EP4694933A1 - Polysialic acid-polymer conjugate and nanoparticle - Google Patents

Abstract

Disclosed herein is a polysialic acid (PSA)-polymer conjugate compound represented by the structural formula (I): or a pharmaceutically acceptable salt thereof, wherein P is a poly(lactide-co-glycolide)-poly(ethylene glycol) copolymer (PLGA-PEG) and p is an integer from 4 to 200, nanoparticles comprising same, and methods of treating ophthalmic diseases using same.

Description

AVQ-00425 POLYSIALIC ACID-POLYMER CONJUGATE AND NANOPARTICLE RELATED APPLICATIONS [0001] This Application claims the benefit of U.S. Provisional Application No. 63/459,486, filed on April 14, 2023; U.S. Provisional Application No.63/529,059, filed on July 26, 2023; U.S. Provisional Application No.63/542,147, filed on October 3, 2023; and U.S. Provisional Application No.63/546,950, filed November 2, 2023. The entire contents of each of said applications are incorporated herein in their entirety by this reference. BACKGROUND OF THE INVENTION [0002] The ability to recognize self is what downregulates the body’s immune system so that it does not destroy its own healthy host cells. The composition of the glycome (carbohydrate moieties that coat all cells) of a particular cell determines whether a cell is recognized as a self-associated cell, non-self-cell, or damaged cell. During the process of immune surveillance and inflammation, the immune system checks the glycome signature of an encountered cell to determine if the cell requires elimination via immune activation, or if the cell constitutes an undamaged host cell that should signal a suppression of immune activation or inflammatory resolution. The receptors or binding regions found on inflammatory cells that are responsible for recognizing this glycome signature are considered self-associated pattern recognition receptors. [0003] The largest family of self-associated molecular pattern recognition receptors are called Siglecs (sialic-acid-binding immunoglobulin-type lectins). Currently there are 16 described Siglecs. Siglecs are found on the surface of inflammatory cells with different Siglec expression patterns found on different inflammatory cells. When presented with a specific sialic-acid ligand pattern on the surface of a healthy host cell, an agonized inhibitory Siglec receptor will activate the immunoglobulin tyrosine kinase inhibitory motif (ITIM), which recruits src homology 2 domain-containing protein tyrosine phosphatase 1 and 2 (SHP-1 and 2), both phosphatases that dephosphorylate kinases that keep the inflammatory cell in an activated state. This inhibitory Siglec-controlled mechanism can shut down activated inflammatory cells profoundly, resulting in resolution of inflammation. Different Siglecs have different sialic-acid signatures that bind and agonize the receptor, resulting in the profound deactivation of inflammatory cells. AVQ-00425 [0004] A need exists for improved compositions and methods for modulating, e.g. agonizing, sialic-acid binding self-associated pattern recognition receptors, for treatment of diseases resulting from acute, chronic, or aberrant immune system activation. SUMMARY OF THE INVENTION [0005] In one embodiment, the present invention is a polysialic (PSA)-polymer conjugate compound represented by the structural formula (I): or a pharmaceutically acceptable salt thereof. In formula (I): P is a poly(lactide-co- glycoclide)-poly(ethylene glycol) copolymer (PLGA-PEG); and p is an integer from 4 to 200. [0006] In another embodiment, the present invention is a compound represented by the structural formula (IV): or a pharmaceutically acceptable salt thereof. In formula (IV), p is an integer from 17 to 200. [0007] In another embodiment, the present invention relates to a method of treating a subject suffering from an ophthalmic disease, comprising administering to the subject a therapeutically effective amount of the compounds described herein (e.g., a compound of Formula I or Formula II), the particles described herein or the pharmaceutical compositions described herein. AVQ-00425 [0008] In another embodiment, the present invention relates to a method of increasing the Best-Corrected Visual Acuity (BCVA) score in a subject in need thereof comprising administering to the subject a therapeutically effective amount of the compounds described herein (e.g., the compounds of Formula I or Formula II), the particles described herein or the pharmaceutical compositions described herein. [0009] In another embodiment, the present invention relates to the use of a compound of Formula I or Formula II or a pharmaceutically acceptable salt thereof or particles or pharmaceutical compositions as described herein for the manufacture of a medicament for treating ophthalmic disease in a subject suffering therefrom. [0010] In another embodiment, the present invention relates to the compounds of Formula I or Formula II and pharmaceutically acceptable salts thereof, or the particles or pharmaceutical compositions described herein for use in a method of treating a subject suffering from an ophthalmic disease. [0011] In another embodiment, the present invention is a method of preparing a polysialic (PSA)-polymer conjugate compound represented by represented by the structural formula (I): or a pharmaceutically acceptable salt thereof, the method comprising: reacting a polymer represented by structural formula (III) , with a PSA precursor represented by the structural formula (IV) AVQ-00425 under the condition sufficient to form the compound represented by the structural formula (I). P is a poly(lactide-co-glycoclide)-poly(ethylene glycol) block copolymer (PLGA-PEG); and p is an integer from 4 to 200. BRIEF DESCRIPTION OF THE DRAWINGS [0012] The foregoing will be apparent from the following more particular description of example embodiments of the invention, as illustrated in the accompanying drawings in which like reference characters refer to the same parts throughout the different views. The drawings are not necessarily to scale, emphasis instead being placed upon illustrating embodiments of the present invention. [0013] FIG.1A is a schematic diagram of non-equivalent hydrogens found in a PSA- amine. [0014] FIG.1B shows Table 1, which provides 1H NMR (400 MHz, D2O) peak assignments for the structure shown in FIG.1A. [0015] FIG.1C is a schematic diagram of non-equivalent carbons found in a PSA-amine. [0016] FIG.1D is Table 2, which provides 13C NMR (400 MHz, D2O-d6) peak assignments. [0017] FIG.1E is a plot showing LCMS Q-TOF deconvoluted mass for PSA-amine. [0018] FIG.2A through FIG.2E reproduce Table 3, Table 4, and Tables 4A through 4C, respectively, which list the results of PSA-amine batch analysis. [0019] FIG.3 reproduces Table 5, which describes the Product. [0020] FIGs.4A, 4B, and 4C reproduce Tables 6-8, which show the effect of homogenization pressure, time, and storage temperature on particle size distribution. [0021] FIG.5 shows Table 9, which presents a summary of the Product sample batches. [0022] FIG.6 shows Table 11, which summarizes the results of temperature and photostability studies. AVQ-00425 [0023] FIG.7 shows a representative IR spectrum of the drug product. [0024] FIG.8 shows a representative chromatogram used for the determination of the PSA-amine content in the drug product. [0025] FIG.9 shows a representative histogram of particle size distribution of the Product. [0026] FIG.10 shows a representative histogram of zeta potential distribution the Product. [0027] FIGs.11A through 11D show Table 14A through 14D, respectively, which summarize batch analysis results of the Product for intravitreal injection. [0028] FIGs.12A, 12B, and 12C show Tables 15, 16, and 17, which summarize the results of long-term stability studies. [0029] FIG.13A and FIG.13B are plots showing Siglec-7, -9, and -11 gene transcript (A) and protein expression levels (B) in human eyes with exudative and nonexudative age-related macular degeneration relative to healthy eyes. [0030] FIG.14 is a plot of optical density as a function of total solids concentration demonstrating the binding affinity of AVD-104 for Siglecs 7, 9, and 11. [0031] FIG.15A and FIG.15B are bar plots of showing the level of the identified cytokine in the supernatant. [0032] FIGs.16A, 16B, and 16C are bar are bar plots of showing the level of the identified cytokine in the supernatant. [0033] FIG.17 is a bar plot showing that the Product decreases classical pathway complement activity as measured by CH50 assay. [0034] FIG.18 is a bar plot showing that the Product decreased alternative pathway activity as measured by AH50 assay. [0035] FIG.19A and FIG.19B are bar plots demonstrating the effect of the Product on retinal degeneration assessed by optical coherence tomography. [0036] FIG.20 is a bar plot demonstrating a dose-dependent suppression of TNF-α in RPE/choroid by the Product. [0037] FIG.21 is a bar plot showing the lesion size assessed by fluorescein angiography. [0038] FIG.22 is a bar plot showing the lesion size assessed by immunohistochemistry staining of Isolectin-B4. [0039] FIG.23 is a plot of PEG mean concentration-time profile by plasma and tissue. [0040] FIG.24A is a bar plot showing the effect of the Product on intact C3 protein. AVQ-00425 [0041] FIG.24B is a bar plot showing the effect of the Product on the stabilizers of the alternative complement pathway (CFD and CFP). [0042] FIG.24C is a bar plot showing the effect of the Product on the inhibitor of the alternative complement pathway. [0043] FIG.25 shows the map of human Siglec 11 targeting vector. [0044] FIG.26 is a plot showing the results of a transcriptomic analysis of the RNA expression changes of Siglecs in AMD eyes. [0045] FIG.27 is a bar plot showing the results the administration of the Products on IL- 12 level in supernatants of human M1 macrophages. [0046] FIGs.28A, 28B, and 28C are bar plots showing the effect of the administration of the Product on the levels of C3a, C5a, and sC5b-9, respectively, in the supernatants of human M1 macrophages. [0047] FIGs.29A and 29B are bar plots showing the effect of the administration of the Product on the levels of Ba and Bb, respectively, in the supernatants of human M1 macrophages. [0048] FIG.30 is a bar plot showing the results of an assay evaluating an inhibitory effect of AVD-104 described herein on binding of Siglec-7 Fc and Siglec-9 Fc proteins to sialic acid-expressing Panc-1 cells. [0049] FIG.31A is a plot showing the cytotoxicity effect of AVD-104 on macrophages activated with either LPS or oxidized (Ox) LDL using MTT cell viability assays. [0050] FIG.31B is a bar plot showing the dose-dependent inhibition of TNF-α production in either OxLDL- or LPS-treated macrophages by AVD-104. [0051] FIG.32 is a graphic representation of a study design of NCT05839041. [0052] FIG.33 presents tables summarizing the intermediate results of a clinical study of AVD-104 in patients suffering from geographic atrophy. [0053] FIG.34 is a plot of the lesion leading edge hyper-AF area over a 1-month period for two GA patients treated by AVD-104 over a 1-month period. [0054] FIG.35A and FIG.35B show the plots of the hyper-AF area and the BCVA score for a representative patient case study. [0055] FIG.36A, 36B, 36C, and 36D show plots of the level of IL-6, complement C3a and C4a, and Complement Factor H (CFH) over time of treatment for a representative patient case study. [0056] FIG.37 shows a design of the Phase 2/3 Part 2 US Clinical Trial for GA Secondary to AMD. AVQ-00425 [0057] FIG.38A and FIG.38B show percent change of area of lesion from baseline (A) and mean change of area of lesion from baseline (B). [0058] FIG.39 and FIG.40 show mean change of lesion areas as a function of time for cohorts 3 and 4 was plotted against similar data for the clinical studies involving the SoC medications. [0059] FIG.41 is a plot showing percent change in hyper-autofluorescence for all patients (pooled cohorts). [0060] FIG.42 is a plot showing the BCVA score (mean change from baseline) for all cohorts. [0061] FIG.43 is a bar plot showing percentage of patients (all cohorts) categorized by the amount of the BCVA score loss or gain. [0062] FIG.44A and FIG.44B are bar plots showing percentage of patients (cohorts 3 and 4) categorized by the amount of the BCVA score loss or gain. [0063] FIG.45A and FIG.45B are plots representing mean change of BCVA as a function of time for cohorts 3 and 4 compared to Syfovre PM and lampalizumab (Trials Chroma & Spectri – 4qw and Chroma & Spectri – 6qw). [0064] FIG.46 is a bar plot showing the BCVA score change for each patient in each cohort at 3 months. [0065] FIG.47 is a bar plot demonstrating that human macrophages treated with AVD- 104 showed significant TNF-α suppression compared to PSA ligand alone. [0066] FIG.48 is a bar plot demonstrating that human macrophages treated with AVD- 104 having DP of not less than 20 showed significant TNF-α suppression than nanoparticle compositions having a lower DP of PSA. [0067] FIG.49 is a dose-response curve TNF-α inhibition in PMBC-derived macrophages by AVD-104. DETAILED DESCRIPTION OF THE INVENTION [0068] A description of example embodiments of the invention follows. [0069] As used herein, a “sialic acid” refers to a monosaccharide and a “polysialic acid” (PSA) refers to any polysaccharide derivative of a sialic acid that is cognate to at least one of the sialic acid receptors. A sialic acid refers to neuraminic acid or any chemical modification of neuraminic acid, either naturally occurring or synthetically derived. The structural formula of neuraminic acid is reproduced below: AVQ-00425 [0071] Examples of a sialic acid derivative include N-acetylneuraminic acid (Neu5Ac), represented by the following structural formula: and N-Glycolylneuraminic acid (Neu5Gc), represented by the following structural formula . [0072] As used herein, a carbohydrate residue is a monosaccharide in which one or more positions are modified for covalent linkage. [0073] As used herein, an “infectious agent” is a viral, bacterial, or a parasitic agent, and the receptor can be a capsid/capsule, membrane or nuclear glycan binding molecules/proteins/enzymes (lectins) such as hemagglutinin esterase, coronavirus spike protein, viral neuraminidase/sialidase. [0074] As used herein, an “average cross-sectional width” is the widest part in a non- spherical nanoparticle, averaged over an ensemble