino, nitro, oxo, azido, alkanoyl (such as a C2-C6 alkanoyl group such as acyl or the like (-(C=0)alkyl)); carboxamido; alkylcarboxamide; alkyl groups, alkoxy groups, alkylthio groups including those having one or more thioether linkages, alkylsulfinyl groups including those having one or more sulfinyl linkages, alkylsulfonyl groups including those having one or more sulfonyl linkages, mono- and di-aminoalkyl groups including groups having one or more N atoms, all of the foregoing optional alkyl substituents may have one or more methylene groups replaced by an oxygen or -NH-, and have from about 1 to about 8, from about 1 to about 6, or from 1 to about 4 carbon atoms, cycloalkyl; phenyl; phenylalkyl with benzyl being an exemplary phenylalkyl group, phenylalkoxy with benzyloxy being an exemplary phenylalkoxy group. Alkylthio and alkoxy groups are attached to the position they substitute by the sulfur or oxygen atom respectively.

[00207] “Alkyl” includes both branched and straight chain saturated aliphatic hydrocarbon groups, having the specified number of carbon atoms, generally from 1 to about 8 carbon atoms. The term Ci-C6alkyl as used herein indicates an alkyl group having from 1, 2, 3, 4, 5, or 6 carbon atoms. Other embodiments include alkyl groups having from 1 to 8 carbon atoms, 1 to 4 carbon atoms or 1 or 2 carbon atoms, e.g. Ci-Csalkyl, Ci-C4alkyl, and Ci-C2alkyl. When Co-Cn alkyl is used herein in conjunction with another group, for example, -Co-C2alkyl(phenyl), the indicated group, in this case phenyl, is either directly bound by a single covalent bond (Coalkyl), or attached by an alkyl chain having the specified number of carbon atoms, in this case 1, 2, 3, or 4 carbon atoms. Alkyls can also be attached via other groups such as heteroatoms as in -0-Co-C4alkyl(C3-C7cycloalkyl). Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, 3 -methylbutyl, t- butyl, n- pentyl, and sec-pentyl.

[00208] “Alkenyl” is a branched or straight chain aliphatic hydrocarbon group having one or more carbon-carbon double bonds that may occur at any stable point along the chain, having the specified number of carbon atoms. Examples of alkenyl include, but are not limited to, ethenyl and propenyl.

[00209] “Alkynyl” is a branched or straight chain aliphatic hydrocarbon group having one or more double carbon-carbon triple bonds that may occur at any stable point along the chain, having the specified number of carbon atoms.

[00210] “Alkoxy” is an alkyl group as defined above with the indicated number of carbon atoms covalently bound to the group it substitutes by an oxygen bridge (-O-). Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, 2- butoxy, t-butoxy, n-pentoxy, 2-pentoxy, 3- pentoxy, isopentoxy, neopentoxy, n- hexoxy, 2- hexoxy, 3-hexoxy, and 3- methylpentoxy. Similarly, an “Alkylthio” or a “thioalkyl” group is an alkyl group as defined above with the indicated number of carbon atoms covalently bound to the group it substitutes by a sulfur bridge (-S-).

[00211] “Aryl” is a substituted stable monocyclic or polycyclic aromatic ring having 1 to 60 ring carbon atoms. Aryl groups include, but are not limited to, tolyl, xylyl, naphthyl, phenanthryl, and anthracenyl.

[00212] “Cycloalkyl” is a saturated hydrocarbon ring group, having the specified number of carbon atoms, usually from 3 to about 7 carbon atoms. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl as well as bridged or caged saturated ring groups such as norborane or adamantane. “-(Co-Cnalkyl)cycloalkyl” is a cycloalkyl group attached to the position it substitutes either by a single covalent bond (Co) or by an alkylene linker having 1 to n carbon atoms.

[00213] “Halo” or “halogen” means fluoro, chloro, bromo, or iodo. [00214] “Heteroaryl” is a stable monocyclic aromatic ring having the indicated number of ring atoms which contains from 1 to 3, or in some embodiments from 1 to 2, heteroatoms chosen from N, O, and S, with remaining ring atoms being carbon, or a stable bicyclic or tricyclic system containing at least one 5- to 7-membered aromatic ring which contains from 1 to 3, or in some embodiments from 1 to 2, heteroatoms chosen from N, O, and S, with remaining ring atoms being carbon. Monocyclic heteroaryl groups typically have from 5 to 7 ring atoms. In some embodiments bicyclic heteroaryl groups are 9- to 10-membered heteroaryl groups, that is, groups containing 9 or 10 ring atoms in which one 5- to 7-member aromatic ring is fused to a second aromatic or non-aromatic ring. When the total number of S and O atoms in the heteroaryl group exceeds 1, these heteroatoms are not adjacent to one another. It is preferred that the total number of S and O atoms in the heteroaryl group is not more than 2. It is particularly preferred that the total number of S and O atoms in the aromatic heterocycle is not more than 1. Heteroaryl groups include, but are not limited to, oxazolyl, piperazinyl, pyranyl, pyrazinyl, pyrazolopyrimidinyl, pyrazolyl, pyridizinyl, pyridyl, pyrimidinyl, pyrrolyl, quinolinyl, tetrazolyl, thiazolyl, thienylpyrazolyl, thiophenyl, triazolyl, benzol d|oxazolyl, benzofuranyl, benzothiazolyl, benzothiophenyl, benzoxadiazolyl, dihydrobenzodioxynyl, furanyl, imidazolyl, indolyl, isothiazolyl, and isoxazolyl.

[00215] “Heterocycle” is a saturated, unsaturated, or aromatic cyclic group having the indicated number of ring atoms containing from 1 to about 3 heteroatoms chosen from N, O, and S, with remaining ring atoms being carbon. Examples of heterocycle groups include piperazine and thiazole groups.

[00216] “Heterocycloalkyl” is a saturated cyclic group having the indicated number of ring atoms containing from 1 to about 3 heteroatoms chosen from N, O, and S, with remaining ring atoms being carbon. Examples of heterocycloalkyl groups include tetrahydrofuranyl and pyrrolidinyl groups.

[00217] “Haloalkyl” means both branched and straight-chain alkyl groups having the specified number of carbon atoms, substituted with 1 or more halogen atoms, generally up to the maximum allowable number of halogen atoms. Examples of haloalkyl include, but are not limited to, trifluoromethyl, difluoromethyl, 2-fluoroethyl, and penta-fluoroethyl.

[00218] “Haloalkoxy” is a haloalkyl group as defined above attached through an oxygen bridge (oxygen of an alcohol radical).

[00219] “Pharmaceutically acceptable salts” include derivatives of the disclosed compounds in which the parent compound is modified by making inorganic and organic, nontoxic, acid or base addition salts thereof. The salts of the present compounds can be synthesized from a parent compound that contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting free acid forms of these compounds with a stoichiometric amount of the appropriate base (such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate, or the like), or by reacting free base forms of these compounds with a stoichiometric amount of the appropriate acid. Such reactions are typically carried out in water or in an organic solvent, or in a mixture of the two. Generally, nonaqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are used, where practicable. Salts of the present compounds further include solvates of the compounds and of the compound salts.

[00220] Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts and the quaternary ammonium salts of the parent compound formed, for example, from non- toxic inorganic or organic acids. For example, conventional non-toxic acid salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxy maleic, phenylacetic, glutamic, benzoic, salicylic, mesylic, esylic, besylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, HOOC-(CH2)n-COOH where n is 0-4, and the like. Lists of additional suitable salts may be found, e.g., in G. Steffen Paulekuhn, et al, Journal of Medicinal Chemistry 2007, 50, 6665 and Handbook of Pharmaceutically Acceptable Salts: Properties, Selection and Use, P. Heinrich Stahl and Camille G. Wermuth Editors, Wiley- VCH, 2002.

[00221] Methods of Treatment

[00222] In some embodiments of the disclosure, methods are provided to administer a therapeutic agent to a subject to treat diabetic retinopathy and/or AMD. In some embodiments of the disclosure, the therapeutic agent is a CD206 modulator. In some embodiments, the CD206 modulator is a competitive antagonist of the CD206 receptor. In some embodiments, the CD206 modulator is an allosteric antagonist of the CD206 receptor. In some embodiments, the CD206 modulator is NCGC00413972. In some aspects and embodiments of the disclosure, the CD206 modulator can affect one or more of the following activities in the eye of a subject: (1) reducing the production of CD206 protein; (2) reducing the expression of gene MRC1 (mannose receptor C-type 1), which encodes CD206 protein; (3) reducing oxidative stress in endothelial cells and/or pericytes; (4) reducing the concentration of one or more of peroxides, superoxides, nitric oxide, and oxygen free radicals; (5) reducing production of VEGF protein; (6) reducing the expression of gene VEGF,' (7) reducing the amount of inflammatory and/or fibrotic proteins; (8) reducing the production of a protein that promotes inflammation and/or fibrosis, including, e.g., IL-ip, CSF-1, IL-4, IFNy, ANGPT2, TGFp-2, IL-6, CCL2, IL- 10, TNF-a, or IL-13; (9) reducing the expression of a gene that encodes a protein that promotes inflammation and/or fibrosis, including, e.g., genes ILB1, CSF1, IL4, INFG, ANGPT2, TGFB2, IL6, CCL2, IL10, TNF and IL13\ (10) reducing aberrant blood vessel growth; (11) reducing vitreous hemorrhages; (12) reducing epiretinal fibrovascular membrane formation; (13) reducing tractional retinal detachment; (14) reducing subretinal fibrosis; (15) reducing production of α -SMA (alphasmooth muscle actin; ACTA2); (16) reducing expression of gene ACTA2, which encodes a- SMA; (16) reducing chronic inflammation; (17) reducing Ibal+ (ionized calcium binding adaptor molecule 1 positive) mononuclear phagocytes in a sub-retinal area; (18) reducing or eliminating CD206 positive cells in the subretinal space; (19) increasing production of CD86 in microglia cells; (20) reducing or eliminating M2 -like macrophages; (21) increasing Ml- like macrophages; (22) preventing pericyte loss; (23) reducing or eliminating pericyte loss; (24) preventing a proliferative phase of diabetic retinopathy; (25) delaying onset of a proliferative phase of diabetic retinopathy; (26) preventing the onset of fibrosis and proliferative retinopathy; and (27) delaying the onset of fibrosis and proliferative retinopathy. (28) preventing a wet type of AMD; (29) delaying onset of a wet type of AMD; (30) preventing the onset of fibrosis in wet AMD; and (31) delaying the onset of fibrosis in wet AMD.

[00223] Another embodiment of the disclosure treats a subject by administering a therapeutically effective amount of a CD206 modulator to reduce, eliminate or prevent chronic ocular inflammation. An embodiment of the disclosure treats a subject with symptoms of diabetic retinopathy and AMD by administering a therapeutically effective amount of a CD206 modulator. In some embodiments of the disclosure methods are provided to treat a subject with symptoms of Type II diabetes by administering a therapeutically effective amount of a CD206 modulator. In yet other embodiments of the disclosure, methods are provided to treat a subject by administering a therapeutically effective amount of a CD206 modulator to decrease retinal and choroidal neovascularization in an eye of the subject. In some embodiments of the disclosure, methods are provided to treat a subject by administering a therapeutically effective amount of a CD206 modulator to halt, reduce or eliminate the loss of vision due to diabetic retinopathy and AMD. In some embodiments, methods are provided to treat a subject by administering a therapeutically effective amount of a CD206 modulator to decrease retinal ischemia in an eye of the subject. In other embodiments, methods are provided to decrease fibrovascular growth over, within, and beneath a retina in an eye of a subject suffering from diabetic retinopathy and AMD, by administering a therapeutically effective amount of a CD206 modulator. In some embodiments, methods are provided to reduce retinal injury or degeneration due to diabetic retinopathy and AMD in an eye of a subject suffering from diabetic retinopathy and AMD, by administering a therapeutically effective amount of a CD206 modulator. In other embodiments, methods are provided to limit non-proliferative damage to a retina in an eye of a subject suffering from diabetic retinopathy and AMD, by administering a therapeutically effective amount of a CD206 modulator. In other embodiments, methods are provided to slow proliferative damage to a retina in an eye of a subject suffering from diabetic retinopathy and AMD, by administering a therapeutically effective amount of a CD206 modulator. In other embodiments, methods are provided to reduce or prevent adhesion of leukocytes to capillary epithelial cells in an eye of a subject in need thereof, by administering a therapeutically effective amount of a CD206 modulator. In some embodiments of the disclosure, methods are provided wherein the CD206 modulator which is administered to the subject suffering from diabetic retinopathy and AMD, binds to CD206 receptors in the eye of a subject. Some embodiments of the disclosure utilize compounds that are competitive inhibitors of the CD206 receptor. In some embodiments, methods are provided which administer to a subject in need of treatment a therapeutically effective amount of a CD206 modulator which is a compound of Formulas I, II, or III, and/or of Compounds 1-33.