of particles. [0075] As used herein, the term “particle” includes a microparticle and a nanoparticle, as defined herein. AVQ-00425 [0076] The present disclosure provides therapeutic agents comprising polysialic acid for use as immune system modulators, i.e., suppressors or activators of the immune system, inhibitors of viral/bacterial/parasitic infectivity, unmasking damage-associated molecular patterns (DAMPs) to enhance immune surveillance. Target cell populations include those expressing Siglec receptors, CFH CCP 4-6, 19-20, viral HE, viral N, viral SP, and CD147. In a specific embodiment, the delivery vehicles comprise polymers formulated as nanoparticles or microparticles, tethered (conjugated or linked) to ligands comprising PSA and derivatives thereof for presentation on the nanoparticle surface. The tethered PSA functions as a ligand for targeted binding of the nanoparticle to receptors, such as Siglec receptors, expressed on the surface of targeted cells. [0077] In one aspect, the present disclosure provides nanoparticles comprising polymers that provide for tethering via covalent chemical conjugation to the PSA or derivatives thereof for presentation on the nanoparticle surface. The nanoparticles can be used to contact immune cells expressing sialic-acid-binding immunoglobulin-type lectins (Siglecs) in order to modulate inflammatory processes. It has been determined that the PSA, capable of targeting and binding to immune cells expressing sialic-acid-binding immunoglobulin-like lectins (Siglecs) can be used to modulate an inflammatory response in the targeted cells and associated environment. Siglecs are members of the self-associated pattern recognition family of receptors and include Siglec isotypes that are expressed selectivity on different cell populations. Accordingly, the ability to design nanoparticles that bind selectively to specific Siglec receptors allows one to target binding to a desired cell population of interest. Such binding of the nanoparticle to the Siglec receptor may be used as a means for modulating the signal transduction activity of the Siglec receptor within the cell of interest, resulting in a decrease in inflammatory responses or enhancement of anti-inflammatory responses in a treated subject. [0078] Presentation of a PSA on a nanoparticle surface means that the PSA is available to be bound by a Siglec receptor on a target cell, or organism. Suitably the PSA may be provided to bind, activate or block the receptor. Without wishing to be bound by theory, the presentation of the PSA on a nanoparticle requires the PSA to be presented at a specific concentration density in order to modulate inflammatory response, enhance immune surveillance or block infectivity. [0079] A single nanoparticle may be decorated with a multivalent complex of PSA, which will allow for multivalent binding of different Siglec receptors by this single nanoparticle resulting in modulation of the inflammatory response. Nanoparticles decorated AVQ-00425 with a unique type of a PSA moiety can also be mixed with other ligand-decorated nanoparticles that may target different Siglec receptors, again enabling desired modulation of the inflammatory response. In some embodiments, the presentation of the PSA on the surface of a nanoparticle, or microparticle, can provide for an increased uptake of the particle by a cell of at least about two-fold, at least about three-fold, at least about four-fold, at least about five-fold, at least about six-fold, or at least about 10-fold. In some embodiments, the presentation of the PSA on the surface of nanoparticle or microparticle can decrease an inflammatory response. In a non-limiting embodiment, the decrease in an inflammatory response is over about two-fold, over about three-fold, over about four-fold, over about five- fold, over about 10-fold, over about 20-fold, over about 50-fold, over about 100-fold, over about 500-fold or over about 1000-fold. [0080] The nanoparticle or microparticles may be used for systemic delivery or local delivery to target diseased tissues in a subject in need of treatment resulting in modulation of an inflammatory response in said subject to resolve innate and adaptive inflammation, activate innate and/or adaptive immunity when enhanced immune surveillance is desired, or reduce infectivity of infectious organisms. The targeted immune cells or virus should possess Siglec receptors or viral sialic-ligand binding regions, respectively. The activity of the innate immune system includes, for example, the cellular response of the innate immune system; the non-cellular / humoral response of the innate immune system, the complement system, the alternative complement pathway, the amplification loop of the alternative complement pathway, and/or the amplification loop of the alternative complement pathway activated by complement factor H. The activity of the adaptive immune system involves dendritic cell maturation and presentation to T cells, T-cell activation, T-cell modulation, T-cell checkpoint inhibition or activation, neutrophil NETosis, and B-cell activation. The reduction of infectivity includes reduction of viral ingress into host cells, reduction in reproduction of viral particles, or reduction in inflammatory response to the viral infection. [0081] As used herein, “subject” refers to the subject being treated according to the provided treatment methods. A subject can be human, a primate, canine, feline, bovine, equine, murine, etc. Subject also refers to those animals being used for laboratory testing. [0082] As used herein, “nanoparticle” refers to a particle, composed of one or more polymers, whose size in nanometers (nm) includes a range of linear dimensions between 10 nanometers to 2000 nanometers. As used herein, “linear dimension” refers to the distance between any two points on the surface of a nanoparticle measured in a straight line. Nanoparticles of the present disclosure can be irregular, oblong, spindle, rod, cylindrical, AVQ-00425 pancake, discoid, spherical, biconcave, or red blood cell shaped. Linear dimension can be measured using multiple methods including but not exclusive to transmission electron microscopy or tunable resistive pulse sensing which are some of the standard means of determining nanoparticle size. One of the widely used techniques for measuring the size of nanoparticles is dynamic light scattering (DLS) that can provide the diameter and polydispersity of the nanoparticles. DLS assumes that the nanoparticles are spherical in nature, and the size of the nanoparticles are the average diameter (or radius) of such assumed spheres. In such measurements, the nanoparticles can be described to have a size range of 10 nm to 1000 nm or 1 nm to 500 nm. [0083] As used herein, “microparticle”, refers to a microscopic particle, composed of one or more polymers, whose size in micrometers (µm) includes a greatest cross-sectional width less than 1000 µm and which is greater than or equal to 1 µm. [0084] Several types and configurations of nanoparticles are encompassed by the present disclosure. For example, nanoparticles may be composed of a range of materials including, but not limited to, a biodegradable polymer, biocompatible polymer, a bioabsorbable polymer, or a combination thereof. Biocompatible refers to polymers that do not undesirably interfere with biological function of tissues. The terms biodegradable, bioabsorbable, and bioerodible, as well as degraded, eroded, and absorbed, are used interchangeably (unless the context shows otherwise) and refer to polymers and metals that are capable of being degraded or absorbed when exposed to bodily fluids such as blood, and components thereof such as enzymes, and that can be gradually resorbed, absorbed, and/or eliminated by the body. [0085] The polymer backbone of the nanoparticle, upon which the sialic-acid ligands are linked, may be composed of naturally occurring polymers, such as carbohydrates or proteins, or may be composed of synthetic polymers. The polymer backbone will have a unique terminal functional group to provide for tethering of the sialic-acid ligand to the nanoparticle surface. The polymer backbone may first be joined with a plurality of sialic-acid ligands prior to forming the nanoparticle via chemical conjugation methods, or the polymer backbone may first be formed into a nanoparticle and then the functional groups displayed on the surface of the nanoparticle can be joined with sialic-acid ligands via chemical conjugation methods. [0086] Suitable nanoparticles include polymer particles and hydrogel particles. As used herein, a “polymer” refers to a molecule(s) composed of a plurality of repeating structural units connected by covalent bonds. As used herein, a “polymer particle” refers to a solid or porous particle in contrast to the shell-like structure of liposomes and polymersomes and the relatively open structures of hydrogel particles. As used herein, a “hydrogel particle” refers to AVQ-00425 a cross-linked network of polymer chains that is absorbent but stable in an aqueous environment. [0087] Polymers that may be used to prepare nanoparticles include, but are not limited to, poly(N-acetylglucosamine) (Chitin), Chitosan, poly(3-hydroxyvalerate), poly(D,L-lactide-co- glycolide), poly(1-lactide-co-glycolide) poly(3-hydroxybutyrate), poly(4-hydroxybutyrate), poly(3-hydroxybutyrate-co-3-hydroxyvalerate), polyorthoester, polyanhydride, poly(glycolic acid), poly(glycolide), poly(L-lactic acid), poly(L-lactide), poly(D,L-lactic acid), Poly((D,L)Lactide)-b-Poly(ethylene glycol)-Azide, Poly(DL-lactide)-b-poly(ethylene glycol)-methyltetrazine, poly(D,L-lactide), poly(L-lactide-co-D,L-lactide), Poly(D,L-lactide)- b-poly(ethylene glycol)-carboxylic acid, Poly(ethylene glycol) methyl ether-block- poly(lactide-co-glycolide), Poly(lactide-co-glycolide)-b-poly(ethylene glycol)-b-poly(lactide- co-glycolide), Poly(lactide-co-glycolide)-b-poly(ethylene glycol)-azide, Poly(lactide-co- glycolide)-b-poly(ethylene glycol)-alkyne, Poly((D,L)Lactic acid)-b-Poly(ethylene glycol)- Azide, Poly((D,L)Lactic acid)-b-Poly(ethylene glycol)-alkyne, poly(caprolactone), Poly(caprolactone)-b-Poly(ethylene glycol), Polycaprolactone-b-poly(ethylene glycol), Poly(lactide-co-caprolactone)-b-poly(ethylene glycol)-b-poly(lactide-co-caprolactone), poly(L-lactide-co-caprolactone), Poly(L-lactide-co-caprolactone), poly(D,L-lactide-co- caprolactone), poly(glycolide-co-caprolactone), Poly(DL-lactide)-b-Poly(ethylene glycol)-b- Poly(DL-lactide), poly(trimethylene carbonate), polyester amide, poly(glycolic acid-co- trimethylene carbonate), Acrylate-Poly(caprolactone)-b-Poly(ethylene glycol)-alkyne, co- poly(ether-esters) (e.g. PEO/PLA), Poly(N-isopropylacrylamide-co-acrylic acid), Poly(N- isopropylacrylamide-co-methoxy poly(ethylene glycol) methacrylate), polyphosphazenes, biomolecules (such as fibrin, fibrin glue, fibrinogen, cellulose, starch, collagen and hyaluronic acid, elastin and hyaluronic acid), polyurethanes, silicones, polyesters, polyolefins, polyisobutylene and ethylene-alphaolefin copolymers, acrylic polymers and copolymers other than polyacrylates, vinyl halide polymers and copolymers (such as polyvinyl chloride), polyvinyl ethers (such as polyvinyl methyl ether), polyvinylidene halides (such as polyvinylidene chloride), poly(vinylidene fluoride), poly(vinylidene fluoride-co- hexafluoropropylene), polyacrylonitrile, polyvinyl ketones, polyvinyl aromatics (such as polystyrene), polyvinyl esters (such as polyvinyl acetate), acrylonitrile-styrene copolymers, ABS resins, polyamides (such as Nylon 66 and polycaprolactam), polycarbonates including tyrosine-based polycarbonates, polyoxymethylenes, polyimides, polyethers, polyurethanes, rayon, rayon-triacetate, cellulose, cellulose acetate, cellulose butyrate, cellulose acetate AVQ-00425 butyrate, cellophane, cellulose nitrate, cellulose propionate, cellulose ethers, carboxymethyl cellulose, and fullerenes. [0088] In one aspect, the nanoparticles are formed from a biodegradable polymer polycaprolactone, and in other embodiments formed of a polymer comprising polyglycolic acid, poly(L-lactic acid), poly(lactic-co-glycolic acid), polycaprolactone, poly(3- hydroxybutyric acid), In embodiments, the nanoparticle may be a polymeric particle, in particular a particle may be formed from a biodegradable polyester such as poly(lactide) (PLA), poly(glycolide)(PGA), poly lactic-10-glycolic acid (PLGA), poly(butyl cyanoacrylate) (PBCA), or N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers. In another aspect, the nanoparticles are formed from a polymer such as poly(ethylene glycol), polyethylene oxide, Pluronic F127, Pluronic F68, poloxamer, poly(hydroxymethylmethacrylate), polyvinyl alcohol and poly(vinylpyrrolidone). [0089] In a particular embodiment, the nanoparticles are formed from poly(lactic-co- glycolide)-poly(ethylene glycol) copolymer (PLGA-PEG), for example, a (lactide co- glycoclide)-block-poly(ethylene glycol). In one example embodiment, the polymer is PLGA(10k)-PEG(5k). [0090] Methods for synthesis of nanoparticles are well known to those of skill in the art. (see, for example, Spence et al., Science Translational Medicine, 2015, 7: 303303ra140 and references cited therein), for example, methods for synthesis of nanoparticles with known degradation rates are known to those skilled in the art, as described in U.S. Pat. No. 6,451,338 to Gregoriadis et al., U.S. Pat. No.6,168,804 to Samuel et al. and U.S. Pat. No. 6,258,378 to Schneider et al., which are hereby incorporated by reference in their entirety. [0091] Formulated nanoparticles or microparticles, tethered to a PSA for use in selective binding to receptors expressed on target cells of interest are provided. The term sialic acid refers to any monosialic-acid, and the term PSA refers to any oligomeric sialic acid, or polymeric sialic acid or polysialic acid, including disialic-acids which can bind to a Siglec receptor, in particular a sialic acid with binding specificity to inhibitory Siglec receptors, such as for example Siglec 7. In embodiments, a PSA for use in the presently disclosed compositions or methods can be any group of amino carbohydrates that are components of mucoproteins and glycoproteins in animal tissue and blood cells. In embodiments sialic acids (also known as nonulosonic acids) are members of a family of amino containing sugars containing nine or more carbon atoms, for example, N-acetylneuraminic acid (also known as 5-(acetylamino)-3,5-dideoxy-D-glycero-D-D-galacto-nonulosonic, lactaminic acid and O- sialic-acid). AVQ-00425 [0092] In embodiments, it is envisaged that the PSA may be linked 2→8 and/or 2→9, and/or 2→6, and/or 2→3, usually in the α-configuration. In embodiments, a PSA is tethered to the surface of the nanoparticle or microparticle. A PSA is a homopolymer comprising of multiple sialic acid units. A PSA may be less than five sialic-acid units, less than four sialic- acid units, less than three sialic-acid units long, and two sialic-acid units in length. In embodiments, the degree of polymerization (DP) may range from DP2 to over DP250, for example from DP2 to DP200. The DP may be between DP2 and DP100, between DP2 and 90, between DP2 and DP80, between DP2 and DP70, between DP2 and DP60, between DP2 and DP50, between DP2 and DP40, between DP2 and DP30, between DP2 and DP30, between DP2 and DP20, between DP2 and DP10. In a specific non-limiting embodiment, the degree of polymerization is from DP3 to DP100. In alternative embodiments, a PSA can comprise five or more sialic-acid units. For example, a polysialic acid can comprise at least six sialic-acid units, at least seven sialic-acid units, or at least eight sialic-acid. In embodiments, the degree of polymerization (DP) may range from DP5 to DP1000. For example, the degree of polymerization can be from DP5 to DP500, from DP5 to DP100, from DP5 to DP90, between DP5 to DP80, from DP5 to DP70, from DP5 to DP60, from DP5 and DP50, from DP5 to DP40, from DP5 to DP30, from DP5 to DP20or from DP15 to DP25. In a specific non-limiting embodiment, the degree of polymerization is from DP10 to DP400, from DP20 to DP300, or from DP30 to DP 200. In certain embodiments, the DP is from DP5 to DP30, for example, DP5, DP10, DP15, DP20, DP25, DP30, DP35, DP40, DP45 or DP50. In certain embodiments, DP is from DP5 to DP500. In example embodiment, DP is from DP10 to DP30. In some embodiments, DP is DP20. [0093] In certain example embodiments, DP of the PSA as measured by the ¹H-NMR method is from about 17 to about 60. For example, DP is from about 17 to about 60, for example from about 22 to about 60. In some example embodiments, DP was about 22. [0094] In certain example embodiments, DP of the PSA as measured by the ¹H-NMR method is from about 17 to about 60. For example, DP is about 17, about 18, about 19, about 20, about 21, about 22, about 23, about 24, about 25, about 26, about 27, about 28, about 29 or about 30. [0095] In certain embodiments, DP of the PSA is selected from any one of the following ranges: from 17 to 100, from 17 to 60, from 17 to 25, from 20 to 100, from 20 to 60, from 20 to 30, from 22 to 100, from 22 to 60, from 22 to 30, and from 22 to 25. [0096] In embodiments wherein an analog of sialic acid is used, the analog may have structural similarity to sialic acid as disclosed herein and have binding affinity to certain AVQ-00425 Siglecs. Suitable analogs would be known in the art. It is believed that the feature which influences binding of a sialic-acid ligand to a Siglec receptor is the charge-distance- coordination relationship between the carboxylic acid functionality of sialic acid. [0097] In specific embodiments, a PSA is selected from NeuAcα2-3Galβ1-4Glc, NeuAcα2-3Galβ1-4GlcNAc, NeuAcα2-3Galβ1-3GlcNAc, NeuAcα2-3Galβ1-3GalNAc, NeuGcα2-3Galβ1-4GlcNAc, NeuGcα2-3Galβ1-3GlcNAc, NeuAcα2-6Galβ1-4Glc, NeuAcα2-6Galβ1-4GlcNAc, NeuAcα2-6GalNAc, Galβ1-3(NeuAcα2-6)GalNAc, NeuGcα2- 6Galβ1-4Glc, NeuGcα2-6Galβ1-4GlcNAc, NeuGcα2-6GalNAc, NeuAcα2-8NeuAcα2- 3Galβ1-4Glc, NeuAcα2-6Galβ1-4GlcNAc, NeuAcα2-3Galβ1-4[Fucα1-3]GlcNAc, NeuAcα2- 6Galβ1-4GlcNAc6S, NeuAcα2-3Galβ1-4GalNAc, NeuAcα2-8NeuAc, NeuAcα2-3GalβSβ1- 4GlcNAcα2-3Fuc, NeuAcα2-3Galβ1-4GlcNAc6Sα2-3Fuc, and NeuAcα2-8NeuAc or sialoside derivatives of such sialic acids, for example BPCNeuAc sialosides. [0098] In certain embodiments, a PSA may be first joined to a polymer backbone via chemical conjugation techniques, and then subsequently the polymer-conjugated-PSA construct can be formed into to the nanoparticle surface. In other embodiments, the polymers are formed into nanoparticles with exposed functional groups on the nanoparticle surface, such that these functional groups can be conjugated with a PSA. [0099] PSA comprising oligomers and polymers may be joined together by any combination of α2-3, α2-6, α2-8, or α2-9 glycosidic linkages. The type of glycosidic linkages joining a sialic acids or sialic-acid analog to the nanoparticle surface can be controlled to maximize binding affinity to target Siglec receptors and enhance specificity for a particular Siglec. As different Siglecs are known to be differentially expressed by different cell types, the selection of specific types of sialic-acid linkages can be used to determine the type of cells to be contacted, or targeted, by the nanoparticles with the sialic-acid ligands. A PSA in the form of oligomers and polymers may have linear or branched structures. The branched structure of the oligomer or polymer form may be created by introduction of a glycosidic linkage different from adjacent glycosidic linkages. The oligomer and polymer forms may be homogeneous in composition, composed of a one type of sialic-acid, or they may be heterogeneous in composition, composed of a plurality of sialic-acid. The oligomer and polymer forms may also be comprised of other carbohydrate monomers, such as galactose, N-acetylgalactoseamine, glucose, N-acetylglucoseamine, mannose, N-acetylmannosamine, fucose, or other sugar/carbohydrates in addition to a sialic acid and/or a sialic acid analog. [00100] The sialic acid may be naturally derived (e.g., Neu5Ac, Neu5Gc, Neu5Ac9Ac, etc) or may include any synthetically prepared sialic acid analog. Sialic acid analogs are AVQ-00425 known in the art. In embodiments, such analogs can have substitutes at position C9. Analogs can also have substitutes at C1, C4, C5, C7, and C8. Analogs can include neuraminic acid derivatives, sialosides, and carbohydrate oligomers comprising a neuraminic acid molecule. [00101] The sialic acid analogs may be prepared by means of chemical synthesis, chemoenzymatic synthesis (e.g., one-pot multienzyme; OPME), or via mammalian or bacterial cellular synthesis such as by cell feeding of precursor carbohydrates (e.g., mannose derivatives), recombinant methods, or genetic engineering methods. The PSA comprising sialic acid analogs prepared for use as nanoparticle ligands may be prepared using one-pot synthesis or microarray platform. Arrays of sialic acid analogs can be prepared in-situ using HTS methods. [00102] Chemical linkage of the sialic-acid ligand to the nanoparticle surface may be achieved through a variety of chemistry reactions. In such reactions, a chemical reaction occurs between a terminal functional group of a nanoparticle polymer and a terminal functional group of a PSA (referred to herein as “terminal functional group conjugate pairs”) resulting in linkage of the polymer and the PSA. The types of terminal functional groups found on the surface of the polymer, and its binding partner ligand, will determine the type of chemistry reaction that is to be used to chemically link the PSA to the surface of the nanoparticles. Additionally, the selection of polymers having specific terminal functional groups can be used to control the types, density and spatial arrangement of a PSA conjugate partners to be presented on the surface of the nanoparticle. [00103] For example, a position for linkage of a PSA is provided on the surface of the nanoparticle. In one example, the nanoparticle is formed of a PLGA-PEG polymer with an ester (for example, activated ester) moiety, such as PLGA-PEG-NHS (N- hydroxysuccinimide). In a non-limiting embodiment, blends of different polymers having different terminal functional groups may be used. Such polymers include, for example, PLGA-PEG-alkyne, PLGA-PEG-ester and PLGA-PEG-DBCO. In a specific aspect, a blend of PLGA-PEG-ester and PLGA-PEG-carboxylic acid may be prepared as nanoparticles. In another specific aspect, PLGA-PEG-ester may be prepared as nanoparticles. In example embodiments, the use of PLGA-PEG-NHS as a conjugation site to a PSA-amine is preferable to the use of other linkages, e.g. the DBCO. [00104] Suitably the polymer or copolymer can be branched or linear and can have a plurality of terminal functional groups. [00105] In other embodiments, a PSA comprise terminal functional groups (i.e., conjugation sites) that provide for tethering at the nanoparticle surface. Such terminal AVQ-00425 functional groups include azide, alkyne, aryl ester, amide, amine, aryl amide, aldehyde, acetyl, substituted aryl ester, alkyl ester, alkyl ketone, aryl ketone, substituted aryl ketone, ketone, alkyl halide, amnioxy, alcohols, aza-ylide, carboxylic acid, ester, amide, bicyclononyne, dihydrazide, halo-carbonyl, halosulfonyl, hydrazide, N-hydroxysuccinimide, norbornene, oxanorbornadiene, succinimidyl ester, isothiocyanate, iodoacetamide, monofluorinated and difluorinated cyclooctynes, maleimide, methylcyclopropene, isocyanopropanoate, hydrazine, nitrile, nitro, phosphine, phosphazide, tertazine, methyl- tetrazine, trans-cyclooctene, strained alkynes, dibenzocyclooctyne, biarylazacyclooctynone, propargyl, isocyanide, azadibenzylcyclooctyne, vinyl, sulfonyl ester, thioester, thiocarboxylate, thioester a sulfonyl halide, thiol, and thiolene. [00106] The plurality of a PSA and/or its analogs, in the form of monomers, polymers or oligomers, and with adjoining glycans, can be tethered to the surface of the nanoparticle by means of chemical conjugation. Such chemical conjugation can include, for example, click chemistry, carbodiimide chemistry, reductive amination, or chemisorption. [00107] The functional group of PSA may be found at different positions on the sialic acid unit located at the C1, C2, C4, C5, C7, C8, or C9 position. Accordingly, linkage of the PSA to surface of the nanoparticle may occur via conjugation at the C1, C2, C4, C5, C7, C8, or C9 position, yielding different orientations of the ligand in 3-dimensional space on the nanoparticle surface, which can influence ligand presentation to the immune cell of interest. Ligand presentation can, thus, be controlled in this manner to elicit the desired cell response upon contacting an immune cell via receptor binding. [00108] A PSA and sialic-acid analogs thereof, with known spacing and/or density of ligands, are to be presented on the surface of the nanoparticles as ligands for Siglec receptors. By tethering a specific PSA to the surface of the nanoparticles, the nanoparticles can contact a known set of immune cells expressing Siglec receptors in order to elicit specific biological responses thereby modulating inflammation. The diversity of the PSA composition, structure, density, and architecture presented on the surface of the nanoparticle provides a means for regulating the degree and direction of the modulation of the response of immune cells. [00109] In various embodiments, an average molecular weight of a polymer, e.g., PEG, PLGA, PEG-PLGA block copolymer, or polysialic acid, can be determined by any of the methods known in the art, such as anion-exchaneg chromatography, gel permeation chromatography concentration measurements, among others. [00110] The tethering of a PSA or to a sialic acid and its analogs, to the surface of the nanoparticles is performed in such a way so as to provide presentation of the PSA for AVQ-00425 maximum binding affinity to the Siglec receptors expressed on the surface of immune cells or sialic-acid ligand receptor expressed on the surface of viral particles. The ligand density can be controlled to provide the desired multivalent or polyvalent ligand interactions with the Siglec receptors when contacting the immune cells, as such interactions are correlated with a desired cellular immune response. Multivalent or polyvalent sialic-acid-receptor interactions may be controlled based upon the density of the ligands provided on the nanoparticle surface, and this density can influence the response elicited by the immune cells upon contact. [00111] Suitably, a PSA may be immobilized on the surface of the nanoparticle. The PSA may be bound directly to the nanoparticle or via a linker. The nanoparticle may be derivatized or activated to allow binding of the PSA. Alternatively, the nanoparticle may be derivatized or activated to allow binding of a linker to a nanoparticle and the linker may be attached to the PSA. By linking the PSA to a nanoparticle, the nanoparticle can be adapted to target a cell comprising a Siglec receptor to induce binding of the Siglec receptor such that production of pro-inflammatory cytokines within the cell is inhibited or production of anti-inflammatory cytokines is increased, thereby suppressing a pro-inflammatory immune response. [00112] The density of the different functional groups can be controlled by the ratio of the different polymers to one another, the concentration of the polymers, and the type of conjugate pairs, the type of reactions, and the size and shape of a PSA. The number of different ligands that can be presented on the surface can be determined by those skilled in the art. In a non-limiting embodiment, the number of different ligands present on the nanoparticle surface is in the range of 1 to 20. The number of different ligands include, for example, is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20. In another embodiment, the number of different ligands present on the nanoparticle surface is in the range of 2 to 20. The number of different ligands include, for example, is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20. In another embodiment, the nanoparticle will comprise at least two different PSAs. In another embodiment, the nanoparticle will comprise least three different PSAs. In another embodiment, the nanoparticle will comprise least four different PSAs. In another embodiment, the nanoparticle will comprise least five different PSAs. [00113] In general, the density of the functional groups on the nanoparticle surface dictates the maximum ligand density that can be tethered to the surface of the nanoparticle via covalent chemical conjugation via click chemistry. The ligand density can be controlled and quantified in terms of the number of functional groups per square nanometer of