[00224] The methods generally involve the administration of one or more drugs for the treatment of diabetic retinopathy and AMD where the drug is delivered systemically, e.g., orally, or directly to the intraocular region of the eye, among other modes of administration described elsewhere herein. Combinations of agents can be used to treat diabetic retinopathy and AMD or to modulate the side-effects of one or more agents in the combination. Since the pathological events in these disease states are marked by a combination of impaired autoregulation, apoptosis, ischemia, reperfused tissue, neovascularization, and inflammatory stimuli, it may be desirable to administer the CD206 modulators of the disclosure in combination with other therapeutic agents to additively or synergistically intervene. In some embodiments, the second therapeutic agent is an antioxidant, an anti-VEGF agent, and/or anti-apoptotic agent. In some embodiments of the disclosure, in addition to administering a compound which directly competes for binding to the CD206 receptor, an additional therapeutic agent may be administered which is an allosteric, but not a directly competitive, anatagonist of the CD206 receptor, potentially resulting in synergistic efficacy. Examples of antagonists include Peptide A, which comprises, consists essentially of, or consists of a peptide having the sequence Lys-Phe-Arg-Lys-Ala-Phe-Lys-Arg-Phe-Phe (SEQ ID NO: 1) and Peptide B, which comprises, consists essentially of, or consists of a peptide having the sequence Phe-Ala-Lys-Lys-Phe-Ala-Lys-Lys-Phe-Lys (SEQ ID NO:2).

[00225] Another class of therapeutic agents which may be useful to administer in combination, prior to, after, or concomitantly with the CD206 modulators of the disclosure is the group of drugs that specifically inhibit Vascular Endothelial Growth Factor (VEGF) and thus may target another route of initiation of neovascularization. Any VEGF inhibitor may be of use in the compositions of the disclosure, which include, but are not limited to neutralizing monoclonal antibodies against VEGF or its receptor, small molecule tyrosine kinase inhibitors of VEGF receptors, soluble VEGF decoy receptors, ribozymes which specifically target VEGF, and siRNA which specifically target VEGF signaling proteins. Some examples of antibodies which are active against VEGF include ranibizumab, bevacizumab and faricimab. An example of a soluble VEGF decoy receptor is aflibercept. An example of an oligonucleotide drug is pegaptanib sodium (injection). Small molecule tyrosine kinase inhibitors include, for example, pazopanib, sorafenib, sutent, and the like.

[00226] Oxidative stress may be induced in cells with impaired autoregulatory and ischemic processes induced by diabetic retinopathy and AMD. Thus, anti-oxidants may be useful to administer in combination with the CD206 modulators of the disclosure.

Examples include, e.g., ascorbic acid, tocopherols, tocotrienols, carotinoids, glutathione, alpha-lipoic acid, ubiquinols, bioflavonoids, carnitine, and superoxide dismutase mimetics, such as, for example, 2,2,6,6-tetramethyl-l-piperidinyloxy (TEMPO), DOXYL, PROXYL nitroxide compounds; 4-hydroxy-2,2,6,6-tetramethyl-l-piperidinyloxy (Tempol), M-40401, M-40403, M-40407, M-40419, M-40484, M-40587, M-40588, and the like.

[00227] In some stages of diabetic retinopathy and AMD, retinal ischemia can result, causing further cell death. In some embodiments, methods are provided wherein anti- apoptotic therapeutic agents may be administered in combination with the CD206 modulators of the disclosure. Examples include, for example, inhibitors of caspases, cathepsins, and TNF-a. [00228] Examples of other therapeutic agents which may be useful to administer in combination, prior to, after, or concomitantly with the CD206 modulator of the disclosure are peptides. Examples include Peptide A, which comprises, consists essentially of, or consists of a peptide having the sequence Lys-Phe-Arg-Lys-Ala-Phe-Lys-Arg-Phe-Phe (SEQ ID NO: 1) and Peptide B, which comprises, consists essentially of, or consists of a peptide having the sequence Phe-Ala-Lys-Lys-Phe-Ala-Lys-Lys-Phe-Lys (SEQ ID NO:2).

[00229] In some embodiments, the CD206 modulator is present in an amount sufficient to exert a therapeutic effect to reduce one or more symptoms of diabetic retinopathy and AMD by an average of at least about 5, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, 90, more than 90%, or substantially eliminate one or more symptoms of diabetic retinopathy and AMD.

[00230] In some embodiments, the CD206 modulator is present in an amount sufficient to reduce the production of CD206 protein in a treated eye of a subject by an average of at least about 5, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, 90, more than 90%, or substantially eliminate production of CD206 protein in the eye either overall or, e.g., as compared to levels measured in healthy, non-DR, non-AMD eyes.

[00231] In some embodiments, the CD206 modulator is present in an amount sufficient to reduce the expression of gene MRC1 (mannose receptor C-type 1), which encodes CD206 protein in a treated eye of a subject by an average of at least about 5, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, 90, more than 90%, or substantially eliminate such expression either overall or, e.g., as compared to levels measured in healthy, non-DR, non-AMD eyes.

[00232] In some embodiments, the CD206 modulator is present in an amount sufficient to reduce oxidative stress in endothelial cells and/or pericytes in a treated eye of a subject by an average of at least about 5, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, 90, more than 90%, or substantially eliminate such oxidative stress either overall or, e.g., as compared to levels measured in healthy, non-DR, non-AMD eyes.

[00233] In some embodiments, the CD206 modulator is present in an amount sufficient to reduce the concentration of one or more of peroxides, superoxides, nitric oxide, and oxygen free radicals in a treated eye of a subject by an average of at least about 5, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, 90, more than 90%, or substantially eliminate such peroxides, superoxides, nitric oxide, and oxygen free radicals overall or, e.g., present above levels measured in healthy, non-DR, non-AMD eyes.

[00234] In some embodiments, the CD206 modulator is present in an amount sufficient to reduce production of VEGF protein in a treated eye of a subject by an average of at least about 5, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, 90, more than 90%, or substantially eliminate such VEGF production overall or, e.g., present above levels measured in healthy, non-DR, non- AMD eyes.

[00235] In some embodiments, the CD206 modulator is present in an amount sufficient to reduce the expression of gene VEGF in a treated eye of a subject by an average of at least about 5, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, 90, more than 90%, or substantially eliminate the expression of gene VEGF either overall or, e.g., as compared to levels measured in healthy, non-DR, non- AMD eyes.

[00236] In some embodiments, the CD206 modulator is present in an amount sufficient to reduce the amount of inflammatory and/or fibrotic proteins in a treated eye of a subject by an average of at least about 5, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, 90, more than 90%, or substantially eliminate inflammatory and/or fibrotic proteins either overall or, e.g., as compared to levels measured in healthy, non-DR, non-AMD eyes.

[00237] In some embodiments, the CD206 modulator is present in an amount sufficient to reduce the production of one or more proteins that promote inflammation and/or fibrosis, including, e.g., IL-1 p, CSF-1, IL-4, IFNy, ANGPT2, TGFp-2, IL-6, CCL2, IL-10, TNF-a, and IL-13 in a treated eye of a subject by an average of at least about 5, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, 90, more than 90%, or substantially eliminate such production of inflammatory and/or fibrosis-promoting proteins either overall or, e.g., as compared to levels measured in healthy, non-DR, non-AMD eyes.

[00238] In some embodiments, the CD206 modulator is present in an amount sufficient to reduce the expression of a gene that encodes a protein that promotes inflammation and/or fibrosis, including, e.g., genes ILB1, CSF1, IL4, INFG, ANGPT2, TGFB2, IL6, CCL2, IL10, TNF and ELI 3 in a treated eye of a subject by an average of at least about 5, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, 90, more than 90%, or substantially eliminate such gene expression either overall or, e.g., as compared to levels measured in healthy, non-DR, non-AMD eyes.

[00239] In some embodiments, the CD206 modulator is present in an amount sufficient to reduce (e.g., aberrant) blood vessel growth in a treated eye of a subject by an average of at least about 5, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, 90, more than 90%, or substantially eliminate such blood vessel growth either overall or, e.g., as compared to levels measured in healthy, non-DR, non-AMD eyes.

[00240] In some embodiments, the CD206 modulator is present in an amount sufficient to reduce vitreous hemorrhages in a treated eye of a subject by an average of at least about 5, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, 90, more than 90%, or substantially eliminate such vitreous hemorrhages either overall or, e.g., as compared to levels measured in healthy, non- DR, non-AMD eyes.

[00241] In some embodiments, the CD206 modulator is present in an amount sufficient to reduce fibrovascular epiretinal membrane formation in a treated eye of a subject by an average of at least about 5, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, 90, more than 90%, or substantially eliminate such fibrovascular epiretinal membrane formation either overall or, e.g., as compared to levels measured in healthy, non-DR, non-AMD eyes.

[00242] In some embodiments, the CD206 modulator is present in an amount sufficient to reduce tractional retinal detachment in a treated eye of a subject by an average of at least about 5, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, 90, more than 90%, or substantially eliminate such tractional retinal detachment either overall or, e.g., as compared to levels measured in healthy, non-DR, non-AMD eyes.

[00243] In some embodiments, the CD206 modulator is present in an amount sufficient to reduce subretinal fibrosis associated with retinal detachment in a treated eye of a subject by an average of at least about 5, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, 90, more than 90%, or substantially eliminate such subretinal fibrosis associated with retinal detachment either overall or, e.g., as compared to levels measured in healthy, non-DR, non-AMD eyes.

[00244] In some embodiments, the CD206 modulator is present in an amount sufficient to reduce production of α -SMA (alpha-smooth muscle actin; ACTA2) in a treated eye of a subject by an average of at least about 5, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, 90, more than 90%, or substantially eliminate such production of α -SMA (alpha-smooth muscle actin;

ACTA2) either overall or, e.g., as compared to levels measured in healthy, non-DR, non- AMD eyes.

[00245] In some embodiments, the CD206 modulator is present in an amount sufficient to reduce expression of gene ACTA2, which encodes α -SMA in a treated eye of a subject by an average of at least about 5, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, 90, more than 90%, or substantially eliminate such gene expression either overall or, e.g., as compared to levels measured in healthy, non-DR, non-AMD eyes.

[00246] In some embodiments, the CD206 modulator is present in an amount sufficient to reduce chronic inflammation in a treated eye of a subject by an average of at least about 5, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, 90, more than 90%, or substantially eliminate such chronic inflammation either overall or, e.g., as compared to levels measured in healthy, non- DR, non-AMD eyes. [00247] In some embodiments, the CD206 modulator is present in an amount sufficient to reduce Ibal+ (ionized calcium binding adaptor molecule 1 positive) mononuclear phagocytes in a sub-retinal area in a treated eye of a subject by an average of at least about 5, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, 90, more than 90%, or substantially eliminate such Iba+ mononuclear phagocytes in the sub-retinal area either overall or, e.g., as compared to levels measured in healthy, non-DR, non-AMD eyes.

[00248] In some embodiments, the CD206 modulator is present in an amount sufficient to reduce or eliminating CD206 positive cells in the subretinal space in a treated eye of a subject by an average of at least about 5, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, 90, more than 90%, or substantially eliminate such CD206 positive cells in the subretinal space either overall or, e.g., as compared to levels measured in healthy, non-DR, non-AMD eyes.