surface area. The density reached allows for the transition of the ligands to transition from mushroom AVQ-00425 confirmation to brush confirmation. The brush confirmation provides for the highest density packing of the PSA. Tuning the density of the ligands on the nanoparticle surface provides a means by which the biological response of the target immune cells contacted by the nanoparticles can be modulated. The density of ligands presented on the surface of the nanoparticles can be quantified as nmol of ligands per mg of the total nanoparticle solids. The density can range from 0.05nmol/mg to 50nmol/mg of the nanoparticles. The diameter of the nanoparticles can range from 25nm to 200nm. [00114] The density of the ligands on the nanoparticle surface can be controlled by several methods including chemical conjugation techniques, ligand density on the polymer, ligand type, solvent, pH, and ionic strength. Ligand density on the surface of the nanoparticles can be tuned such that contacting immune cells with such nanoparticles results in an immune- modulating response, including an anti-inflammatory biological response. Control of the ligand density can also be used to modulate the magnitude of the desired anti-inflammatory response. [00115] In some embodiments, a PSA can be presented on the nanoparticle in groups of at least 2, at least 5, at least 10, at least 15, at least 20 or at least 25, at least 50, at least 100, at least 200, or at least 400. In some embodiments, the PSA can be spaced on the surface of the nanoparticle such that they or the nanoparticle can bind to more than one Siglec receptor. In some embodiments, the PSA can be spaced on the surface of the nanoparticle such that they or the nanoparticle can bind to multiple Siglec receptors presented on individual cell types, which may vary in the quantity of Siglec receptors presented on their plasma membrane. [00116] In some embodiments the nanoparticle can comprise a polymer that includes a PSA at a concentration in the range 0.05 nmol/mg of PSA to nanoparticles to 250 nmol/mg of PSA to nanoparticles, preferably 0.5 nmol/mg to 25 nmol/mg, and most preferably 0.5 to 15 nmol of PSA per mg of nanoparticle. In embodiments, a device can be coated with such a nanoparticle. In alternative embodiments a device can be formed from a polymer, for example wherein the device is a microparticle or nanoparticle, wherein a PSA is provided in the polymer at a concentration in the range 0.05 nmol/mg of PSA to nanoparticle to 250 nmol /mg of PSA to nanoparticle, preferably 1 nmol/mg to 25 µg/mg, and most preferably 2 to 15 nmol of PSA per mg of nanoparticle. [00117] In some embodiments, a nanoparticle can have a greatest cross-sectional width or diameter of less than about 1000 nm, less than about 500 nm, less than about 250 nm or less than about 200 nm. In embodiments, a nanoparticle can have a width greater than about 1 nm, greater than about 10 nm, greater than about 50 nm, or greater than about 100 nm. In AVQ-00425 embodiments, a nanoparticle coated with sialic-acid or a sialic-acid analog can have a greatest cross-sectional width or diameter in the range of about 130 nm to about 170 nm, more preferably a width of about 150 nm. In embodiments these range of sizes can be average widths of nanoparticles. In embodiments, at least 80% of the nanoparticles are within a disclosed range. [00118] Suitably, in some embodiments around at least 80%, more preferably at least 90% of the particles have a greatest cross-sectional width between 130 nm to 170 nm. In embodiments, the particles can have an average greatest cross-sectional width of 150 nm with the particles having no width greater or less than a value not within one standard deviation of 150 nm. In some embodiments, the nanoparticle can have a volume equal to that of a sphere with a diameter between 10 nm to 500 nm, suitably between 50 nm to 250 nm, or 100 nm to 200 nm, or 130 nm to 170 nm. In some embodiments, an average particle size is from 80 nm to 120 nm, for example, 100 nm. [00119] In a non-limiting embodiment, the nanoparticle can have a volume equal to that of a sphere with a diameter of about 100 nm, for example 70 nm to 130 nm. In some embodiments, the polydispersity index (PDI) of the nanoparticle sizes of less than 0.5, less than 0.4, less than 0.3, less than 0.2, less than 0.1, less than 0.05, less than 0.25, less than 0.01. For example, the PDI can be less 0.15. [00120] In another aspect of the invention, the linkage of the nanoparticles with a PSA provides a means for the nanoparticles to evade the immune system, i.e., opsonization and phagocytosis via the reticuloendothelial system (RES). It is known that PEGylation of nanoparticles, i.e., the coating of nanoparticles with polyethylene glycol, provides barrier of protection from detection by immune cells. However, PEG has disadvantages of toxicity, immunogenicity, reduced cellular uptake, reduced binding, and nonbiodegradable or bioresorbable properties. PSA coating of nanoparticles overcomes the disadvantages of PEG, and provides for a natural, non-immunogenic nanoparticle coating that can evade the RES and immune detection. Therefore, the nanoparticles disclosed herein possess the ability to evade immune detection and mitigate immunogenic response. [00121] The nanoparticles, or microparticles, disclosed herein may further comprise a bioactive agent encapsulated within, adhered to the surface of, or integrated into the structure of said nanoparticles. For example, the nanoparticle can further comprise at least one of an antibiotic, an anti-viral agent, an anti-inflammatory, a cytokine, a cytokine inhibitor, an immunomodulator, an immunotoxin, an anti-angiogenic agent, an anti-hypertensive agent, an anti-edema agent, a radiosensitizer, an oligonucleotide comprising DNA or RNA, a peptide, AVQ-00425 or any combination thereof. Methods of preparing nanoparticles that include a bioactive agent encapsulated within, adhered to a surface of, or integrated into the structure of the nanoparticle are known to those skilled in the art. [00122] The present disclosure further provides pharmaceutical or veterinary compositions comprising the PSA-linked nanoparticles disclosed herein. Such a pharmaceutical composition is formulated to be compatible with its intended route of administration. Examples of routes of administration include both parenteral and non-parenteral administration methods including, for example, intravenous, intravitreal, oral, intraocular, subretinal, subtenons, intrascleral, periocular, intravenous, inhalational nasal and oral, intramuscular, intra-areterial, intraspinal, intrathecal, intracranial, intradermal, transdermal (topical), transmucosal, subcutaneous, pulmonary lavage, gastric lavage, intrahepatic, subcutaneous, and rectal administration. [00123] Suitably, in some embodiments nanoparticles can be parenterally administered. After parenteral administration, nanoparticles can selectively accumulate in particular tissues or body locations. In some embodiments, nanoparticles can deliver a therapeutic payload to the cell or tissue. In some embodiments, nanoparticles can access diseased tissue through an enhanced permeability and retention effect. [00124] In general, pharmaceutical compositions are provided comprising an effective amount of a nanoparticle with pharmaceutically acceptable diluents, preservatives, solubilizers, emulsifiers, adjuvants, and/or carriers. Such compositions include diluents of various buffer content (e.g., Tris-HCl, acetate, phosphate), pH and ionic strength; additives such as detergents and solubilizing agents (e.g., tween 80, polysorbate 80), anti-oxidants (e.g., ascorbic acid, sodium metabisulfite), preservatives (e.g., thimersol, benzyl alcohol) and bulking substances (e.g., lactose, mannitol). Such compositions may influence the physical state, stability, rate of in vivo release, and rate of in vivo clearance of the nanoparticle. See, e.g., Remington’s Pharmaceutical Sciences, 18^th Ed. (1990, Mack Publishing Co., Easton, Pa. 18042) pages 1435-1712 which are herein incorporated by reference. The compositions may be prepared in liquid form, or may be formulated into a dried powder, such as lyophilized form. [00125] The present disclosure provides for a method of treating immune and inflammatory-related diseases, including, but not limited to, dry and wet macular degeneration, retinal vascular disease, diabetic retinopathy, diabetic macular edema, cystoid macular edema, proliferative diabetic retinopathy, proliferative vitreoretinopathy, dry eye, allergic conjunctivitis, rheumatoid arthritis, inflammatory arthritis, lupus, nephritis, immune AVQ-00425 complex nephropathy, allergic esophagitis, allergic gastritis, hepatitis, fibrotic diseases of the liver, idiopathic pulmonary fibrosis, acute respiratory distress syndrome, sepsis, bacterial and viral infections, influenza, SARS-CoV-1 and SARS-CoV-2, HIV/AIDS, Group B streptococcal infection, Neisseria infection, in each case in an afflicted subject through the administration of such pharmaceutical compositions. The present disclosure provides a method of modulating an inflammatory response in a cell, the method comprising: providing sialic acid or analogs thereof to a cell, wherein the sialic acid or analogs are presented on a nanoparticle such that a pro-inflammatory response in a cell is suppressed or an anti- inflammatory response in increased in the cell. In embodiments, the method provides for the suppression of a pro-inflammatory response. In alternative embodiments, the method provides for the increase in an anti-inflammatory response. In some embodiments, the method provides for the enhancement of a pro-inflammatory response in situations such as infections. [00126] The term “treatment” or “treating” as used herein to characterize a method or process that is aimed at (1) delaying or preventing the onset of a disease, disorder, or condition; (2) slowing down or stopping the progression, aggravation, or deterioration of one or more symptoms of the disease, disorder, or condition; (3) bringing about ameliorations of the symptoms of the disease, disorder, or condition; (4) reducing the severity or incidence of the disease, disorder, or condition; or (5) curing the disease, disorder, or condition. A treatment may be administered prior to the onset of the disease, disorder, or condition, for a prophylactic or preventive action. Alternatively, or additionally, the treatment may be administered after initiation of the disease, disorder, or condition, for a therapeutic action. [00127] Depending on the route of administration and disease, effective doses may be calculated according to the body weight, body surface area, primary organ/tumor size, and/or number, sizes, and/or types of metastases of the subject to be treated. Optimization of the appropriate dosages can readily be made by one skilled in the art considering pharmacokinetic data observed in human clinical trials. The final dosage regimen will be determined by considering various factors which modify the action of the drugs, e.g., the drug’s specific activity, the severity of the damage and the responsiveness of the patient, the age, condition, body weight, sex and diet of the patient, the severity of any present infection, time of administration, the use (or not) of other therapies, and other clinical factors. [00128] The compositions and nanoparticles described herein can be used for the treatment of acute life-threatening inflammation including but not exclusive to sepsis and cytokine storm sialic-acid. In a specific embodiment, provided are methods of treating a plurality of AVQ-00425 ocular inflammatory diseases such as macular degeneration, uveitis, optic neuritis, neuromyelitis, and inflammation arising from infections of the eye, eye exposure to drugs and toxins, and general immune disorders including autoimmune disorders. In a non-limiting embodiment, provides useful methods are provided for preventing, treating, or ameliorating a macular degeneration such as dry macular degeneration, wet macular degeneration, geographic atrophy, for example, geographic atrophy secondary to Age-related Macular Degeneration (AMD), intermediate macular degeneration and age-related macular degeneration in a patient. The methods of treating, preventing or ameliorating ocular inflammation, including macular degeneration, comprise administering a composition of PSA nanoparticles to a patient suffering from, or a risk of developing, ocular inflammation such as macular degeneration. [00129] In certain non-limiting embodiments, the present disclosure provides for a method of treating immune and inflammatory-related diseases, including, but not limited to, dry and wet macular degeneration, retinal vascular disease, diabetic retinopathy, diabetic macular edema, cystoid macular edema, proliferative diabetic retinopathy, proliferative vitreoretinopathy, dry eye, and allergic conjunctivitis. [00130] In a non-limiting embodiment, methods are provided for preventing, treating, or ameliorating a macular degeneration such as dry macular degeneration, wet macular degeneration, geographic atrophy, intermediate macular degeneration and age-related macular degeneration in a patient. [00131] In some embodiments, an ophthalmic preparation is provided as an eye drop, an eye ointment or an ophthalmic injection. For an ophthalmic injection, intravitreous or subconjunctival injection, may be used to administer the nanoparticles. [00132] Co-administration of additional compounds having applications in methods to treat, prevent or ameliorate a macular degeneration may be co-administered in conjunction with the nanoparticle containing pharmaceutical compositions used for treating macular degeneration. For example, anti-angiogenic pharmaceuticals for the treatment of wet age- related macular degeneration such as pegaptanib sodium, ranibizumab, bevacizumab, aflibrecept and brolucizumab can be used as a combination. While particular embodiments of the present disclosure have been shown and described, it will be obvious to those skilled in the art that changes and modifications can be made without departing from the disclosure in its broader aspects. Therefore, the appended claims are to encompass within their scope all such changes and modifications as fall within the true spirit and scope of this disclosure. AVQ-00425 [00133] Age-related