[00249] In some embodiments, the CD206 modulator is present in an amount sufficient to increase production of CD86 in microglia cells in a treated eye of a subject by an average of at least about 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 2-fold, 3- fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold or more than 10-fold the amount of CD86 in microglia cells either overall or, e.g., as compared to levels measured in healthy, non-DR, non-AMD eyes.

[00250] In some embodiments, the CD206 modulator is present in an amount sufficient to reduce or eliminating M2 -like macrophages in a treated eye of a subject by an average of at least about 5, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, 90, more than 90%, or substantially eliminate such M2-like macrophages either overall or, e.g., as compared to levels measured in healthy, non-DR, non-AMD eyes.

[00251] In some embodiments, the CD206 modulator is present in an amount sufficient to increase Ml -like macrophages in a treated eye of a subject by an average of at least about 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 2-fold, 3-fold, 4-fold, 5- fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold or more than 10-fold the amount of Ml-like macrophages either overall or, e.g., as compared to levels measured in healthy, non-DR, non- AMD eyes.

[00252] In some embodiments, the CD206 modulator is present in an amount sufficient to prevent pericyte loss in a treated eye of a subject.

[00253] In some embodiments, the CD206 modulator is present in an amount sufficient to reduce or eliminating pericyte loss in a treated eye of a subject by an average of at least about 5, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, 90, more than 90%, or substantially eliminate such pericyte loss either overall or, e.g., as compared to levels measured in healthy, non-DR, nonAMD eyes.

[00254] In some embodiments, the CD206 modulator is present in an amount sufficient to prevent the occurrence of the proliferative phase of diabetic retinopathy.

[00255] In some embodiments, the CD206 modulator is present in an amount sufficient to delay onset of the proliferative phase of diabetic retinopathy in a treated eye of a subject by an average of at least about 1 day, 7 days, 14 days, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 18 months, 24 months, 30 months, 36 months, 42 months, 48 months, 54 months, 5 years, 6 years, 7 years, 8 years, 9 years, 10 years, or more than 10 years.

[00256] In some embodiments, the CD206 modulator is present in an amount sufficient to prevent the onset of fibrosis and proliferative retinopathy.

[00257] In some embodiments, the CD206 modulator is present in an amount sufficient to delay the onset of fibrosis and proliferative retinopathy in a treated eye of a subject by an average of at least about 1 day, 7 days, 14 days, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 18 months, 24 months, 30 months, 36 months, 42 months, 48 months, 54 months, 5 years, 6 years, 7 years, 8 years, 9 years, 10 years, or more than 10 years.

[00258] In other embodiments, the CD206 modulator is present in an amount sufficient to reduce retinal degeneration in a subject by an average of at least about 5, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, 90, more than 90%, or substantially eliminate retinal degeneration.

[00259] In some embodiments, the CD206 modulator is present in an amount sufficient to reduce retinal edema in a treated eye of a subject by an average of at least about 5, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, 90, more than 90%, or substantially eliminate retinal edema.

[00260] In yet other embodiments, the CD206 modulator is present in an amount sufficient to reduce basement membrane thickening in a treated eye of a subject by an average of at least about 5, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, 90, more than 90%, or substantially eliminate basement membrane thickening.

[00261] In some embodiments, the CD206 modulator is present in an amount sufficient to reduce retinal neovascularization in a treated eye of a subject by an average of at least about 5, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, 90, more than 90%, or substantially eliminate retinal neovascularization.

[00262] In some embodiments, the CD206 modulator is present in an amount sufficient to reduce fibrovascular growth over the retina in a treated eye of a subject by an average of at least about 5, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, 90, more than 90%, or substantially eliminate fibrovascular growth over the retina.

[00263] In some embodiments, the CD206 modulator is present in an amount sufficient to reduce loss of vision due to diabetic retinopathy in a treated eye of a subject by an average of at least about 5, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, 90, more than 90%, or substantially eliminate further loss of vision.

[00264] In some embodiments, the CD206 modulator is present in an amount sufficient to limit non-proliferative damage to a retina of a subject by an average of at least about 5, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, 90, more than 90%, or substantially eliminate the nonproliferative damage to the retina.

[00265] In some embodiments, the CD206 modulator is present in an amount sufficient to slow proliferative damage to a retina of a subject by an average of at least about 5, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, 90, more than 90%, or substantially eliminate further proliferative damage to the retina.

[00266] In some embodiments, the CD206 modulator is present in an amount sufficient to prevent the occurrence of non-exudative (dry) or exudative (wet) age-related macular degeneration (AMD).

[00267] In some embodiments, the CD206 modulator is present in an amount sufficient to prevent the onset of early or intermediate AMD.

[00268] In some embodiments, the CD206 modulator is present in an amount sufficient to prevent the onset of late AMD.

[00269] In some embodiments, the CD206 modulator is present in an amount sufficient to prevent the onset of dry or wet AMD.

[00270] In some embodiments, the CD206 modulator is present in an amount sufficient to delay the onset of early or intermediate AMD in a treated eye of a subject by an average of at least about 1 day, 7 days, 14 days, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 18 months, 24 months, 30 months, 36 months, 42 months, 48 months, 54 months, 5 years, 6 years, 7 years, 8 years, 9 years, 10 years, or more than 10 years.

[00271] In some embodiments, the CD206 modulator is present in an amount sufficient to delay the onset of late AMD in a treated eye of a subject by an average of at least about 1 day, 7 days, 14 days, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 18 months, 24 months, 30 months, 36 months, 42 months, 48 months, 54 months, 5 years, 6 years, 7 years, 8 years, 9 years, 10 years, or more than 10 years.

[00272] In some embodiments, the CD206 modulator is present in an amount sufficient to delay the onset of dry or wet AMD in a treated eye of a subject by an average of at least about 1 day, 7 days, 14 days, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 18 months, 24 months, 30 months, 36 months, 42 months, 48 months, 54 months, 5 years, 6 years, 7 years, 8 years, 9 years, 10 years, or more than 10 years.

[00273] In other embodiments, the CD206 modulator is present in an amount sufficient to reduce macular degeneration in a subject by an average of at least about 5, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, 90, more than 90%, or substantially eliminate macular degeneration.

[00274] In some embodiments, the CD206 modulator is present in an amount sufficient to prevent the onset of sub-retinal fibrosis of AMD.

[00275] In some embodiments, the CD206 modulator is present in an amount sufficient to delay the onset of sub-retinal fibrosis of AMD in a treated eye of a subject by an average of at least about 1 day, 7 days, 14 days, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 18 months, 24 months, 30 months, 36 months, 42 months, 48 months, 54 months, 5 years, 6 years, 7 years, 8 years, 9 years, 10 years, or more than 10 years.

[00276] In some embodiments, an effective amount of the CD206 modulator is a daily dose of about 1 >< 10^-9g, 1 x 10^-8g, 1 x 10^-7g, 1 x 10^-6g, 1 x 10^-5g, 1 x 10^-4g, 1 x 10^-3g, 1 x 10^-2g, l x l0^-1g, or 1 gram.

[00277] Formulations and Administration of Pharmaceutical Compositions

[00278] The methods of the disclosure include many suitable modes of administration to deliver a CD206 modulator, and any co-administered drug or therapy as part of a combination therapy, either via local or systemic administration. Suitable formulations and additional carriers are described in, e.g., Remington “The Science and Practice of Pharmacy” (20th Ed., Lippincott Williams & Wilkins, Baltimore Md.), the teachings of which are incorporated by reference in their entirety herein.

[00279] After formulation with an appropriate pharmaceutically acceptable carrier in a desired dosage, the pharmaceutical compositions of the disclosure can be administered to humans and other mammals orally, via injection into the eye including, e.g., invitreally, subtenonally, and subretinally, and topically, such as ocularly (as by gels, ointments, or drops), i.e., as applied directly to external tissues of the eye. Alternative and additional routes such as rectally, parenterally, intraci sternally, intravaginally, intraperitoneally, or bucally are envisioned. Ocular injections include intra-ocular injection into the aqueous or the vitreous humor, or injection into the external layers of the eye, such as via subconjunctival injection or subtenon injection.

[00280] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3 -butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables. The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[00281] In order to prolong the effect of an active agent, it is often desirable to slow the absorption of the agent from subcutaneous or intramuscular injection. Delayed absorption of a parenterally administered active agent may be accomplished by dissolving or suspending the agent in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the agent in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of active agent to polymer and the nature of the particular polymer employed, the rate of active agent release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the agent in liposomes or microemulsions which are compatible with body tissues.

[00282] Solid dosage forms for oral administration include capsules, tablets, pills, troches, wafers, powders, and granules. In such solid dosage forms, the active agent is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or (a) fillers or extenders such as starches, sucrose, glucose, mannitol, and silicic acid, (b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, (c) humectants such as glycerol, (d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, (e) solution retarding agents such as paraffin, (f) absorption accelerators such as quaternary ammonium compounds, (g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, (h) absorbents such as kaolin and bentonite clay, and (i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof.

[00283] Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active agent(s) may be admixed with at least one inert diluent such as sucrose or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active agent(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes.

[00284] Liquid dosage forms for ocular administration include buffers and solubilizing agents, preferred diluents such as water, preservatives such as thymosol, and one or more biopolymers or polymers for conditioning the solution, such as polyethylene glycol, hydroxypropylmethylcellulose, sodium hyaluronate, sodium polyacrylate or tamarind gum. [00285] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active agent(s), the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[00286] Dosage forms for topical or transdermal administration of an inventive pharmaceutical composition include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, or patches. The active agent is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. For example, ocular or cutaneous infections may be treated with aqueous drops, a mist, an emulsion, or a cream.

[00287] The ointments, pastes, creams, and gels may contain, in addition to an active agents of the disclosure, excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc, zinc oxide, or mixtures thereof.

[00288] Powders and sprays can contain, in addition to the agents of this disclosure, excipients such as talc, silicic acid, aluminum hydroxide, calcium silicates, polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants such as chlorofluorohydrocarbons.

[00289] Transdermal patches have the added advantage of providing controlled delivery of the active ingredients to the body. Such dosage forms can be made by dissolving or dispensing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.

[00290] Administration of a CD206 modulator, and any co-administered drug or therapy as part of a combination therapy, may be therapeutic or may be prophylactic. The CD206 modulator and co-administered drug or therapy may share the same purpose (both therapeutic or prophylactic) or have divergent purposes (one therapeutic and one prophylactic).

[00291] Combination Therapy

[00292] In some aspects, the disclosure provides methods of treatment (and compositions) in which a CD206 modulator (or pharmaceutical compositions comprising such CD206 modulator) can be administered in combination with at least one other drug or therapy currently known or later discovered to be effective in the treatment of diabetic retinopathy and AMD, as well as processes associated with diabetic retinopathy and AMD (e.g., angiogenesis, inflammation, fibrosis) to a subject with diabetic retinopathy and AMD or at risk for developing diabetic retinopathy and AMD. In embodiments, the drug(s) include an anti-angiogenic agent and/or an anti -oxi dative agent and/or an anti-apoptotic agent.

[00293] The combination therapy can be administered prior to, concurrently with, or after the administration of the CD206 modulator. In one embodiment, the inventive method includes a step of assessing the efficacy of the therapeutic treatment. Such assessment of efficacy can be based on any number of assessment results, including, without limitation, a reduction in tissue inflammation, a suppression or reduction of the excessive production of inflammatory mediators such as IL-1, IL-6, IL-12, and TNF in eye tissue or vitreous, a reduction in the level of inflammatory cytokines (e.g., in the serum), and the like. Depending on the level of efficacy assessed, the dosage of combination therapy can be adjusted up or down, as needed.

[00294] Thus, by “in combination with,” it is not intended to imply that the CD206 modulator and additional agent or therapy must be administered at the same time or formulated for delivery together, although these methods of delivery are within the scope of the disclosure. Furthermore, it will be appreciated that therapeutically active agents utilized in combination may be administered together in a single composition or administered separately in different compositions. In general, each agent will be administered at a dose and/or on a time schedule determined for that agent.

[00295] In general, each agent (in this context, one of the “agents” is a composition of this disclosure) will be administered at a dose and on a time schedule determined for that agent. Additionally, the disclosure encompasses the delivery of the compositions in combination with agents that may improve their bioavailability, reduce or modify their metabolism, inhibit their excretion, or modify their distribution within the body.

[00296] The particular combination of therapies (e.g., therapeutics or procedures) to employ in a combination regimen will consider compatibility of the desired therapeutics and/or procedures and the desired therapeutic effect to be achieved. In general, it is expected that agents utilized in combination will be utilized at levels that do not exceed the levels at which they are utilized individually. In some embodiments, the levels utilized in combination will be lower than those utilized individually.

[00297] Dosing for CD206 modulators in the methods of the disclosure may be found by routine experimentation. The daily dose can range from about l x 10^-9 g to 1 g. Daily dose range may depend on the form of CD206 modulator e.g., the salts used, and/or route of administration, as described herein. For example, for systemic administration, typical daily dose ranges can be, e.g. about 1-100,000 ng, or about 1-10,000 ng, or about 1-1,000 ng, or about 1-100 ng, or about 1-10 ng, or about 10 ng to 1 mg, or about 10 ng to 0.1 mg, or about 10 ng to O.Olmg, or about 10 ng to 1 pg, or about 10 ng to 0.1 pg, or about 100 ng to 10 mg, or about 100 ng to 1 mg, or about 100 ng to 0.1 mg, or about 100 ng to 0.01 mg, or about 100 ng to 1 pg, or about 1 pg to 100 mg, or about 1 pg to 10 mg, or about 1 pg to 1 mg, or about 1 pg to 0.1 mg, or about 1 pg to 0.01 mg, or about 10 pg to 1 g, or about 10 pg to 0.1 g, or about 10 pg to 0.01 g, or about 10 pg to 1 mg, or about 10 pg to 0.1 mg, or about 100 pg to 1 g, or about 100 pg to 0.1g, or about 100 pg to 0.01 g, or about 100 pg to 1 mg, or about 1 mg to 1 g, or about 1 mg to 0.1 g, or about 1 mg to 0.01 g, or about 10 mg to 1 g, or about 10 mg to 0.1 g, or about 100 mg to 1 g. In some embodiments, the daily dose of CD206 modulator is about 5, 10, 50, 100, 200, 300, 400, 500, 600, 700, 800, 900, or 1000 mg. In some embodiments, the daily dose of the CD206 modulator is 10 mg. In some embodiments, the daily dose of the CD206 modulators is 100 mg. In some embodiments, the daily dose of CD206 modulator is 500 mg. In some embodiments, the daily dose of CD206 modulator is 1000 mg.

[00298] For topical delivery to the ocular surface, the typical daily dose ranges are, e.g. about 1 x 10^-9 g to 1.00 g, or about 1 * 10^-9 g to 0.5 g, or about 1 x IO^-9 g to 0.25 g, or about l x l0’⁹ g to 0.1 g, or about l x 10^-9 g to 0.05 g, or about l x 10^-9g to 0.025 g, or about l x 10^-9 g to 1 x 10"² g, or about 1 x 10^-9 g to 5x 10^-3 g, or about 1 x 10^-9 g to 2.5x 10^-3 g, or about 1 x 10^-9 g to l x l0"³ g, or about l x 10^-9g to 5x l0^-4 g, or about l x 10^-9 g to l x l0^-4 g, or about l x 10^-8 g to 1.00 g, or about 1 x IO^-8 g to 0.5 g, or about 1 x IO^-8 g to 0.25 g, or about 1 x IO^-8 g to 0.1 g, or about 1 x 10^-8 g to 0.05 g, or about 1 x 10^-8 g to 0.025 g, or about 1 x 10^-8 g to 1 x 10^-2 g, or about l x l0’⁸ g to 5x l0^-3 g, or about l x 10^-8 g to 2.5x l0^-3 g, or about l x 10^-8g to l x l0^-3 g, or about 1 x 10^-8 g to 5 x 10^-4 g, or about 1 x IO^-8 g to 1 x 10^-4 g, or about 1 x 10^-7 g to 1.00 g, or about 1 x 10^-7 g to 0.5 g, or about 1 x 10^-7 g to 0.25 g, or about 1 x 10^-7 g to 0.1 g, or about 1 x 10^-7 g to 0.05 g, or about 1 x 10^-7 g to 0.025 g, or about 1 x 10^-7 g to 1 x 10^-2 g, or about 1 x 10"⁷ g to 5x 10^-3 g, or about 1 x 10^-7 g to 2.5x 10^-3 g, or about 1 x 10^-7 g to 1 x 10^-3 g, or about 1 x 10"⁷ g to 5x 10^-4 g, or about 1 x 10^-7 g to 1 x 10^-4 g, or about or about 1 x 10^-6 g to 1 g, or about 1 x 10^-6 g to 0.5 g, or about 1 x IO^-6 g to 0.25 g, or about 1 x IO^-6 g to 0.1 g, or about

1 x 10’⁶ g to 5x 10^-2 g, or about 1 x 10^-6 g to 5x 10^-2 g, or about 1 x 10^-6 g to 2.5x 10^-2 g, or about

1 x 10"⁶ g to 1 x 10"² g, or about 1 x 10^-6 g to 5x 10^-3 g, or about 1 x 10^-6 g to 2.5x 10^-3 g, or about

1 x 10"⁶ g to 1 x l0^-3 g, or about 1 x IO^-6 g to 5x IO^-4 g, or about 1 x IO^-6 g to 1 x IO^-4 g, or about or about 1 x 10^-5 g to 1 g, or about 1 x IO^-5 g to 0.5 g, or about 1 x 10^-5 g to 0.25 g, or about lxlO-⁵gto 0.1 g, or about lxlO^-5gto 0.05 g, or about lx 10^-5g to 2.5xl0^-2g, or about 1 x 10^-5 g to 1 x 10^-2 g, or about 1 x 10^-5 g to 5x 10^-3 g, or about 1 x 10^-5 g to 2.5x 10^-3 g, or about 1 x 10^-5 g to 1 xl0^-3 g, or about 1 x 10^-5 g to 5x 10^-4 g, or about 1 x 10^-5 g to 1 x 10^-4 g. In some embodiments, the daily dose of CD206 modulator is about 1 x 10^-7, 1 x 10^-6, 1 x 10^-5, 1 x 10^-4, 1 x 10^-3 g, 1 x 10^-2 g, 1 x 10¹ g, or 1 g. In some embodiments, the daily dose of the CD206 modulator is lx 10^-7g. In some embodiments, the daily dose of the CD206 modulator is 1 x IO^-5 g. In some embodiments, the daily dose of CD206 modulator is 1 x IO^-3 g. In some embodiments, the daily dose of CD206 modulator is 1 x IO^-2 g.

[00299] In some embodiments the individual dose ranges from about 1x10⁹ g to 1.00 g, or about 1 x 10^-9 g to 0.5 g, or about 1 x 10^-9 g to 0.25 g, or about 1 x 10^-9 g to 0.1 g, or about 1 x 10^-9 g to 0.05 g, or about 1 x 10^-9 g to 0.025 g, or about 1 x 10^-9 g to 1 x 10^-2 g, or about lxl0"⁹gto 5xl0^-3g, or about lx10^-9gto 2.5xl0^-3g, or about lx10^-9gto lxl0^-3g, or about lxl0"9gto 5xl0-4g, or about lx10-9gto lxl0^-4g, or about lx10-8gto 1.00 g, or about 1 x 10^-8 g to 0.5 g, or about 1 x 10^-8 g to 0.25 g, or about 1 x 10^-8 g to 0.1 g, or about 1 x 10^-8 g to 0.05 g, or about 1 x 10^-8 g to 0.025 g, or about 1 x 10^-8 g to 1 x 10^-2 g, or about 1 x 10^-8 g to 5xl0^-3g, or about lx 10^-8gto 2.5xl0^-3g, or about lx10^-8gto lxl0^-3g, or about lx10^-8gto 5xl0^-4g, or about lx10^-8g to lxl0^-4g, or about lx10^-7g to 1.00 g, or about lx10^-7g to 0.5 g, or about 1 x 10^-7 g to 0.25 g, or about 1 x 10^-7 g to 0.1 g, or about 1 x 10^-7 g to 0.05 g, or about 1 x 10^-7 g to 0.025 g, or about 1 x 10^-7 g to 1 x 10^-2 g, or about 1 x 10^-7 g to 5x 10^-3 g, or about 1 x 10’⁷ g to 2.5x 10^-3 g, or about 1 x 10^-7 g to 1 x 10^-3 g, or about 1 x 10^-7 g to 5x 10^-4 g, or about 1 x 10^-7 g to 1 x 10^-4 g, or about 1 x 10^-6 g to 1 g, or about 1 x 10^-6 g to 0.5 g, or about 1 x 10^-6 g to 0.25 g, or about 1 x 10^-6 g to 0.1 g, or about 1 x 10^-6 g to 5 x 10^-2 g, or about 1 x 10’⁶ g to 5x 10^-2 g, or about 1 x 10^-6 g to 2.5x 10^-2 g, or about 1 x 10^-6 g to 1 x 10^-2 g, or about 1 x 10"⁶ g to 5x 10^-3 g, or about 1 x 10^-6 g to 2.5x 10^-3 g, or about 1 x 10^-6 g to 1 x 10^-3 g, or about 1 x 10"⁶ g to 5x IO^-4 g, or about 1 x IO^-6 g to 1 x IO^-4 g, or about 1 x IO^-5 g to 1 g, or about

1 x IO^-5 g to 0.5 g, or about 1 x 10^-5 g to 0.25 g, or about 1 x 10^-5 g to 0.1 g, or about 1 x 10^-5 g to 0.05 g, or about 1 x 10^-5 g to 2.5x 10^-2 g, or about 1 x 10^-5 g to 1 x 10^-2 g, or about 1 x 10^-5 g to 5xl0^-3g, or about lxlO^-5gto 2.5xl0^-3g, or about lxlO^-5gto lxl0^-3g, or about lxlO^-5gto 5x 10^-4 g or about 1 x 10^-5 g to 1 x 10^-4 g or about . In some embodiments, the individual doses as described above, is repeated 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 times per day.

[00300] For other forms of administration, the daily dosages may range about the range described for systemic administration or may range about the range described for topical administration. [00301] Having described the present disclosure, the same will be explained in greater detail in the following examples, which are included herein for illustration purposes only, and which are not intended to be limiting to the disclosure.

EXAMPLES

[00302] The Examples that follow are illustrative of specific embodiments of the disclosure, and various uses thereof. They are set forth for explanatory purposes only and should not be construed as limiting the scope of the disclosure in any way.

EXAMPLE 1: Diabetic retinopathy model

[00303] Histological analyses of human retinas imply that dropout of pericytes from retinal capillary walls leads to blood-retina barrier (BRB) breakdown in diabetic retinopathy. Consistent with this, pericyte depletion in developing mouse retinas through disruption of PDGF-B/PDGFRP signaling produces clinical features of diabetic retinopathy, such as retinal vascular tortuosity and dilation and retinal edema and hemorrhage. Notably, in developing retinal vessels, pericyte deficiency directly induces inflammatory responses in endothelial cells (ECs) and subsequent infiltration of macrophages. The infiltrating macrophages further inflame ECs by secreting pro-permeable and pro-inflammatory cytokines, including VEGF.

[00304] Intraperitoneal injections of an anti-PDGFRp monoclonal antibody (clone APB5) to neonatal mice inhibited pericyte recruitment to retinal vessels, reduced pericyte content in the retina, which caused vascular hyperpermeability and retinal edema characteristic of human DR. The DR model was generated according as follows.

[00305] Pericyte deficiency-induced blood-retina barrier (BRB) breakdown model. Rat anti-mouse PDGFRP monoclonal antibody APB5 was intraperitoneally injected into postnatal day one (Pl) mice (40 pg in 40 pl PBS). Mock-treated littermate controls received injections of vehicle only or, where indicated herein, with NCGC00123051, an inactive analog of NCGC00413972.