macular degeneration (AMD) is a major cause of moderate and severe vision loss in adults over 60 worldwide, currently affecting approximately 11 million people in the United States. Central vision can be prominently, and permanently, reduced such that affected patients can lose their independence and become limited in many basic functions including reading, driving, and recognizing faces. The wet, or neovascular, form of AMD occurs because of abnormal blood vessel growth, bleeding, and scarring that destroys central retinal cells. Approved anti-VEGF therapies have helped control and treat this form. The source of VEGF is from chronic inflammation in particular the polarization of macrophages to the M2d phenotype. The dry, or non-neovascular, form of AMD is characterized initially by the development of drusen and RPE changes which can develop into geographic atrophy (GA) in which there is irreversible progressive destruction of central retinal cells and underlying blood vessels due to chronic inflammation (with over-activated macrophage activity with resultant phagocytosis of retinal and RPE cells) and abnormal complement activation in the retinal photoreceptor, retinal pigment epithelial, and choriocapillaris regions in the back of the eye. Current therapeutics are under development to treat early and late dry AMD by reducing chronic inflammation and inhibiting elements of the complement cascade. [00134] In a first example embodiment, the present invention is a polysialic (PSA)- polymer conjugate compound. In a 1^st aspect of the 1^st example embodiment, the conjugate compound is represented by the structural formula (I): or a pharmaceutically acceptable salt thereof, wherein: P is a poly(lactide-co-glycoclide)- poly(ethylene glycol) copolymer (PLGA-PEG); and p is an integer from 4 to 200. [00135] In a 2^nd aspect of the 1^st example embodiment, P is a PLGA(10k)-PEG(5k). The remainder of values and example values are as defined above with respect to the 1^st aspect of the 1^st example embodiment. [00136] In a 3^rd aspect of the 1^st example embodiment, the compound is represented by the following structural formula (II): AVQ-00425 wherein: y is an integer from 1 to 1000, x is an integer from 1 to 1000, and m is an integer from 1 to 450. The remainder of values and example values are as defined above with respect to the 1^st and 2^nd aspects of the 1^st example embodiment. [00137] In a 4^th aspect of the 1^st example embodiment, y is an integer from 1 to 500, x is an integer from 1 to 500, and m is an integer from 1 to 250. The remainder of values and example values are as defined above with respect to the 1^st to 3^rd aspects of the 1^st example embodiment. [00138] In a 5^th aspect of the 1^st example embodiment, x is an integer from 90 to 140; y is an integer from 10 to 75; and m is an integer from 90 to 140. The remainder of values and example values are as defined above with respect to the 1^st to 4^th aspects of the 1^st example embodiment. [00139] In a 6^th aspect of the 1^st example embodiment, the value of p is selected from any one of the following ranges: from 10 to 20, from 20 to 30, from 30 to 40, from 40 to 50, and from 50 to 60. For example, p is 22. The remainder of values and example values are as defined above with respect to the 1^st to 5^th aspects of the 1^st example embodiment. [00140] In a 7^th aspect of the 1^st example embodiment, P is a PLGA(10k)-PEG(5k), and p is 15-25. The remainder of values and example values are as defined above with respect to the 1^st to 6^th aspects of the 1^st example embodiment. [00141] In a 2^nd example embodiment, the present invention is a particle, comprising the compound of any of the aspects of the 1^st example embodiment or a pharmaceutically acceptable salt thereof. For example, a particle can be a nanoparticle. [00142] In a 1^st aspect of the 3^rd example embodiment, the weight of the PSA per unit weight of the particle is from 1µg/mg to 1000 µg/mg. [00143] In a 2^nd aspect of the 3^rd example embodiment, the weight of the PSA per unit weight of P is from 10 to 75 µg/mg. AVQ-00425 [00144] In a 3^rd aspect of the 3^rd example embodiment, an average particle size is from 80 nm to 120 nm. The remainder of features and example features of the 3^rd example embodiment are as defined above with respect to the 1^st to 2^nd aspects of the 3^rd example embodiment. [00145] In a 3^rd example embodiment, the present invention is a pharmaceutical composition comprising the particle described by any aspect of the 2^nd example embodiment in a pharmaceutically acceptable carrier or diluent. [00146] In one aspect of the 3^rd example embodiment, the composition is aqueous and further comprises sucrose. The remainder of features and example features of the 3^rd example embodiment are as defined above with respect to any of the aspects of the 2^nd example embodiment. [00147] In a 4^th example embodiment, the present invention is a method of treating a subject suffering from an ophthalmic disease, comprising administering to the subject a therapeutically effective amount of the compound according to any of the aspects of the 1^st example embodiment, the particle according to any of the aspects of the 2^nd example embodiment, or the pharmaceutical composition according to any of the aspects of the 3^rd example embodiment. [00148] In a 1^st aspect of the 4^th example embodiment, the ophthalmic disease is Age- related Macular Degeneration (AMD). For example, the age-related macular degeneration can be dry age-related macular degeneration. In another example, the age-related macular degeneration is wet age-related macular degeneration. The remainder of features and example features of the 4^th example embodiment are as defined above with respect to any of the aspects of the 1^st, 2^nd, and 3^rd example embodiments. [00149] In a 2^nd aspect of the 4^th example embodiment, the ophthalmic disease is geographic atrophy secondary to AMD. The remainder of features and example features of the 4^th example embodiment are as defined above with respect to any of the aspects of the 1^st, 2^nd, and 3^rd example embodiments. [00150] In a 3^rd aspect of the 4^th example embodiment, the ophthalmic disease is retinitis pigmentosa. The remainder of features and example features of the 4^th example embodiment are as defined above with respect to any of the aspects of the 1^st, 2^nd, and 3^rd example embodiments. [00151] In a 4^th aspect of the 4^th example embodiment, the ophthalmic disease is diabetic macular edema. The remainder of features and example features of the 4^th example AVQ-00425 embodiment are as defined above with respect to any of the aspects of the 1^st, 2^nd, and 3^rd example embodiments. [00152] In a 5^th aspect of the 4^th example embodiment, the administering is intravitreal. The remainder of features and example features of the 4^th example embodiment are as defined above with respect to any of the aspects of the 1^st, 2^nd, and 3^rd example embodiments. [00153] As used herein, retinitis pigmentosa (RP) refers to any one of a group of rare genetic eye diseases that affect the retina. The genetic forms of RP occur in 1 in 5000 persons worldwide and represent a leading cause of irreversible blindness in the younger population. RP is linked to polymorphisms in genes that play a role in the visual cycle, support of retinal cell function or represent structural genes of the retina tissue... Sometimes RP is a complications in genetic syndromes-like Ushers,Bardet-Biedl, Alports, Waardenberg’s and Kearns Sayres syndrome. Many genes that cause RP are yet to be identified and RP can also be caused by non-genetic factors such as toxic medicines, infections, or eye injury. [00154] The clinical findings of photoreceptor degeneration and death followed by loss of retinal pigment epithelial cells are the hallmark of this collection of retinal degenerations. The complete loss of retinal cells often seen in the end stage of these diseases is mediated by microglial phagocytosis of pre-apoptotic cells which if abrogated would result in preservation of photoreceptors and other retinal cells. Clinically complete blindness requires several decades to manifest providing a therapeutic window to preserve lifelong vision. Because of this long development time, the genetic abnormalities are considered predisposition genes except in a few rare cases, making the majority of RP not amenable to gene therapy. Repolarization of microglia to the neuroprotective homeostatic state would prove a universally effective therapeutic for both genetic and non-genetic forms of RP. [00155] In a 5^th example embodiment, the present invention is a method of preparing a polysialic (PSA)-polymer conjugate compound represented by represented by the structural formula (I): AVQ-00425 or a pharmaceutically acceptable salt thereof. [00156] In a 1^st aspect of the 5^th example embodiment, the method comprises reacting a polymer represented by structural formula (III) , with a PSA precursor represented by the structural formula (IV) under the condition sufficient to form the compound represented by the structural formula (I), wherein: P is a poly(lactide-co-glycoclide)-poly(ethylene glycol) copolymer (PLGA-PEG); and p is an integer from 4 to 200. [00157] In a 2^nd aspect of the 5^th example embodiment, P is a PLGA(10k)-PEG(5k). The remainder of values and example values of the 2^nd aspect of the 5^th example embodiment are as defined above with respect to the 1^st aspect of the 5^th example embodiment. [00158] In a 3^rd aspect of the 5^th example embodiment, the compound represented by the structural formula (I) is represented by structural formula (II): (II), wherein: y is an integer from 1 to 1000, x is an integer from 1 to 1000, and m is an integer from 1 to 450. The remainder of values and example values of the 3^rd aspect of the 5^th AVQ-00425 example embodiment are as defined above with respect to the 1^st to 2^nd aspects of the 5^th example embodiment. [00159] In a 4^th aspect of the 5^th example embodiment, y is an integer from 1 to 500, x is an integer from 1 to 500, and m is an integer from 1 to 250. The remainder of values and example values of the 4^th aspect of the 5^th example embodiment are as defined above with respect to the 1^st to 3^rd aspects of the 5^th example embodiment. [00160] In a 5^th aspect of the 5^th example embodiment, x is an integer from 90 to 140; y is an integer from 10 to 75; and m is an integer from 90 to 140. The remainder of values and example values of the 5^th aspect of the 5^th example embodiment are as defined above with respect to the 1^st to 4^th aspects of the 5^th example embodiment. [00161] In a 6^th aspect of the 5^th example embodiment, the value of p is selected from any one of the following ranges: from 10 to 20, from 20 to 30, from 30 to 40, from 40 to 50, and from 50 to 60. The remainder of values and example values of the 6^th aspect of the 5^th example embodiment are as defined above with respect to the 1^st to 5^th aspects of the 5^th example embodiment. [00162] In an 7^th aspect of the 5^th example embodiment, the value of p is selected from any one of the following ranges: from 17-200, from 17 to 100, from 17 to 60, from 17 to 25, from 20 to 100, from 20 to 60, from 20 to 30, from 22 to 100, from 22 to 60, from 22 to 30, and from 22 to 25. The remainder of values and example values of the 7^th aspect of the 5^th example embodiment are as defined above with respect to the 1^st to 6^th aspects of the 5^th example embodiment. [00163] In an 8^th aspect of the 5^th example embodiment, P is a PLGA(10k)-PEG(5k), and p is 15-25. The remainder of values and example values of the 8^th aspect of the 5^th example embodiment are as defined above with respect to the 1^st to 6^th aspects of the 5^th example embodiment. [00164] In an 9^th aspect of the 5^th example embodiment, the method further comprises the step of preparing the compound represented by the structural formula (IV) by reacting a compound represented by the structural formula (V) AVQ-00425 with a compound represented by the structural formula (VI) (VI), under the conditions sufficient to prepare the compound represented by the structural formula (IV). [00165] The remainder of values and example values of the 9^th aspect of the 5^th example embodiment are as defined above with respect to the 1^st to 8^th aspects of the 5^th example embodiment. [00166] In a 6^th example embodying, the present invention is a method of increasing the Best-Corrected Visual Acuity(BCVA) score in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound according to any of the aspects of the 1^st example embodiment, the particle according to any of the aspects of the 2^nd example embodiment, or the pharmaceutical composition according to any of the aspects of the 3^rd example embodiment. [00167] In a 1^st aspect of the 6^th example embodiment, the subject’s BVCA score gain is 1- 4 letters. [00168] In a 2^nd aspect of the 6^th example embodiment, the subject’s BVCA score gain is 5-9 letters. [00169] In a 3^rd aspect of the 6^th example embodiment, the subject’s BVCA score gain is 10-14 letters. [00170] In a 4^th aspect of the 6^th example embodiment, the subject’s BVCA score gain is greater than or equal to 15 letters. [00171] In a 7^th example embodiment, the present invention is a compound represented by the structural formula (IV): AVQ-00425 [00172] or a pharmaceutically acceptable salt thereof. [00173] In a 1^st aspect of the 7^th example embodiment, p is an integer from 17 to 200. [00174] In a 2^nd aspect of the 7^th example embodiment, the value of p is selected from any one of the following ranges: from 17 to 100, from 17 to 60, from 17 to 25, from 20 to 100, from 20 to 60, from 20 to 30, from 22 to 100, from 22 to 60, from 22 to 30, and from 22 to 25. [00175] In a 3^rd aspect of the 7^th example embodiment, p is 22. EXEMPLIFICATION [00176] I. Preparation and Characterization of the PSA-linker Conjugate [00177] A PSA-linker conjugate, represented by the structural formula (IV) was prepared and characterized according to the following procedures. The compound represented by the structural formula (IV) is also referred to herein as “PSA-amine.” [00178] The PSA-amine used in the experiments described below was determined to have an average molecular weight of not less than 6,000 Da, with a unit molecular weight of 309.27 g/mol. [00179] The PSA-amine was manufactured according to the Scheme 1: AVQ-00425 Scheme 1 [00180] Briefly, commercially available colominic acid sodium salt is dissolved in water for injection and the solution is heated at about 85°C for 5 hours. Upon completion, the reaction mixture was allowed to cool to room temperature (25°C). The batch was then subjected to 30KDa filtration four times by adding water for injection to the batch each time and passing it through the filter under pressure. The filtration was performed to remove undesired shorter PSA fragments. The complete retained fraction was lyophilized to produce free PSA. [00181] Free PSA size was controlled by measuring its mass by Liquid Chromatography Quadrupole Time Of Flight Mass Spectrometry (LC Q-TOF MS) analysis. [00182] The lyophilized PSA was dissolved in 0.1 M Sodium Acetate Buffer (pH 6), and 2-aminoethoxyamine dihydrochloride was added at a range from 1 to 20 equivalents of aminoethoxyamine dihydrochloride to 1 equivalent of PSA. The recommended amount of the aminoethoxyamine dihydrochloride was 5 equivalents. pH was adjusted to 6.0 to 6.5 with 1 M NaOH. The reaction mixture was stirred at about 37°C for not less than10 hours. The batch is subjected to 30KDa filtration five times by adding water for injection to the batch each time and passing it through the filter under pressure. The retained fraction is subjected to 10KDa filtration three times by adding water for injection to the batch and passing it through the filter under pressure. The filtration is performed to remove traces of excess buffer. The AVQ-00425 product-containing retained fraction is lyophilized to obtain PSA-amine as white to off-white solid. The 10K filtration residue was lyophilized to solid with a loss of no more than 5.0 w/w. [00183] PSA-amine lot A022216873 was used to provide the evidence of chemical structure using ¹H and ¹³C NMR. A 10 mg sample is dissolved in 0.6 mL D2O (Deuterium oxide, deuterated water) and transferred to an NMR tube to record the NMR spectrum. [00184] Based on the NMR studies, all protons and carbons were matching the expected structure of the product. FIG.1A is a schematic diagram of non-equivalent hydrogens found in a PSA-amine. FIG.1B is Table 1, which provides a probable 1H NMR (400 MHz, D2O) peak assignments. FIG.1C is a schematic diagram of non-equivalent carbons found in a PSA- amine. FIG.1D is Table 2, which provides a probable 13C NMR (400 MHz, D2O-d6) peak assignments. Based on LCMS Q-TOF analysis, the synthesized PSA-amine has a mass of not less than 6000 Da. FIG.1E is a plot showing LCMS Q-TOF deconvoluted mass for PSA- amine lot A022216873. [00185] In addition to batch A022216873, five other batches were analyzed. The results are provided in Table 3 and Tables 4 through 4C reproduced in FIG.2A through FIG.2E. [00186] In these tables, the following abbreviations are used: CAD= Charged Aerosol Detector; BDL= Below Detection Limit; EU= Endotoxin unit; GC= Gas chromatography; GLP = Good Laboratory Practice; HPLC= High Performance Liquid Chromatography; KF= Karl Fisher; LAL= Kinetic Quantitative Turbidimetric Lysate Endotoxin Test; LC Q-TOF MS= Liquid chromatography quadrupole time-of-flight mass spectrometer; NLT= Not less than; NMR= Nuclear Magnetic Resonance; ppm= Parts per million; RI= Refractive Index; SEC= Size Exclusion Chromatography; SEC-MALS= size-exclusion chromatography with multi-angle light scattering, RRT= Relative Retention Time, **Biosynth lot 0000044791 was the first batch of drug substance manufactured. Hence, the 1H-NMR spectrum was used as a reference for future drug substance lots. The specifications and acceptance criteria for this lot were not defined as it was the first lot. [00187] IA. Determination of the Degree of Polymerization (DP) of the PSA amine [00188] As used herein in relation to structural formula (IV), above, p as the DP value measured by any of methods known in the art, for example, by ¹H-NMR. A skilled person would appreciate that any given value of p corresponds to an average of values over an ensemble of molecules in a batch. [00189] The degree of polymerization (DP) is an experimentally measurable property of an ensemble of polymer molecules. Several analytical techniques for measuring DP exist. For example, for a homopolymer such as the PSA, an average molecular weight of a polymer can AVQ-00425 be measured by any of the known chromatographic techniques, and the result divided by the molecular weight of the repeat unit. [00190] In one embodiment, the ¹H-NMR was used as a method of determining DP of the polymer of formula (IV). In this method, the intensity of the integrated NMR signal produced by the sole equatorial hydrogen of the repeat unit was measured. The ratio of this integrated intensity to the intensity of a reference signal produced by the hydrogens on the CH2-N moiety of the terminal unit (modified by the oxime) directly produces the value of DP. Thus, DP measured by ¹H-NMR was averaged over the entire ensemble of the polymer molecules of a given batch. Based on formula (IV), the value of DP was determined as equal to the value of p averaged over the ensemble of molecules. [00191] Additionally, LC-Q-TOF method can be used for determining molecular weight for PSA. From molecular weight, DP can be estimated. Similarly, MALDI-TOF or GPC or SEC-MALS methods can be used. These methods can produce molecular weight distribution profile. By this molecular weight, a range of DP of PSA can be calculated, along with PDI value. For example, the average molecular weight of PSA can be 9000 daltons with PDI value of 0.15. [00192] Overall, the PSA-amine produced in the course of this study ranged in size from about 6,000 Da to about 20,000 Da. The DP (p) values of the PSA were measured by the ¹H- NMR method to be from about 17 to about 60, for example, from about 20 to about 60, for example from about 22 to about 60. In some example embodiments, DP was about 22. [00193] II. Preparation and Characterization of the PSA-Polymer Conjugate [00194] Summary of the Product [00195] The “Product” (also referred to as the “drug product”) is an intravitreal injection suitable for delivery to the posterior segment of the eye. The Product consists of Polysialic acid-amine (PSA-amine) as an active ingredient and it is coated onto a biodegradable Poly (lactide co-glycoclide)-poly(ethylene glycol)- (PLGA-PEG) nanoparticle. Sucrose and water for injection are used as tonicity agent and vehicle respectively for the Product. Sodium hydroxide may be added to adjust the pH of the formulation to pH 6.0 – 7.5. The final product is described in Table 5, reproduced in FIG.3. As used herein, “AVD-104” refers to the PSA-amine/PLGA-PEG nanoparticle. [00196] Summary of the Manufacturing Process [00197] The Product comprises a PLGA-PEG based nanoparticle core with surface- conjugated PSA (Polysialic acid) amine. The nanoparticle core is composed of PLGA-PEG- AVQ-00425 NHS [Poly(L-lactideco-glycolide)-Polyethylene glycol-N-Hydroxysuccinimide] polymer (lactide to glycolide (75:25), molecular weight ~10 kDa) and PEG block (molecular weight ~ 4.6 kDa, end group, NHS). [00198] To compound the drug product, the following process was developed: An organic phase was prepared consisting of PLGA-PEG-NHS polymer dissolved in N,N- dimethylformamide, benzyl alcohol and ethyl acetate solvent mixture. Separately, an aqueous phase was prepared, where the drug substance (PSA) was dissolved in water and N,N- dimethylformamide. Both the phases were mixed and N,N-Diisopropylethylamine was added to the mixture and kept overnight for conjugation between drug substance and polymer. [00199] An additional aqueous phase was prepared by mixing of 92% (v/v) water for injection (WFI) and 8% v/v ethyl acetate and stored at 2-8°C. A primary coarse suspension was formed by mixing the organic phase with the aqueous phase under high-speed homogenization using a rotor stator mixer. The suspension was further processed via a standard 3-stroke (3-passe) procedure with the Microfluidizer at 15,000 psi pressure to reduce the final average particle size down to ~100 nm. The resulting particles were purified via Tangential Flow Filtration (TFF) and filtered through a 0.2-micron filter under aseptic conditions. [00200] Summary of the Formulation for Intravitreal Injection [00201] A defined particle size is important for an intravitreal injection to avoid endocytosis while still allowing for target engagement. Siglec receptors are outside the cell and particle sizes such as those ranging from about 150 nm to 50 nm can be used to promote engagement of nanoparticle and receptor. Thus, control of particle size was evaluated during process development. [00202] To evaluate the impact of manufacturing process parameters on particle size, various parameters like pressure, the number of passes, time, and temperature effect were investigated using a drug-free formulation. The polymer was dissolved in solvents and then mixed with water for injection to form a coarse suspension. It was then processed using a microfluidizer. It was concluded that a desirable particle size distribution was achieved with 3-pass processing at 15,000 psi pressure as shown in Table 6, shown in FIG.4A. [00203] In another study, formulations processed using a different number of passes and fixed pressure showed no significant change in particle size distribution up to 6 hours as shown in Table 7, shown in FIG.4B. Formulations processed at fixed pressure and passes, AVQ-00425 which were then stored at various temperature conditions showed no significant change in particle size either as shown in Table 8, shown in FIG.4C. [00204] Table 9, shown in FIG.5, shows a summary of the Product intravitreal injection development batches prepared at Aviceda. These batches were prepared using PLGA-PEG- NHS polymer and PSA-amine drug substance. Drug substance batches with different degree of polymerization of sialic acid monomers were also evaluated. The manufacturing process demonstrated similar particle size distribution profile in all the batches. [00205] Product Attributes [00206] The product obtained by the above-described procedure was determined to have the attributes listed in Table 10. Table 10 [00207] Stability [00208] Based on the stability studies, the Product intravitreal injection was determined to be stable for three months when stored at long-term (-20°C±5°C) and accelerated (5°C±3°C) storage conditions. The results of the stability studies are presented in Table 11 shown in FIG.6. [00209] Batch Manufacturing [00210] A polysialic (PSA)-polymer conjugate compound represented by the structural formula (I) AVQ-00425 wherein P is a poly(lactide-co-glycoclide)-poly(ethylene glycol) block copolymer (PLGA- PEG); and p is an integer from 4 to 200, was prepared by the following process. [00211] PLGA-PEG-NHS was dissolved in N,N-Dimethylformamide (DMF), benzyl alcohol and ethyl acetate and mixed till a clear to white translucent solution was obtained. PSA-amine was dissolved in Water for injection to obtain a clear colorless solution. To this solution, DMF was added and mixed to obtain clear solution. [00212] The polymer solution and drug solutions were mixed. Subsequently, N,N- Diisopropylethylamine (DIPEA) was added to obtain a clear to cloudy solution. This solution was stirred for 18 hours at room temperature. An 8% v/v aqueous solution (water for injection) of ethyl acetate was prepared, kept at 2°-8°C for 18 hours. [00213] The polymer solution was homogenized into an aqueous phase at about 9,500 RPM for about 2 minutes (aqueous to organic mass ratio is 9:1) to obtain a white milky suspension. The coarse suspension was processed through 3 passes with the Microfluidizer operating at about 15,000 psi pressure, to obtain required particle size distribution. The product temperature was maintained between 2-8° during the process. [00214] The homogenized product was quenched into cold water for injection for 60 minutes at 2°-8°C. The mass was purified using Tangential Flow Filtration (C/D/C) using WFI which had already been cooled to 2°-8°C. Concentrated the product to target volume. To the concentrated product volume, 10% sucrose was added and dissolved. [00215] The product was filtered using a pre-filtration step followed by aseptic filtration. The product was pre-filtered using a 0.8 μm followed by a 0.45 μm filter. Following pre- filtration, the drug product was filtered by aseptic filtration using a sterilizing grade 0.2μm filter. [00216] The product was then filled into 2 mL clear USP type I glass vials under aseptic conditions. AVQ-00425 [00217] The dose of the Product administered to a subject in need thereof can vary according to the subject’s condition, its severity, and the subject’s weight. In certain embodiments, the dose is expressed as the weight of the PSA delivered per eye. When computed in terms of the weight of the PSA delivered per eye, the dose can be from 0.01 µg/eye to 1000 µg/eye. For example, the weight of the PSA per eye can be from 0.01 to 0.1 µg/eye, from 0.1 µg/eye to 1 µg/eye, from 1 µg/eye to 10 µg/eye, from 10 µg/eye to 100 µg/eye, or from 100 µg/eye to 1000 µg/eye. For example, the weight of the PSA per eye can be from 0.1 µg/eye to 1000 µg/eye, from 1 µg/eye to 1000 µg/eye, or from 10 µg/eye to 1000 µg/eye. For example, the weight of the PSA per eye can be about 0.01 µg/eye, 0.1 µg/eye, 1 µg/eye, 10 µg/eye, 100 µg/eye or 1000 µg/eye. [00218] In certain embodiments, the dose of the product is expressed in terms of the weight of “total solids”, for example as the weight of the “total solids” per eye. The “total solids” is a measure of the weight of the Product amount in a unit volume of the aqueous suspension of the Product. It can be calculated by direct measurement of the concentration, or by weighting the lyophilized solid suspended in a known volume of the sample. In example embodiments, a therapeutically effective dose of the Product, expressed in terms of the “total solids” can be between 0.05 mg/eye and 2.0 mg/eye. For example, 0.1 mg/eye, 0.15 mg/eye, 0.2 mg/eye, 0.25 mg/eye, 0.3 mg/eye, 0.35 mg/eye, 0.4 mg/eye, 0.45 mg/eye, 0.5 mg/eye, 0.55 mg/eye, 0.6 mg/eye, 0.65 mg/eye, 0.7 mg/eye, 0.75 mg/eye, 0.8 mg/eye, 0.85 mg/eye, 0.9 mg/eye, 0.95 mg/eye, 1 mg/eye, 1.1 mg/eye, 1.2 mg/eye, 1.3 mg/eye, 1.3 mg/eye, 1.4 mg/eye, or 1.5 mg/eye. [00219] In other example embodiments, a