[00306] Morphological analysis. Following fixation of mouse eyes with 4% paraformaldehyde (PF A) in PBS for 20 minutes on the postnatal day indicated in each Figure herein (e.g., P8, P9, P10 and P12 for Fig. 8), the eye cups were dissected and further fixed in 4% PFA in PBS overnight. The fixed eyes were washed in PBS, serially immersed in 30% sucrose in PBS and OCT compound, and frozen. The cryo-sectioned eye tissues were blocked with 1% bovine serum albumin and 0.5% Triton X-100 in PBS for 2 hours and then incubated overnight with primary antibodies. Nuclei were labeled with DAPI (Millipore Sigma) at 1 pg/ml for 15 minutes. Fluorescent and confocal microscopic images were captured using a an LSM700 confocal microscope (Zeiss) with ZEN software (Zeiss), or a BZ-X710 microscope (Keyence) with BZ-Z software (Keyence).

[00307] Real-time PCR. Retinas were harvested at P8, Pl 1, P14, P21, P28, and at 6 weeks and 10 weeks postnatal from mice treated by intraperitoneal injection of 40-60 pg APB5 in 40 pl PBS or were mock treated with vehicle only at Pl. From 1 pg of total RNA extracted from a single retina using the RNeasy Mini Kit including on-column DNase digestion (Qiagen), the cDNAs were synthesized using Superscript Vilo transcriptase (Thermo Fisher Scientific). The qRT-PCR analyses were performed using the Quantitect SYBR Green PCR Mastermix (Qiagen), followed by quantitative measurements. The TATA box-binding protein was used as an internal control.

Flow cytometry. Retinas from each indicated postnatal day were mechanically dissociated and enzymatically digested using 0.5 mg/ml collagenase D (Millipore Sigma) and 750 U/ml DNase (Millipore Sigma) in Hanks’ balanced salt solution (Millipore Sigma) for 15 minutes. Retinas were then forced through a 100-pm nylon mesh to obtain single-cell suspensions. Non-permeabilized cells were labeled with phycoerythrin (PE) conjugated antibodies for 30 minutes prior to flow cytometry. Viability staining solution 7-aminoactinomycin D (7-AAD; BD Biosciences) was applied for 5 minutes, and the analyses were conducted using a FACS Canto II (BD Biosciences). Following removal of dead cells based on 7-AAD labeling, the doublet cells were excluded using forward scatter height (FSC-H) versus forward scatter width (FSC-W) gates.

[00308] Statistics. Data are shown as mean ± SEM. Statistical evaluation between 2 groups was conducted by Student’s t test (2 tailed, parametric) or Mann-Whitney’s U test (nonparametric). Statistical evaluation of 3 groups was performed by 1-way ANOVA followed by Tukey’s test. A value of P < 0.05 was considered to indicate statistically significant differences.

[00309] Example 2: Liquid formulations of NCGC00413972

[00310] Preparation of formulated solution of NCGC00413972 in PEG300/propylene glycol/40% 2-hydoxypropyl-beta-cyclodextrin in water (40/40/20). This method was suitable for formulations up to about 15 mg/ml solution. [00311] 15 mg of NCGC00413972 was treated with PEG300 (0.4ml). The solution was sonicated for 2 minutes, and then swirled at 37 °C for 2 minutes with a vortex mixer. To the slightly cloudy solution was added 0.4 ml propylene glycol, followed by sonicating for 1 minute then by swirling for 2 minutes at 37 °C. The clear solution was treated with 40% 2- hydoxypropyl-beta-cyclodextrin in water (0.2 ml; prepared by solubilizing 4g of 2- hydoxypropyl-beta-cyclodextrin in water q.s. to 10 ml). The solution was warmed to 37 °C for 5 minutes. The resulting clear, slightly yellow solution was allowed to cool to room temperature. The solution, as prepared, was suitable for intraperitoneal injection and oral administration.

[00312] Preparation of formulated solution of NCGC00413972 in PEG300/propylene glycol/40% 2-hydoxypropyl-beta-cyclodextrin in water (40/40/20). This method was suitable for formulations up to 4 mg/ml solution.

[00313] 4.0 mg of NCGC00413972 was treated with a solution of PEG300 (0.4ml), propylene glycol (0.4ml) and 40% 2-hydoxypropyl-beta-cyclodextrin (0.2 ml; prepared by solubilizing 4g of 2-hydoxypropyl-beta-cyclodextrin in water q.s. to 10 ml). The solution was sonicated for 2 minutes, swirled at 37 °C for 2 minutes. The clear solution was allowed to cool to room temperature. A clear, slightly yellow solution resulted. The solution, as prepared, was suitable for intraperitoneal injection and oral administration.

[00314] Liquid chromatography-mass spectroscopy (LCMS) was used to analyze a 4 mg/ml formulated solution. An standard 4% - 100% acetonitrile (0.05% TFA) gradient was run over 3 minutes on a Luna Cl 8 3 micron 3x75 mm column. Figure 15 shows a representative LCMS run.

[00315] Various aspects and embodiments of the disclosure are provided by the following enumerated embodiments, which can be combined in any number and in any fashion not technically or logically inconsistent.

Embodiment 1. A method of treating diabetic retinopathy with or without age-related macular degeneration in a subject, comprising administering to the subject in need thereof a CD206 modulator.

Embodiment 2. A method of reducing production of CD206 (mannose receptor C-type 1) protein in an eye of a subject, comprising administering to the subject in need thereof a CD206 modulator Embodiment 3. A method for reducing the expression of gene MRC1 (mannose receptor C-type 1), which encodes CD206 protein, in an eye of a subject, comprising administering to the subject in need thereof a CD206 modulator.

Embodiment 4. A method for reducing oxidative stress in endothelial cells and/or pericytes in an eye of a subject, comprising administering to the subject in need thereof a CD206 modulator.

Embodiment 5. A method for reducing the concentration of one or more of peroxides, superoxides, nitric oxide, and oxygen free radicals in an eye of a subject, comprising administering to the subject in need thereof a CD206 modulator.

Embodiment 6. A method for reducing production of VEGF protein in an eye of a subject, comprising administering to the subject in need thereof a CD206 modulator.

Embodiment 7. A method for reducing the expression of gene VEGF, which encodes VEGF protein, in an eye of a subject, comprising administering to the subject in need thereof a CD206 modulator.

Embodiment 8. The method of embodiment 7, wherein the VEGF gene is one or more selected from the group consisting of one or more of VEGF-A, VEGF-B, VEGF-C and VEGF-D.

Embodiment 9. The method of embodiment 8, wherein the VEGF gene is VEGF-A.

Embodiment 10. A method for reducing the amount of inflammatory and/or fibrotic proteins in an eye of a subject, comprising administering to the subject in need thereof a CD206 modulator.

Embodiment 11. A method for reducing the production of a protein that promotes inflammation and/or fibrosis in an eye of a subject, comprising administering to the subject in need thereof a CD206 modulator. Embodiment 12. The method of either of embodiment 10 or embodiment 11, wherein the protein that promotes inflammation and/or fibrosis is selected from the group consisting of IL-lp, CSF-1, IL-4, IFNy, ANGPT2, TGFp-2, IL-6, CCL2, IL-10, TNF-a, or IL-13.

Embodiment 13. A method for reducing the expression of a gene that encodes a protein that promotes inflammation and/or fibrosis in an eye of a subject, comprising administering to the subject in need thereof a CD206 modulator.

Embodiment 14. The method of embodiment 13, wherein the gene that encodes a protein that promotes inflammation and/or fibrosis is selected from the group consisting ofILBI, CSF1, IL4, INFG, ANGPT2, TGFB2, IL6, CCL2, IL10, TNF and IL13.

Embodiment 15. A method for reducing aberrant blood vessel growth in an eye of a subject, comprising administering to the subject in need thereof a CD206 modulator.

Embodiment 16. The method of embodiment 15, wherein the blood vessel growth comprises NVE (new vessels every whereelsewhere) growth.

Embodiment 17. The method of embodiment 15, wherein the blood vessel growth comprises NVD (new vessels at disk) growth.

Embodiment 18. A method for reducing vitreous hemorrhages in an eye of a subject, comprising administering to the subject in need thereof a CD206 modulator.

Embodiment 19. A method for reducing epiretinal fibrovascular membrane formation in an eye of a subject, comprising administering to the subject in need thereof a CD206 modulator.

Embodiment 20. A method for reducing tractional retinal detachment in an eye of a subject, comprising administering to the subject in need thereof a CD206 modulator.

Embodiment 21. A method for reducing subretinal fibrosis in an eye of a subject, comprising administering to the subject in need thereof a CD206 modulator. Embodiment 22. A method for reducing production of α -SMA (alpha-smooth muscle actin; ACTA2) in an eye of a subject, comprising administering to the subject in need thereof a CD206 modulator.

Embodiment 23. A method for reducing expression of gene ACTA2, which encodes a- SMA, in an eye of a subject, comprising administering to the subject in need thereof a CD206 modulator.

Embodiment 24. A method for reducing chronic inflammation in an eye of a subject, comprising administering to the subject in need thereof a CD206 modulator.

Embodiment 25. A method for reducing Ibal+ (ionized calcium binding adaptor molecule 1 positive) mononuclear phagocytes in a sub-retinal area of an eye of a subject, comprising administering to the subject in need thereof a CD206 modulator.

Embodiment 26. A method for reducing or eliminating CD206 positive cells in the subretinal space in an eye of a subject, comprising administering to the subject in need thereof a CD206 modulator.

Embodiment 27. A method for increasing production of CD86 in microglia cells in an eye of a subject, comprising administering to the subject in need thereof a CD206 modulator.

Embodiment 28. A method for reducing or eliminating M2-like macrophages in an eye of a subject, comprising administering to the subject in need thereof a CD206 modulator.

Embodiment 29. A method for increasing Ml -like macrophages in an eye of a subject, comprising administering to the subject in need thereof a CD206 modulator.

Embodiment 30. A method for preventing pericyte loss in an eye of a subject, comprising administering to the subject at risk for pericyte loss in need thereof a CD206 modulator. Embodiment 31. A method for reducing or eliminating pericyte loss in an eye of a subject, comprising administering to the subject in need thereof a CD206 modulator.

Embodiment 32. A method for preventing a proliferative phase of diabetic retinopathy in an eye of a subject, comprising administering to the subject in need thereof a CD206 modulator.

Embodiment 33. A method for delaying onset of a proliferative phase of diabetic retinopathy in an eye of a subject, comprising administering to the subject in need thereof a CD206 modulator.

Embodiment 34. A method for preventing onset of fibrosis and proliferative retinopathy in an eye of a subject, comprising administering to the subject in need thereof a CD206 modulator.

Embodiment 35. A method for delaying onset of fibrosis and proliferative retinopathy in an eye of a subject, comprising administering to the subject in need thereof a CD206 modulator.

Embodiment 36. A method for preventing the onset of early or intermediate AMD in an eye of a subject, comprising administering to the subject in need thereof a CD206 modulator.

Embodiment 37. A method for delaying the onset of early or intermediate AMD in an eye of a subject, comprising administering to the subject in need thereof a CD206 modulator.

Embodiment 38. The method of embodiment 37, wherein the CD206 modulator is present in an amount sufficient to delay the onset of early or intermediate AMD in a treated eye of a subject by an average of at least about 1 day, 7 days, 14 days, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 18 months, 24 months, 30 months, 36 months, 42 months, 48 months, 54 months, 5 years, 6 years, 7 years, 8 years, 9 years, 10 years, or more than 10 year.

Embodiment 39. A method for preventing the onset of late AMD in an eye of a subject, comprising administering to the subject in need thereof a CD206 modulator.

Embodiment 40. A method for delaying the onset of late AMD in an eye of a subject, comprising administering to the subject in need thereof a CD206 modulator.

Embodiment 41. The method of embodiment 40, wherein the CD206 modulator is present in an amount sufficient to delay the onset of late AMD in a treated eye of a subject by an average of at least about 1 day, 7 days, 14 days, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 18 months, 24 months, 30 months, 36 months, 42 months, 48 months, 54 months, 5 years, 6 years, 7 years, 8 years, 9 years, 10 years, or more than 10 year.

Embodiment 42. A method for preventing the onset of non-exudative (dry) or exudative (wet) age-related macular degeneration (AMD) in an eye of a subject, comprising administering to the subject in need thereof a CD206 modulator.

Embodiment 43. A method for delaying the onset of non-exudative (dry) or exudative (wet) age-related macular degeneration (AMD) in an eye of a subject, comprising administering to the subject in need thereof a CD206 modulator.

Embodiment 44. The method of embodiment 43, wherein the CD206 modulator is present in an amount sufficient to delay the onset of dry or wet AMD in a treated eye of a subject by an average of at least about 1 day, 7 days, 14 days, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 18 months, 24 months, 30 months, 36 months, 42 months, 48 months, 54 months, 5 years, 6 years, 7 years, 8 years, 9 years, 10 years, or more than 10 years.

Embodiment 45. A method for preventing onset of sub-retinal fibrosis of AMD in an eye of a subject, including administering to the subject in need thereof a CD206 modulator. Embodiment 46. A method for delaying onset of sub-retinal fibrosis of AMD in an eye of a subject, including administering to the subject in need thereof a CD206 modulator.

Embodiment 47. The method of embodiment 46, wherein the CD206 modulator is present in an amount sufficient to delay the onset of sub-retinal fibrosis of AMD in a treated eye of a subject by an average of at least about 1 day, 7 days, 14 days, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 18 months, 24 months, 30 months, 36 months, 42 months, 48 months, 54 months, 5 years, 6 years, 7 years, 8 years, 9 years, 10 years, or more than 10 years.

Embodiment 48. A method for reducing macular degeneration in a subject by an average of at least about 5, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, 90, more than 90%, or substantially eliminate macular degeneration.

Embodiment 49. The method of any of embodiments 1-48, wherein the CD206 modulator is NGCG00413972.

Embodiment 50. The method of embodiment 49, wherein the effective amount of the CD206 modulator is a daily dose of about 1 x 10^-8, 1 MO^-7, 1 MO^-6, 1 MO^-5, 1 MO^-4, I x lO^-3, I x lO^-2, or I x lO^-1 grams.

Embodiment 51. The method of any of embodiments 1-50, wherein the CD206 modulator is administered topically, orally, periocularly, via an insert, via an implanted device, or via a drop.

Embodiment 52. The method of embodiment 51 wherein the CD206 modulator is administered in a carrier vehicle which is liquid drops, liquid wash, gel, ointment, polymer micro and nanoparticles, solution, suspension, solid, biodegradable matrix, powder, crystals, foam, or liposomes.

Embodiment 53. The method of embodiment 51, wherein the CD206 modulator is administered orally. Embodiment 54. The method of embodiment 51, wherein the CD206 modulator is administered topically, wherein the topical administration comprises infusion of the CD206 modulator to the eyes via a device selected from the group consisting of a pumpcatheter system, an insert, a continuous or selective release device, a bioabsorbable implant, a continuous or sustained release formulation, and a contact lens.

Embodiment 55. The method of any of embodiments 1-50, wherein a therapeutically effective amount of the CD206 modulator is delivered to an eye of said subject via local or systemic delivery.

Embodiment 56. The method of any of embodiments 1-50, wherein the administration is accomplished by administering an intra-ocular instillation of a gel, cream, powder, foam, crystals, liposomes, spray, polymer micro or nanoparticles, or liquid suspension form of the CD206 modulator.

Embodiment 57. The method of any of embodiments 1-56, wherein the CD206 modulator is administered to the subject in an amount sufficient to achieve intraocular or retinal concentrations of from about 10 nM to about 10 pM.

Embodiment 58. The method of any of embodiments 1-57, wherein said compound is administered at least once a day.

59. The method of any of embodiments 1-57, wherein said compound is administered at least once a week.

Embodiment 60. The method of any of embodiments 1-57, wherein said compound is administered at least once a month.

Embodiment 61. The method of any of embodiments 1-57, wherein said compound is administered at least once a year.

Embodiment 62. The method of any of embodiments 1-61, further comprising the step of determining that said subject is in need of treatment for diabetic retinopathy. Embodiment 63. The method of any of embodiments 1-62, further comprising administering a second therapeutic agent prior to, in combination with, at the same time, or after administration of the CD206 modulator.

Embodiment 64. The method of embodiment 63, wherein the second therapeutic agent is selected from the group consisting of anti-angiogenic agents, anti-oxidative agents, anti- apoptotic agents, and combinations thereof.

Embodiment 65. The method of embodiment 63, wherein the second therapeutic agent is an anti -angiogenic agent.

Embodiment 66. The method of embodiment 63, wherein the second therapeutic agent is an anti -oxi dative agent.

Embodiment 67. The method of embodiment 63, wherein the second therapeutic agent is an anti-apoptotic agent.

Embodiment 68. A pharmaceutical composition formulated for ocular delivery comprising a CD206 modulator and a pharmaceutically acceptable carrier.

Embodiment 69. The pharmaceutical composition of embodiment 68, wherein the CD206 modulator is NCGC00413972.

Embodiment 70. The pharmaceutical compositions of either one of embodiment 68 or 69, wherein the pharmaceutical composition is suitable for periocular and intraocular administration.

Embodiment 71. The pharmaceutical compositions of either one of embodiment 68 or 69, wherein the pharmaceutical composition is suitable for oral administration.

Embodiment 72. A method of treating diabetic retinopathy in a subject in need thereof comprising: identifying a subject in need of treatment for diabetic retinopathy; and administering to the subject an effective amount of a composition comprising a compound according to:

or a pharmaceutically acceptable salt thereof.

Embodiment 73. A method of treating age-related macular degeneration in a subject in need thereof comprising: identifying a subject in need of treatment for age-related macular degeneration; and administering to the subject an effective amount of a composition comprising a compound according to:

or a pharmaceutically acceptable salt thereof.

Embodiment 74. The method of any of embodiments 1-35, or 49-72, wherein the

CD206 modulator is administered prior to the inflammatory phase of diabetic retinopathy.

Embodiment 75. The method of any of embodiments 1-35, or 49-72, wherein the

CD206 modulator is administered during inflammatory phase of diabetic retinopathy.

Embodiment 76. The method of any of embodiments 1-35, or 49-72, wherein the

CD206 modulator is administered prior to the proliferative phase of diabetic retinopathy.

Embodiment 77. The method of any of embodiments 1-35, or 49-72, wherein the

CD206 modulator is administered during the proliferative phase of diabetic retinopathy. Embodiment 78. The method of any of embodiments 36-71 or 73, wherein the CD206 modulator is administered prior to the formation of or onset of AMD.

Embodiment 79. The method of any of embodiments 36-71 or 73, wherein the CD206 modulator is administered after the onset of AMD.

Embodiment 80. The method of embodiment 36-71 or 73, wherein the AMD is selected from the group consisting of early/intermediate AMD, late AMD, dry AMD and wet AMD.

Embodiment 81. The method of any of embodiments 36-71 or 73, wherein the CD206 modulator is administered prior to the formation of or onset of sub-retinal fibrosis of AMD.

Embodiment 82. The method of any of embodiments 36-71 or 73, wherein the CD206 modulator is administered after the onset of sub-retinal fibrosis of AMD.

Embodiment 83. The method or pharmaceutical composition of any of embodiments 1- 82, wherein the CD206 modulator is a compound of Formula I:

Formula I

or a pharmaceutically acceptable salt thereof, wherein each bond shown as a solid line and a dashed line together, , can be a single bond, double, or aromatic bond;

R¹ is hydrogen, halogen, hydroxyl, cyano, -CO2H, C₁-C₆alkyl, C2-C6alkenyl, C2-C6alkynyl, C₁-C₆alkoxy, -(Co-C6alkyl)cycloalkyl, C₁-C₆haloalkyl, -(Co-C6alkyl)phenyl, -(Co- C₆alkyl)aryl, -(Co-C₆alkyl)heteroaryl, -C(O)Ci-C₆alkyl, -C(O)NR⁸R⁹, -(Co- C6alkyl)NR⁵R⁶ -CO2R⁶, -C₆H₄-R⁷, and a monocyclic or bicyclic heterocycle of 4 to 10 ring atoms having 1, 2, or 3 ring atoms independently chosen from N, S and O;

R², R³, and R⁴ are each independently chosen at each occurrence from hydrogen, halogen, hydroxyl, cyano, -CO2H, C₁-C₆alkyl, C2-C6alkenyl, C2-C6alkynyl, C₁-C₆alkoxy, -(Co C6alkyl)cycloalkyl, C₁-C₆haloalkyl, -(Co-C6alkyl)phenyl, -(Co-C6alkyl)aryl, -(Co- C₆alkyl)heteroaryl, -C(O)Ci-C₆alkyl, -C(O)NR⁵R⁶, (Co-C₆alkyl)NR⁸R⁹ -CO2R⁶, and -C6H4-R⁷; a, b, c, d, and X are each independently chosen at each occurrence from N, C, and CH;

R⁵, and R⁶ are each independently chosen at each occurrence from hydrogen, halogen, hydroxy, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆alkoxy, a substituted or unsubstituted -(Co-C6alkyl)cycloalkyl, -(Co-C6alkyl)phenyl, -(Co-C6alkyl)aryl, -(Co- C6alkyl)heteroaryl, -C(O)C₁-C₆alkyl, -C(0)(Co-C6alkyl)phenyl, -(Co- C6alkyl)NR⁸R⁹, -C(0)(Co-C6alkyl)aryl, -C(0)(Co-C6alkyl)heteroaryl, and a 4- to 7- membered heterocycloalkyl ring having 1, 2, or 3 ring atoms independently chosen from N, O, and S; any R⁵ and R⁶ bound to the same nitrogen atom may be taken together to form a 4- to 7- membered monocyclic heterocycloalkyl ring or 6- to 11 -membered bridged bicyclic heterocycloalkyl ring, which heterocycloalkyl ring contains 0, 1, or 2 additional heteroatoms chosen from N, O, S, S(O), and SO2 which heterocycloalkyl ring is optionally substituted at any carbon or hetero ring atom with halogen, hydroxyl, cyano, oxo, dioxo, C₁-C₆alkyl, C₁-C₆alkoxy, C₁-C₆haloalkyl, -(Co-C6alkyl)cycloalkyl, -(Co- C₆alkyl)phenyl, -(Co-C₆alkyl)aryl, -(Co-C6alkyl)C0₂R⁸, -(Co-C₆alkyl)C(0)NR⁸R⁹, - (C₁-C₆alkyl)OR⁸, -C(O)Ci-C₆alkyl, -(Co-C₆alkyl)NR⁸R⁹, or -C(0)(Co-C₆alkyl)NR⁸R⁹;

R⁷ is hydrogen, halogen, hydroxyl, cyano, -CO2H, C₁-C₆alkyl, C2-C6alkenyl, C2-C6alkynyl, C₁-C₆alkoxy, C₁-C₆haloalkyl, -(Co-C6alkyl)cycloalkyl, -(Co-C6alkyl)phenyl, -(Co- C₆alkyl)aryl, -(Co-C₆alkyl)heteroaryl, -CO2R⁸, -C(O)Ci-C₆alkyl, -C(O)C2-C₆alkenyl, -C(O)C2-C₆alkynyl, -C(O)Ci-C₆alkoxy, -C(O)Ci-C₆hydroxyalkyl, -C(0)-(Co- C6alkyl)cycloalkyl, -C(0)-(Co-C6alkyl)phenyl, -C(0)-(Co-C6alkyl)aryl, -C(0)-(Co- C₆alkyl)heteroaryl, -C(O)NR⁸R⁹, -C(O)NR⁵R⁶, , -C(0)-(Co-C₆alkyl)NR⁵R⁶, -C(O)- NR⁸-(Co-C₆alkyl)NR⁵R⁶, or (Co-C₆alkyl)NR⁵R⁶;

R⁸ and R⁹ are each independently chosen at each occurrence from hydrogen, halogen, Ci- C6 alkyl, C₁-C₆alkoxy, C₁-C₆haloalkyl, -(Co-C6alkyl)phenyl, -(Co-C6alkyl)aryl, -(Co- C₆alkyl)NR⁵R⁶, -CO2R⁶, -C(O)Ci-C₆alkyl, and -(Co-C₆alkyl)cycloalkyl.