therapeutically effective dose of the Product, expressed in terms of the “total solids” can be from 2 mg/eye to 5 mg/eye. For example, 2.1 mg/eye, 2.2 mg/eye, 2.3 mg/eye, 2.4 mg/eye, 2.5 mg/eye, 2.6 mg/eye, 2.7 mg/eye, 2.8 mg/eye, 2.9 mg/eye, 3.0 mg/eye, 3.1 mg/eye, 3.2 mg/eye, 3.3 mg/eye, 3.4 mg/eye, 3.5 mg/eye, 3.6 mg/eye, 3.7 mg/eye, 3.8 mg/eye, 3.8 mg/eye, 3.9 mg/eye, 4.0 mg/eye, 4.1 mg/eye, 4.2 mg/eye, 4.3 mg/eye, 4.4 mg/eye, 4.5 mg/eye, 4.6 mg/eye, 4.7 mg/eye, 4.8 mg/eye, 4.9 mg/eye, and 5.0 mg/eye. In one example embodiment, the therapeutically effective dose is 3.0 mg/eye. [00220] It is understood that the amount of the PSA in the sample can be directly measured by using, for example, UV spectroscopy or HPLC. For example, a sample of nanoparticles can be subjected to chemical degradation of the PSA, freeing the monomers of sialic acid, which are then detected. If the weight of both the PSA and the total solids in a sample of the Product is known, then the ratio of the two values produces the value of “the AVQ-00425 weight of PSA per unit weight of total solids.” Knowing this value permits converting the dose expressed as a weight of the “total solid” into the dose expressed as the weight of the PSA as well as direct comparison of two different samples. [00221] In certain studies described herein, the PSA concentration in a sample was determined by a fluorescent detection of monomers following acid-catalyzed hydrolysis of the PSA (4M acetic acid, 3 hours at 80 °C; quenched by adding NaOH at room temperature). Abcam sialic acid kit (cat# ab83375) was used. Fluorescence was measured at 535/587 nm excitation/emission. [00222] In certain studies described herein, the PSA concentration in a sample was determined by a colorimetric detection of monomers following acid-catalyzed hydrolysis of the PSA (4M acetic acid, 3 hours at 80 °C; quenched by adding NaOH at room temperature). Abcam sialic acid kit (cat# ab83375) was used. Absorbance was read at 570 nm. [00223] III. Analytical Procedures [00224] Determination of Molecular Weight of PLG-PEG Polymer by Gel-Permeation Chromatography [00225] The average molecular weight and Polydispersity (PD) of PLGA10K-PEG5K- NHS are determined by using Gel permeation chromatography (GPC) with Refractive Index detector. About 50 mg sample is dissolved in 5mL diluent. Experiment parameter of this test are listed in Table 12 below. Table 12 [00226] It was determined that number-average molecular weight Mn was 15,000 Da ± 3000 Da, with the PDI of not more than 1.9. [00227] Identification of PSA-Polymer Conjugate by IR Spectroscopy AVQ-00425 [00228] The sample was thawed as follows. Sample vials stored at -20°C temperature were thawed first to attain the refrigerated condition (2-8°C) for 60 minutes or a suitable time until the frozen product is fully thawed. From refrigerated storage (2-8°C), condition the vials at room temperature condition for 60 minutes. The thawed drug product sample was tested by direct addition method. Identification of the drug product was performed by confirmation of amide linkage between PLGA-PEG polymer and PSA-amine drug substance. The presence of amine carbonyl stretch on the IR spectrum at 1630 cm^-1 to 1670 cm^-1 was used as a reference for the confirmation. A representative IR spectrum of the drug product is shown in FIG.7 [00229] Determination of PSA-amine Content by HPLC [00230] The analysis on Polysialic acid amine (PSA-amine) content is performed by high performance liquid chromatography (HPLC) with Ultraviolet/ Photodiode array (UV/PDA) detection technique. PSA content is calculated based on the peak area of sample preparation against the peak area of reference standard. [00231] The following conditions, materials, and equipment were used: Instrument: HPLC is equipped with UV/PDA detection and a quaternary pump. HPLC Column : Waters XBridge Amide, 250mmx4.6mm, 3.5µm Column Temperature: 40°C Sample Cooler Temperature: 5°C Flow Rate: 0.8 mL/min Injection volume: 20 μL Wavelength: UV 214nm Run Time: 45 minutes Elution : Gradient Diluent: HPLC grade water Needle wash: The mixture of Water and Acetonitrile (50:50 %v/v) Mobile Phase-A: 1mLTriethylamine mixed in 1liter milli-Q water, pH adjusted to 6.5 ± 0.05 with dilute orthophosphoric acid and filtered (0.2µm). Mobile Phase-B : Acetonitrile (100%) [00232] Gradient program is shown in Table 13: AVQ-00425 Table 13 [00233] A sample was prepared as follows. Product sample from 3 vials (0.5 mL each) was pooled and 1.0 mL sample is withdrawn. It was diluted with diluent to 5mL and tested. (Prepared in duplicate). The standard was prepared as follows: 1000 µg/mL in diluent (prepared in duplicate). One standard bracketing solution was injected after every 6 sample injections and at the end of the sequence. Multiple blanks were injected to achieve a stable baseline. [00234] Sample was thawed according to the following procedure: the sample vials stored at - 20°C temperature, were thawed first to attain the refrigerated condition (2-8°C) for 60 minutes or a suitable time until the frozen product was fully thawed. From refrigerated storage (2-8°C), the vials were conditioned at room temperature condition for 60 minutes. [00235] PSA content (mg/mL) = (ASPL/ASTD)*(WSTD/DSTD)*(DSPL/VSPL)*(P/100), where: [00236] FIG.8 shows a representative chromatogram used for the determination of the PSA-amine content. [00237] Determination of Particle Size Distribution by Dynamic Light Scattering [00238] The particle size distribution is performed by dynamic light scatter technique using Zetasizer according to USP 1430.3. [00239] The following conditions, materials, and equipment were used: Instrument: Malvern Zetasizer Nano ZS Dispersant: Water (HPLC grade or Milli-Q water) AVQ-00425 Particle Refractive Index: 1.48 Particle absorption: 0.001 Dispersant refraction index: 1.330 Temperature: 25°C Dispersant viscosity: 0.8872 cP (at 25°C) Equilibration time: 60 seconds Cell type: Polystyrene Disposable sizing cuvettes Measurement angle: 173° Backscatter (Non-invasive backscatter default) [00240] Sample thawing procedure: the sample vials stored at -20°C temperature were thawed first to attain the refrigerated condition (2-8°C) for 60 minutes or a suitable time until the frozen product was fully thawed. From refrigerated storage (2-8°C), the vials were conditioned at room temperature condition for 60 minutes. [00241] Sample preparation: Product sample from 3 vials (0.5 mL each) was pooled and 1.0 mL sample was withdrawn. It was diluted with diluent to 10mL and tested. Samples were prepared in singlet. [00242] Calculation of particle size distribution parameters: the Z-average and PDI values are obtained using a Zetasizer proprietary software. [00243] Reporting of results: the value of Z-average is reported in nanometer (nm) and poly dispersity index (PDI) value is reported as a number. [00244] FIG.9 shows a representative histogram of particle size distribution. [00245] Determination of Particle Size Distribution by Electrophoretive Light Scatter [00246] The analysis of zetapotential is performed by Electrophoretive light scatter technique using Zetasizer according to USP 1430.3. [00247] The following conditions, materials, and equipment were used: Instrument: Malvern Zetasizer Nano ZS Dispersant: Water (HPLC grade or Milli-Q water) Particle Refractive Index: 1.59 Particle absorption: 0.010 Dispersant refraction index: 1.330 Temperature: 25°C Dispersant viscosity: 0.8872 cP (at 25°C) Equilibration time: 60 seconds Cell type: Disposable folded capillary cells Measurement angle: 173° Backscatter (Non-invasive backscatter default) AVQ-00425 [00248] Sample thawing procedure: the sample vials stored at -20°C temperature were thawed first to attain the refrigerated condition (2-8°C) for 60 minutes or a suitable time until the frozen product was fully thawed. From refrigerated storage (2-8°C), the vials were conditioned at room temperature condition for 60 minutes. [00249] Sample preparation: Product sample from 3 vials (0.5 mL each) was pooled and 1.0 mL sample was withdrawn and tested. Samples were prepared in singlet. [00250] Calculation of particle size distribution parameters: the Zeta potential value was obtained using a Zetasizer proprietary software. [00251] Reporting of results: Zeta potential value was reported in millivolts (mV). [00252] FIG.10 shows a representative histogram of zeta potential distribution. [00253] Analysis of the Polymer-PSA Conjugate Concentration [00254] The analysis of total solids (the Product concentration) is performed by UV spectrophotometer technique. The calculation is based on the UV absorbance of the Product nanoparticles in the sample against the UV absorbance of the PLGA-PEG-NHS polymer reference standard. [00255] The following conditions, materials, and equipment were used: Instrument: UV Spectrophotometer Wavelength: UV 230 nm Diluent: Acetonitrile [00256] Sample preparation: Product sample from 2 vials (0.5 mL each) was pooled and 0.5 mL sample was withdrawn into a 10mL volumetric flask. The sample was diluted and dissolved with the diluent to 10mL. The diluted sample was then centrifuged and the supernatant solution was used for testing. Samples were prepared in singlet. Standard preparation: Five (5) standard preparations with concentrations from 0.3125 mg/mL to 5mg/mL were prepared using PLGA-PEG-NHS polymer in diluent and a linearity curve was drawn with the UV absorbance values and their corresponding concentrations. A system suitability criterion of a regression coefficient of not less than 0.990 was selected for testing. Sample thawing procedure: the sample vials stored at -20°C temperature were thawed first to attain the refrigerated condition (2-8°C) for 60 minutes or a suitable time until the frozen product was fully thawed. From refrigerated storage (2-8°C), the vials were conditioned at room temperature condition for 60 minutes. AVQ-00425 [00257] Calculation of results: Total solids are calculated using below formula. where: y: UV absorbance in sample preparation. c: Intercept value of the linearity curve. m: Slope value of the linearity curve. Reporting of results: Total solids (the Product concentration) values were reported in mg/mL. [00258] Batch Analysis of the Product [00259] FIGs.11A through 11D show Tables 14A through 14D, respectively, which summarize batch analysis results of the Product for intravitreal injection. In these tables, the following abbreviations are used: BQL= Below Quantitation limit; DIPEA= N,N- Diisopropylethylamine; DMF= N,N-dimethylformamide; EU= Endotoxin unit; GC-HS= Gas chromatography with headspace sampler; HPLC= High Performance Liquid Chromatography; IR= Infrared; MTBE= Methyl tert-butyl ether; N/A = Not applicable; NHS= N-hydroxysuccinimide; NLT= Not less than; NMT= Not more than; RI= Refractive index; USP= United States Pharmacopoeia, N/A= Not Applicable; PDI= Polydispersity index; PSA= Polysialic acid.¹Preliminary testing of total solids (AVD-104 concentration) on batches SF22000208; SF22000414; SF22000417 and SF22000573 was performed as an in- process test using freeze drying technique during manufacturing TFF step. Later a UV spectrophotometry method was developed as a finished product test and it was used in measurement in the technical batch FT22000012. [00260] Long-Term Stability Studies [00261] Certain batches of the Product intravitreal injection were tested for a long-term stability at -20°C±5°C, inverted orientation. The results are presented in Table 15 (batch SF22000414), Table 16 (batch SF22000417), and Table 17 (SF22000573), reproduced in FIGs.12A, 12B, and 12C. [00262] Molecular Weight of the PSA-Polymer Conjugate [00263] The molecular weight of the PSA-Polymer conjugate was determined by adding the separately determined molecular weights of the PSA-amine and the polymer. The molecular weight of the conjugate, in various embodiments, was determined to be in the range of 10-50 kDa, 15-40 kDa, 20-35 kDa. In various embodiments, the molecular weight of AVQ-00425 the conjugate was 15 kDa, 20 kDa, 25 kDa, or 30 kDa. In one example, the molecular weight was 20 kDa. [00264] IV. CHARACTERIZATION OF THE BIOLOGICAL ACTIVITIES OF THE PRODUCT [00265] The “AVD-104” referred to in the figures presenting the results of the studies described below refers to batch SF22000208, characterized in Tables 14A through 14D reproduced in FIGs.11A through 11D. [00266] 1. Batch SF22000208 [00267] Batch SF 22000208 is characterized in Tables 14A through 14D shown in FIGs. 11A through 11D. [00268] 2. The Formulation for Clinical Studies [00269] The final formulation of the Product prepared for clinical studies is poly(lactide co-glycolide)-block-poly(ethylene glycol)-block-poly(sialic acid), with the following excipients: poly(lactide co-glycolide)-block-poly(ethylene glycol)-block-poly(lactide co- glycolide)-succinimidyl ester, sucrose, and water. The sucrose was provided for stability and water for the suspension. [00270] 3. Protein and Gene Expressions of Siglec-7, -9, and -11 [00271] In this study, protein expression level was measured by Western blot assay and the gene transcript levels were measured by real-time qRT-PCR. Results were normalized to healthy donor eyes. [00272] This study demonstrated a significantly increased gene and protein expression for Siglecs 7, 9, and 11 in retina-RPE-choroid complex tissues obtained from three exudative and three nonexudative AMD eyes (one female and two male donor eyes, respectively) aged 85 + 10 years. [00273] Exudative AMD donors exhibited an increase in gene expression of Siglecs 7, 9, and 11 by 90-, 64-, and 58-fold, respectively, compared to healthy donors (FIG.13A and the Table below; as measured by RT-PCR). Similarly, non-exudative AMD donors showed an increase in Siglecs 7, 9, and 11 gene expression by 77-, 32-, and 27- fold, respectively, compared to healthy donors. AVQ-00425 [00274] The Table: Siglec expression in exudative and nonexudative AMD: summary of findings (RT-PCR) Data for Siglec 7, 9, 11 gene transcripts levels are normalized to qRT-PCR for GAPDH (housekeeping gene) and fold change was calculated with respect to normal donors using the relative quantification = 2^-(ddCt). dCt = Ct(gene) - Ct(housekeeper), ddCt = dCt(sample) -dCt(reference). Tukey's multiple comparisons test showed no significant difference between the groups. (d-delta, Ct- cycle threshold). [00275] The significant upregulation