Embodiment 84. The method or pharmaceutical composition of embedment 83, wherein R¹ is -C6H4-R⁷;

R² and R⁴ are hydrogen;

R³ is -(Co-C6alkyl)phenyl, -(Co-C6alkyl)aryl, or -(Co-C6alkyl)heteroaryl; a, c, and X are N; b is C; d is CH;

R⁷ is -C(O)NR⁵R⁶ or -C(0)-NR⁸-(Co-C₆alkyl)NR⁵R⁶;

R⁵ and R⁶ are each independently chosen at each occurrence from hydrogen, a substituted or unsubstituted -(Co-C6alkyl)cycloalkyl, -(Co-C6alkyl)heteroaryl, C₁-C₆hydroxyalkyl, C₁-C₆alkoxy, -(Co-C6alkyl)NR⁸R⁹, and a 4- to 7-membered heterocycloalkyl ring having 1, 2, or 3 ring atoms independently chosen from N, O, and S; any R⁵ and R⁶ bound to the same nitrogen atom may be taken together to form a 4- to 7- membered monocyclic heterocycloalkyl ring or 6- to 11 -membered bridged bicyclic heterocycloalkyl ring, which heterocycloalkyl ring contains 0, 1, or 2 additional heteroatoms chosen from N, O, S, S(O), and SO2 which heterocycloalkyl ring is optionally substituted at any carbon or hetero ring atom with halogen, hydroxyl, cyano, oxo, dioxo, C₁-C₆alkyl, C₁-C₆alkoxy, C₁-C₆haloalkyl, -(Co-C6alkyl)cycloalkyl, -(Co-C₆alkyl)phenyl, -(Co-C₆alkyl)aryl, -(Co-C6alkyl)C0₂R⁸, -(Co- C₆alkyl)C(O)NR⁸R⁹, -(Ci-C₆alkyl)OR⁸, -CO2R⁸, -C(O)Ci-C₆alkyl, -(Co- C₆alkyl)NR⁸R⁹, or -C(0)(Co-C₆alkyl)NR⁸R⁹; and

Embodiment 85. The method or pharmaceutical composition of embodiment 84, wherein the compound of Formula I is a compound represented by at least one of Compound 1, and Compound 4 to Compound 29:

Compound 1 Compound 4

Compound 5 Compound 6

Compound 9 Compound 10

Compound 15 Compound 16

Compound 19 Compound 20

Compound 23 Compound 24

Compound 25 Compound 26

Embodiment 86. The method or pharmaceutical composition of embedment 83, wherein

R¹ is -C₆H₄-R⁷;

R² and R⁴ are hydrogen;

R³ is -(Co-C6alkyl)phenyl, -(Co-C6alkyl)aryl, or -(Co-C6alkyl)heteroaryl; a, c, d, and X are N; b is C;

R⁷ is -C(0)-NR⁸-(Co-C₆alkyl)NR⁵R⁶;

R⁵ and R⁶ bound to the same nitrogen atom may be taken together to form a 4- to 7- membered monocyclic heterocycloalkyl ring or 6- to 11 -membered bridged bicyclic heterocycloalkyl ring, which heterocycloalkyl ring contains 0, 1, or 2 additional heteroatoms chosen from N, O, S, S(O), and SO2 which heterocycloalkyl ring is optionally substituted at any carbon or hetero ring atom with halogen, hydroxyl, cyano, oxo, dioxo, C₁-C₆alkyl, C₁-C₆alkoxy, C₁-C₆haloalkyl, -(Co-C6alkyl)cycloalkyl, -(Co- C6alkyl)phenyl, or -(Co-C6alkyl)aryl; and

R⁸ is hydrogen. Embodiment 87. The method or pharmaceutical composition of embedment 86, wherein the compound of Formula I is a compound represented by at least one of Compound 30 and Compound 31 :

Compound 30 Compound 31

Embodiment 88. The method or pharmaceutical composition of embedment 83, wherein

R¹ is -C₆H₄-R⁷;

R² and R⁴ are hydrogen;

R³ is -(Co-C6alkyl)phenyl, -(Co-C6alkyl)aryl, or -(Co-C6alkyl)heteroaryl; a is C; b, d, and X are N; c is CH;

R⁷ is -C(0)-NR⁸-(Co-C₆alkyl)NR⁵R⁶;

R⁵ and R⁶ bound to the same nitrogen atom may be taken together to form a 4- to 7- membered monocyclic heterocycloalkyl ring or 6- to 11 -membered bridged bicyclic heterocycloalkyl ring, which heterocycloalkyl ring contains 0, 1, or 2 additional heteroatoms chosen from N, O, S, S(O), and SO2 which heterocycloalkyl ring is optionally substituted at any carbon or hetero ring atom with halogen, hydroxyl, cyano, oxo, dioxo, C₁-C₆alkyl, C₁-C₆alkoxy, C₁-C₆haloalkyl, -(Co-C6alkyl)cycloalkyl, -(Co-C6alkyl)phenyl, or -(Co-C6alkyl)aryl; and

R⁸ is hydrogen. Embodiment 89. The method or pharmaceutical composition of embedment 88 wherein the compound of Formula I is a compound represented by Compound 32:

Compound 32

Embodiment 90. The method or pharmaceutical composition of embedment 83, wherein R¹ is -C₆H₄-R⁷;

R² and R⁴ are hydrogen;

R³ is -(Co-C6alkyl)phenyl, -(Co-C6alkyl)aryl, or -(Co-C6alkyl)heteroaryl; a is C; b and X are N; c and d are CH;

R⁷ is -C(0)-NR⁸-(Co-C₆alkyl)NR⁵R⁶;

R⁸ is hydrogen.

Embodiment 91. The method or pharmaceutical composition of embedment 90, wherein the compound of Formula I is a compound represented by Compound 33:

Compound 33

Embodiment 92. The method or pharmaceutical composition of any of embodiments 1- 82, wherein the CD206 modulator is a compound of Formula IE

or a pharmaceutically acceptable salt thereof, wherein each bond shown as a solid line and a dashed line together, = , can be a single bond, double, or aromatic bond;

R¹⁰, R¹¹, and R¹³ are each independently chosen at each occurrence from hydrogen, hydroxyl, -CO2H, C₁-C₆alkyl, C2-C6alkenyl, C2-C6alkynyl, C₁-C₆alkoxy, -(Co- C6alkyl)cycloalkyl, C₁-C₆haloalkyl, -(Co-C6alkyl)phenyl, -(Co-C6alkyl)aryl, -(Co- C6alkyl)heteroaryl, -C(O)C₁-C₆alkyl, -C(O)heteroaryl, and -CO2R¹⁶;

R¹², R¹⁴, and R¹⁵ are each independently chosen at each occurrence from hydrogen, halogen, hydroxyl, and cyano;

X is O or S; and

R¹⁶ is hydrogen, halogen, hydroxy, an amino group, C₁-C₆alkyl, C2-C6alkenyl, C2- C6alkynyl, C₁-C₆alkoxy, -(Co-C6alkyl)cycloalkyl, -C(O)C₁-C₆alkyl, -(Co-C6alkyl)aryl, -(Co-C6alkyl)heteroaryl, -(Co-C6alkyl)phenyl, or a monocyclic or bicyclic heterocycle of 4 to 10 ring atoms having 1, 2, or 3 ring atoms independently chosen from N, S and

O.

Embodiment 93. The method or pharmaceutical composition of embedment 92, wherein the compound of Formula II is a compound of Formula IIA

Formula II A

Embodiment 94. The method or pharmaceutical composition of embedment 93, wherein

R¹⁰ and R¹¹ are each independently chosen at each occurrence from -(Co-C6alkyl)phenyl, -(Co-C6alkyl)aryl, and -(Co-C6alkyl)heteroaryl;

R¹², R¹⁴ and R¹⁵ are hydrogen;

R¹³ is -C(O)heteroaryl.

Embodiment 95. The method or pharmaceutical composition of embedment 94, wherein R¹⁰ is -(Co-C6alkyl)phenyl;

R¹¹is -(Co-C6alkyl)heteroaryl;

R¹², R¹⁴ and R¹⁵ are hydrogen;

R¹³ is -C(O)heteroaryl.

Embodiment 96. The method or pharmaceutical composition of embedment 95, wherein the compound of Formula IIA is Compound

Embodiment 97. The method or pharmaceutical composition of any of embodiments 1- 82, wherein the CD206 modulator is a compound of Formula III:

Formula III. or a pharmaceutically acceptable salt thereof,

R¹⁷, R¹⁸, and R²¹ are each independently chosen at each occurrence from hydrogen, halogen, hydroxyl, cyano, an amidino group, -NR²³R²⁴ a sulfonic acid group or a salt thereof, a phosphoric acid group or a salt thereof, -CO2H, C₁-C₆alkyl, C2-C6alkenyl, C₂-C6alkynyl, C₁-C₆alkoxy, -(Co-C6alkyl)cycloalkyl, C₁-C₆haloalkyl, -(Co- C6alkyl)phenyl, -(Co-C6alkyl)aryl, -(Co-C6alkyl)heteroaryl, -C(O)C₁-C₆alkyl, - C(0)(Co-C6alkyl)phenyl, -C(0)(Co-C6alkyl)aryl, -C(0)(Co-C6alkyl)heteroaryl, - C(O)NR²³R²⁴, -(Co-C6alkyl)NR²³R²⁴, -CO2R²³, and a monocyclic or bicyclic heterocycle of 4 to 10 ring atoms having 1, 2, or 3 ring atoms independently chosen from N, S and O;

X is chosen at each occurrence from O and S;

R¹⁹, R²⁰, and R²² are each independently chosen at each occurrence from hydrogen, halogen, hydroxy, cyano, and an amino group;

R²³ and R²⁴ are each independently chosen at each occurrence from hydrogen, halogen, C₁-C₆ alkyl, C₁-C₆alkoxy, C₁-C₆haloalkyl, C₁-C₆haloalkoxy, C₁-C₆alkoxy, -(Co- C6alkyl)phenyl, -(Co-C6alkyl)aryl, -(Co-C6alkyl)heteroaryl, -C(0)(Co-C6alkyl)phenyl, -C(0)(Co-C6alkyl)aryl, -C(0)(Co-C6alkyl)heteroaryl, -S(O)phenyl, -S(O)aryl, - S(O)heteroaryl, -SO₂phenyl, -SO₂aryl, -SO₂heteroaryl, -(Co-C6alkyl)cycloalkyl, and - CO2R²⁵; and

R²⁵ is hydrogen, halogen, hydroxy, an amino group, C₁-C₆alkyl, C2-C6alkenyl, C2- C6alkynyl, C₁-C₆alkoxy, -(Co-C6alkyl)cycloalkyl, -C(O)C₁-C₆alkyl, -(Co-C6alkyl)aryl, -(Co-C6alkyl)heteroaryl, -(C₀-C₆alkyl)phenyl, or a monocyclic or bicyclic heterocycle of 4 to 10 ring atoms having 1, 2, or 3 ring atoms independently chosen from N, S and O.

Embodiment 98. The method or pharmaceutical composition of embedment 97, wherein R¹⁷ is -C(O)Ci-C₆alkyl, -C(0)(Co-C₆alkyl)phenyl, -C(0)(Co-C₆alkyl)aryl, or -C(0)(Co- C6alkyl)heteroaryl;

R¹⁸ is C₁-C₆alkyl, C2-C6alkenyl, C2-C6alkynyl, C₁-C₆alkoxy, -(Co-C6alkyl)cycloalkyl, C₁-C₆haloalkyl, -(Co-C6alkyl)phenyl, -(Co-C6alkyl)aryl, or -(Co-C6alkyl)heteroaryl;

R¹⁹, R²⁰ and R²² are hydrogen;

R²¹ is -NR²³R²⁴;

X is chosen at each occurrence from O and S;

R²³ and R²⁴ are each independently chosen at each occurrence from -S(O)phenyl, - S(O)aryl, -S(O)heteroaryl, -SO₂phenyl, -SO₂aryl, -SO₂heteroaryl, -(Co- C6alkyl)cycloalkyl, and -CO2R²⁵; and

R²⁵ is C₁-C₆alkyl, -(Co-C6alkyl)cycloalkyl, -(Co-C6alkyl)aryl, or -(Co-C6alkyl)phenyl. Embodiment 99. The method or pharmaceutical composition of embedment 98, wherein R¹⁷ is -C(O)Ci-C₆alkyl;

R¹⁸ is C₁-C₆alkyl;

R¹⁹, R²⁰ and R²² are hydrogen;

R²¹ is -NR²³R²⁴:

X is oxygen;

R²³ and R²⁴ are each independently chosen at each occurrence from a substituted or unsubstituted aryl sulfonyl, -CO2R²⁵, -SO₂phenyl, -SO₂aryl, and -SO2R²⁵; and

R²⁵ is phenyl.

Embodiment 100. The method or pharmaceutical composition of embedment 99, wherein the compound of Formula III is Compound

Embodiment 101. The method or pharmaceutical composition of any of embodiments 1- 82, wherein the CD206 modulator is

or a pharmaceutically acceptable salt thereof.

Claims

What is claimed is:

1. A method of treating diabetic retinopathy with or without age-related macular degeneration in a subject, comprising administering to the subject in need thereof a CD206 modulator.

2. A method of treating diabetic retinopathy in a subject in need thereof comprising: identifying a subject in need of treatment for diabetic retinopathy; and administering to the subject an effective amount of a CD206 modulator.

3. A method for preventing or delaying onset of a proliferative phase of diabetic retinopathy in an eye of a subject, comprising administering to the subject in need thereof a CD206 modulator.

4. The method of any claims 1-3, wherein the CD206 modulator is administered prior to or during the inflammatory phase of diabetic retinopathy.

5. The method of claims , wherein the CD206 modulator is administered during inflammatory phase of diabetic retinopathy.

6. A method for preventing or delaying onset of fibrosis and proliferative retinopathy in an eye of a subject, comprising administering to the subject in need thereof a CD206 modulator.

7. A method of treating age-related macular degeneration in a subject, comprising administering to the subject in need thereof a CD206 modulator.

8. A method of treating age-related macular degeneration in a subject in need thereof comprising: identifying a subject in need of treatment for age-related macular degeneration; and administering to the subject an effective amount of a CD206 modulator. A method for preventing or delaying the onset of early or intermediate AMD in an eye of a subject, comprising administering to the subject in need thereof a CD206 modulator. A method for preventing or delaying the onset of non-exudative (dry) or exudative (wet) age-related macular degeneration (AMD) in an eye of a subject, comprising administering to the subject in need thereof a CD206 modulator. A method for preventing or delaying the onset of late AMD in an eye of a subject, comprising administering to the subject in need thereof a CD206 modulator. A method for preventing or delaying onset of sub-retinal fibrosis of AMD in an eye of a subject, including administering to the subject in need thereof a CD206 modulator. A method for reducing an effect in an eye of a subject, the effect being one or more of aberrant blood vessel growth, vitreous hemorrhages, epiretinal fibrovascular membrane formation, tractional retinal detachment, subretinal fibrosis, chronic inflammation A method of reducing production of CD206 (mannose receptor C-type 1) protein in an eye of a subject, comprising administering to the subject in need thereof a CD206 modulator. A method for causing an effect in an eye of a subject, the effect being one or more of: reducing the expression of gene MRC1 (mannose receptor C-type 1), which encodes

CD206 protein, reducing oxidative stress in endothelial cells and/or pericytes reducing the concentration of one or more of peroxides, superoxides, nitric oxide, and oxygen free radicals reducing production of VEGF protein reducing the expression of gene VEGF, which encodes VEGF protein, reducing the amount of inflammatory and/or fibrotic proteins reducing the production of a protein that promotes inflammation and/or fibrosis reducing the expression of a gene that encodes a protein that promotes inflammation and/or fibrosis reducing production of α -SMA (alpha-smooth muscle actin; ACTA2 reducing expression of gene ACTA2, which encodes α -SMA, reducing Ibal+ (ionized calcium binding adaptor molecule 1 positive) mononuclear phagocytes in a sub-retinal area of the eye of a subject, reducing or eliminating CD206 positive cells in the subretinal space in the eye of the subject, increasing production of CD86 in microglia cells reducing or eliminating M2-like macrophages increasing Ml -like macrophages in an eye of a subject, preventing pericyte loss in an eye of a subject, reducing or eliminating pericyte loss in an eye of a subject, the method comprising administering to the subject in need thereof a CD206 modulator.

16. A pharmaceutical composition formulated for ocular delivery comprising a CD206 modulator and a pharmaceutically acceptable carrier.

17. The method or pharmaceutical composition of any of claims 1-16, wherein the CD206 modulator is

or a pharmaceutically acceptable salt thereof.

18. The method or pharmaceutical composition of any of claims 1-16, wherein the CD206 modulator is a compound of Formula I:

Formula I

or a pharmaceutically acceptable salt thereof, wherein each bond shown as a solid line and a dashed line together, , can be a single bond, double, or aromatic bond; R¹ is hydrogen, halogen, hydroxyl, cyano, -CO2H, C₁-C₆alkyl, C2-C6alkenyl, C2-C6alkynyl, C₁-C₆alkoxy, -(Co-C6alkyl)cycloalkyl, C₁-C₆haloalkyl, -(Co-C6alkyl)phenyl, -(Co- C₆alkyl)aryl, -(Co-C₆alkyl)heteroaryl, -C(O)Ci-C₆alkyl, -C(O)NR⁸R⁹, -(Co- C6alkyl)NR⁵R⁶ -CO2R⁶, -C6H4-R⁷, and a monocyclic or bicyclic heterocycle of 4 to 10 ring atoms having 1, 2, or 3 ring atoms independently chosen from N, S and O;

R², R³, and R⁴ are each independently chosen at each occurrence from hydrogen, halogen, hydroxyl, cyano, -CO2H, C₁-C₆alkyl, C2-C6alkenyl, C2-C6alkynyl, C₁-C₆alkoxy, -(Co- C6alkyl)cycloalkyl, C₁-C₆haloalkyl, -(Co-C6alkyl)phenyl, -(Co-C6alkyl)aryl, -(Co- C₆alkyl)heteroaryl, -C(O)Ci-C₆alkyl, -C(O)NR⁵R⁶, (Co-C₆alkyl)NR⁸R⁹ -CO2R⁶, and -C6H4-R⁷; a, b, c, d, and X are each independently chosen at each occurrence from N, C, and CH;

R⁷ is hydrogen, halogen, hydroxyl, cyano, -CO2H, C₁-C₆alkyl, C2-C6alkenyl, C2-C6alkynyl, C₁-C₆alkoxy, C₁-C₆haloalkyl, -(Co-C6alkyl)cycloalkyl, -(Co-C6alkyl)phenyl, -(Co- C₆alkyl)aryl, -(Co-C₆alkyl)heteroaryl, -CO2R⁸, -C(O)Ci-C₆alkyl, -C(O)C2-C₆alkenyl, -C(O)C2-C₆alkynyl, -C(O)Ci-C₆alkoxy, -C(O)Ci-C₆hydroxyalkyl, -C(0)-(Co- C6alkyl)cycloalkyl, -C(0)-(Co-C6alkyl)phenyl, -C(0)-(Co-C6alkyl)aryl, -C(0)-(Co- C₆alkyl)heteroaryl, -C(O)NR⁸R⁹, -C(O)NR⁵R⁶, , -C(0)-(Co-C₆alkyl)NR⁵R⁶, -C(O)- NR⁸-(Co-C₆alkyl)NR⁵R⁶, or (Co-C₆alkyl)NR⁵R⁶; R⁸ and R⁹ are each independently chosen at each occurrence from hydrogen, halogen, Ci- C6 alkyl, C₁-C₆alkoxy, C₁-C₆haloalkyl, -(Co-C6alkyl)phenyl, -(Co-C6alkyl)aryl, -(Co- C₆alkyl)NR⁵R⁶, -CO2R⁶, -C(O)Ci-C₆alkyl, and -(Co-C₆alkyl)cycloalkyl. The method or pharmaceutical composition of claim 18, wherein

R¹ is -C6H4-R⁷;

R² and R⁴ are hydrogen;

R⁷ is -C(O)NR⁵R⁶ or -C(0)-NR⁸-(Co-C₆alkyl)NR⁵R⁶;

R⁸ and R⁹ are each independently chosen at each occurrence from hydrogen, halogen, Ci- C6 alkyl, C₁-C₆alkoxy, C₁-C₆haloalkyl, -(Co-C6alkyl)phenyl, -(Co-C6alkyl)aryl, -(Co- C₆alkyl)NR⁵R⁶, -CO2R⁶, -C(O)Ci-C₆alkyl, and -(Co-C₆alkyl)cycloalkyl. The method or pharmaceutical composition of claim 18, wherein

R¹ is -C6H4-R⁷;

R² and R⁴ are hydrogen;

R⁷ is -C(0)-NR⁸-(Co-C6alkyl)NR⁵R⁶;

R⁸ is hydrogen. The method or pharmaceutical composition of claim 18, wherein

R¹ is -C6H4-R⁷;

R² and R⁴ are hydrogen;

R⁷ is -C(0)-NR⁸-(Co-C₆alkyl)NR⁵R⁶;

R⁸ is hydrogen. The method or pharmaceutical composition of claim 18, wherein

R¹ is -C6H4-R⁷;

R² and R⁴ are hydrogen;

R⁷ is -C(0)-NR⁸-(Co-C₆alkyl)NR⁵R⁶;

R⁸ is hydrogen.

23. The method or pharmaceutical composition of any of claims 1-16, wherein the CD206 modulator is a compound of Formula IIA:

Formula IIA wherein

R¹², R¹⁴ and R¹⁵ are hydrogen;

R¹³ is -C(O)heteroaryl.

24. The method or pharmaceutical composition of any of claims 1-16, wherein the CD206 modulator is a compound of Formula III:

Formula III.

or a pharmaceutically acceptable salt thereof,

R¹⁷ is -C(O)Ci-C₆alkyl, -C(0)(Co-C₆alkyl)phenyl, -C(0)(Co-C₆alkyl)aryl, or -C(0)(Co- C6alkyl)heteroaryl; R¹⁸ is C₁-C₆alkyl, C₂-C6alkenyl, C₂-C6alkynyl, C₁-C₆alkoxy, -(Co-C6alkyl)cycloalkyl, C₁-C₆haloalkyl, -(Co-C6alkyl)phenyl, -(Co-C6alkyl)aryl, or -(Co-C6alkyl)heteroaryl;

R¹⁹, R²⁰ and R²² are hydrogen;

R²¹ is -NR²³R²⁴;

X is chosen at each occurrence from O and S;

R²³ and R²⁴ are each independently chosen at each occurrence from -S(O)phenyl, -

S(O)aryl, -S(O)heteroaryl, -SO₂phenyl, -SO₂aryl, -SO₂heteroaryl, -(Co- C6alkyl)cycloalkyl, and -CO2R²⁵; and

R²⁵ is C₁-C₆alkyl, -(Co-C6alkyl)cycloalkyl, -(Co-C6alkyl)aryl, or -(Co-C6alkyl)phenyl. The method or pharmaceutical composition of claim 24, wherein

R¹⁷ is -C(O)C₁-C₆alkyl;

R¹⁸ is C₁-C₆alkyl;

R¹⁹, R²⁰ and R²² are hydrogen;

R²¹ is -NR²³R²⁴:

X is oxygen;

R²⁵ is phenyl.