of Siglecs 7, 9, and 11 in Retina/ RPE/ choroid complex extracts from exudative and nonexudative AMD donors compared to healthy donors is shown in FIG.13B. [00276] Data shown in FIGs.13A and 13B are mean ± standard error of the mean among 3 exudative and 3 neAMD donor eyes (1 female and 2 male donors aged 85 ± 10 years). (A) Proteins were extracted and expression of Siglec-7, -9, and -11 was measured by Western blot assay. Proteins were resolved via gel electrophoresis, blotted, and stained with Siglec-7, - 9, and -11 and beta actin as internal control. Total band densities were normalized to beta actin and fold change was compared to normal donor eyes. Tukey's multiple comparisons test showed no significant difference between the exudative AMD (light bars) and neAMD (dark bars) groups. (B) Real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) analysis of mRNA expression of Siglec-7, -9, and -11 in human exudative AMD and neAMD donors. Gene transcript levels were measured by real-time qRT-PCR. Data for Siglec-7, -9, and -11 gene transcripts levels were normalized to qRT-PCR for glyceraldehyde-3-phosphate dehydrogenase (GAPDH; housekeeping gene). Tukey's multiple comparisons test showed no significant difference between the exudative AMD (light bars) and neAMD (dark bars) groups. [00277] This result suggests that, in humans, macrophages bearing Siglec receptors 7, 9, and 11 are resident in eyes from patients with AMD. The higher expression of Siglec receptor proteins in eyes with AMD relative to healthy controls further indicates that the macrophages may be the activated inflammatory source of disease. It is proposed that glycomimetic therapy with AVD-104 could repolarize these cells to a resting state. AVQ-00425 [00278] 4. Cell-Free Binding Affinity of the Product Towards Siglec 7, 9, and 11 [00279] In this study, cell-free binding affinity of the Product toward Siglec-7, -9, and -11 was investigated and confirmed. [00280] The specific binding affinity of the Product to Siglec-7, -9, and -11 was established using a cell-free PEG-ELISA−based method. Batches AT-07-NP12 and SF22000208 were tested and both exhibited significant binding toward Siglec-7, -9, and -11 (FIG.14), suggesting that the Product interacts with macrophages through its specific binding to these Siglecs. At 5 mg/mL total solids, binding affinity of the Product to Siglec-7, -9, and - 11 was greater than that of the blank nanoparticle (a construction of PLGA and PEG without sialic acid). The relative binding affinity was Siglec-7 > Siglec-9 > Siglec-11. This permits the development of a nanoparticle with multivalent affinity for all 3 Siglecs that target macrophages, monocytes, and microglia – key cell types implicated in non-resolving inflammation in GA. [00281] Recombinant Fc protein (R&D Systems) for Siglec-7, -9, and -11 was coated on ELISA plates, and different concentrations measured as total solids (0.01−5 mg/mL) of the Product and a blank control nanoparticle (0.1−5 mg/mL) were added on coated plates and detected using anti-PEG biotin/horseradish peroxidase standard per manufacturer’s ELISA protocol. Absorbance was measured at 490 nm. At 5 mg/mL total solids, the binding affinity of the Product for Siglec-7(solid circles), Siglec-9 (solid triangles), and Siglec-11 (solid diamond) was greater than that of blank nanoparticles. There was a dose-dependent increase in binding of the Product toward all three Siglecs. [00282] 5. Cytokine Analysis in THP-1 Derived Macrophages and in M1 Macrophages Derived From Normal Human PBMC [00283] In this study, the modulation of TNF-α, IL-6, IL-10, and VEGF by the Product was determined in either THP-1−derived human macrophages or by polarization of M1 macrophages to M2c resolution macrophages. [00284] Polarization of M1 macrophages to M2c resolution macrophages was shown, as identified by suppression of pro-inflammatory mediators TNF-α, IL-6, IL-1β, and VEGF and increase in anti-inflammatory cytokine IL-10. [00285] The Product induced a decrease in the release of pro-inflammatory cytokines IL-6 and IL-1β by 1.3-fold (p=0.087) and 1.35-fold (p<0.05), respectively, and an increase in the production of anti-inflammatory (resolution) cytokine IL-10 by 1.4-fold (p<0.05) in retina macrophages compared to controls (FIGs.15A and B and FIGs.16A, B and C). AVQ-00425 [00286] THP-1 cells (ATCC TIB-202™, Gaithersburg, MD) were differentiated using 10 ng/mL of Phorbol-12-myristate-13-acetate (PMA) and activated using LPS at 1 μg/mL. Cells were treated with a serial dose range of the Product (batch SF22000208 (referenced in FIGs.15 and 16 as SF 208; 0.01−1 mg/mL) overnight. LPS served as a positive control. Post- treatment supernatants were collected and assayed by ELISA (R&D Systems) for (FIG.15A) TNF-α and (FIG.15B) IL-10. In vitro Product significantly downregulated the amount of TNF-α and significantly upregulated levels of IL-10. [00287] PBMCs (Stem Cell Research, Cat No-70500.2) were activated to an M1 phenotype (interferon-gamma 50 ng/mL, LPS 10 ng/mL) for 48 hours. Cells were then treated with a serial dose range of the Product (batch SF22000208; 0.01−1 mg/mL) overnight. LPS served as a positive control. Post-treatment supernatants were collected and assayed by ELISA (R&D Systems) for (16A) VEGF, (16B) IL-1β, and (16C) IL-6. In vitro AVD-104 significantly downregulated the amount of VEGF, IL-1β, and IL-6 in the supernatants from activated macrophages. *p<0.05 Dunnett's multiple comparisons test. [00288] The TNF-α ELISA assay was also used to compare dose-dependent response of PMBC-derived cells to AVD-104 and to the PSA ligand alone. For this comparison, the batch of AVD-104 used had DP of not less than 20 (as did the PSA control). The results are presented in FIG.47. It can be seen that, unlike the PSA ligand control, AVD-104 produces a clear dose-dependent inhibition of TNF-α production. [00289] The TNF-α ELISA assay was also used to compare the response of PMBC- derived cells to AVD-104 (a batch in which the PSA had the DP of not less than 20) to the nanoparticles having the PSA of DP 8 and DP 11. [00290] For this comparison test, each type of nanoparticle was synthesized according to the method described in Part II of Exemplification section (conjugation of the polymer to the PSA-amine). The estimated molecular weight of the PSA moiety was about 2500 Da for the DP 8 nanoparticles and about 3,000 Da for the DP 11 nanoparticles. Total solids were computed to be 10 mg/ml for 10 ml of the DP 8 nanoparticles and 12.4 mg/ml for 10 ml of the DP 11 nanoparticles. Particle size was measured to be about 109 nm (PDI 0.23) for the DP 8 nanoparticles and about 61 (PDI 0.17) for the DP 11 nanopatricles. [00291] The results are presented in FIG.48. It can be seen that, unlike the DP 8 and DP 11 nanoparticles, the AVD-104 (DP not less than 20) produces a clear dose-dependent inhibition of TNF-α production. [00292] The TNF-α ELISA assay was also used to measure dose-dependent response of PMBC-derived cells to AVD-104 (a batch having DP of PSA not less than 20). Based on the AVQ-00425 dose-response curve shown in FIG.49, IC50 values were computed for AVD-104-mediated inhibition of TNF-α production. Specifically, IC₅₀ of 191.0 µg/ml was computed for “total solids”, which corresponds to IC50 of 6.075 µg/ml of PSA on the AVD-104 nanoparticles. [00293] 6. Recruitment of Receptor SHP-1 by the Product in Macrophages (M1) Derived From Normal Human Peripheral Blood Mononuclear Cells [00294] This study demonstrated the recruitment of SHP-1, which indicates activation of ITIM and agonism of Siglec. [00295] SHP-1 consists of 3 domains: the N-terminal SH2 domain, the C-terminal SH2 domain, and the C-terminal catalytic protein tyrosine phosphatase (PTP) domain. The N- terminal SH2 domain is autoinhibitory, binding to the PTP domain until the C-terminal SH2 domain binds to a phosphopeptide ligand, allowing a conformational change and the release of autoinhibition. This conformational change results in the reduction in molecular weight from 70 kDa to 60 kDa. [00296] When THP-1 cells are activated with LPS, they polarize macrophages to the M1 state. With Siglec activation, the autoinhibited SHP-1 is disinhibited and shifts to the 60 kDa state. Thus, detection of the 60 kDa fragment in a Western blot indicates the released state of SHP-1, whereas detection of the 70 kDa signal indicates SHP-1 in the autoinhibited state. [00297] To detect the state of SHP-1, the following assay was used. [00298] Immunoprecipitation (IP) was performed by using anti-Siglecs 7 and 9, followed by western blot to visualize SHP-1 recruitment in THP-1 cells and M0/M1 macrophages lysates. The bands at 70kD reveal an 25 % increased recruitment of SHP-1 when THP-1 cells were incubated in presence of Sialic acid-coated NP compared to sucrose control. A similar increase of 10% was observed on M1 macrophages total proteins were immunoprecipitated by using anti-Siglec 7 and 9 (Cat#AF1138-SP and AF1139-SP, RD Systems, Minneapolis, MN) from THP-1 cells lysate (A) followed by WB for SHP-1 and revealed by electrochemiluminescence (ECL) (Thermofisher Scientific, Waltham, MA) according to manufacturer’s instructions. The band intensity mean was quantified using ImageJ, with background subtraction applied. [00299] M0 and M1 macrophages derived from PBMCs lysates were incubated in the presence or absence of LPS, sucrose control and Sialic acid-coated NP. Mean intensity for the bands measured by using ImageJ after subtracting background. The comparison of band intensity between the sucrose control and the Sialic acid-coated nanoparticles produced the results described above. AVQ-00425 [00300] 7. The Product Regulates of Classical and Alternative Complement Pathway [00301] In this study, in hemolytic assays CH 50 assay for total hemolytic complement and AH50 assay for alternative pathway (50% red blood cell (RBC) lysis was measured), the Product demonstrated the ability to attenuate both the alternative and classical complement pathways with a potency similar to a neutralizing antibody to C3. [00302] The Product was shown to modulate complement activation in vitro (FIG.17 and FIG.18) and complement deposition in an in vivo retinal injury model (Karlstetter et al., 2017). [00303] Referring to FIG.17, normal human serum (NHS, CompTech) was treated with either nothing (untreated), sucrose vehicle control, the Product (SF22000208) (0.3 mg/mL, 1 mg/mL), or C3 neutralizing antibody (C3nAb, Millipore; 0.1 mg/mL) and immediately used for CH50 assays. Normal human serum with cobra venom factor pre-activation (NHS-CVF) was included as a negative control. Briefly, antibody-sensitized sheep erythrocytes (CompTech) were added to a dilution series of each serum sample in GVB++, incubated at 37°C for 60 min, centrifuged to pellet remaining red blood cells (RBCs), transferred supernatants (containing heme from lysed RBCs) to 96-well plates, and read on a spectrophotometer at 560 nm absorbance. All data were normalized to positive control at 100% (replaced buffer with water or detergent) and negative control at 0% (no NHS).50% Hemolysis data were averaged across experiments conducted. NHS has robust classical pathway (CP) activity, and NHS-CVF has very low CP activity; both C3nAb and the Product inhibit CP activity. [00304] Referring to FIG.18, normal human serum (NHS, CompTech) was treated with either nothing (untreated), the Product (SF22000208, 0.3 mg/mL, 1 mg/mL), or C3 neutralizing antibody (C3nAb, Millipore; 0.1 mg/mL) and immediately used for AH50 assays. Normal human serum with C3 depletion (NHS-C3dpl, Comp Tech) was included as a negative control. Briefly, rabbit erythrocytes (CompTech) were added to a dilution series of each serum sample plus MgEGTA, incubated at 37°C for 30 min, centrifuged to pellet remaining red blood cells (RBCs), transferred supernatants (containing heme from lysed RBCs) to 96-well plates, and read on a spectrophotometer at 560 nm absorbance. All data were normalized to positive control at 100% (replaced buffer with water or detergent) and negative control at 0% (no NHS or add EDTA). Data were graphed as 50% RBC lysis by serum dilution from which 50% hemolysis (AH50) was determined for each group, then averaged across 2 experiments. NHS has robust alternate pathway (AP) activity, and NHS- C3dpl has low AP activity; both C3nAb and the Product inhibit AP activity. AVQ-00425 [00305] 8. Efficacy of the Product in a Rodent Light-Induced Retinal Degeneration Model in Humanized Siglec 11 Transgenic Mice [00306] This study was completed in BALB/c and C57BL/6 mice, transgenic Siglec-11 humanized mice. It was demonstrated that a single dose of the Product (SF22000208) resulted in statistically significant rescue of retinal degeneration. [00307] The mice were created by knock-in of a human SIGLEC11 gene at the locus of ROSA26 in C57BL/6N mice by CRISPR/Cas-mediated genome engineering. [00308] The mouse ROSA26 gene (NCBI Reference Sequence: NR_027008.1) is located on mouse chromosome 6. The human SIGLEC11 gene (NCBI Reference Sequence: NM_052884.3) is located on human chromosome 19. For the knock-in (KI) model, the “CAG promoter-Kozak-human SIGLEC11 CDS-rBG pA” cassette was cloned into intron 1 of ROSA26 in reverse orientation. Cas9 and gRNA were co-injected into fertilized eggs with targeting vector for KI mice production. Mouse genomic fragments containing homology arms (HAs) were amplified from BAC clone by using high fidelity Taq DNA polymerase, and were sequentially assembled into a targeting vector together with recombination sites and selection markers. [00309] The map of human Siglec 11 targeting vector is shown in FIG.25. [00310] Referring to FIGs.19A, 19B, and 20, at Baseline, the ONL thickness among groups were similar (FIG.19A), as was the total retinal thickness among groups (FIG.19B). At Day 7, all groups had a decrease in both ONL thickness and total retinal thickness from baseline. However, the vehicle group had a larger decrease in both measures than the corresponding thicknesses of both the Product 3 mg/ml (corresponding to 0.35 mg/eye clinical dose in human) group (ONL, p<0.01; total retinal, p<0.0001) and the Product 19 mg/ml (corresponding to 2.3 mg/eye clinical dose in human) (p<0.0001 for both). Thus, the Product significantly attenuated retinal damage, possibly in a dose-dependent manner. Furthermore, the Product induced a dose-dependent decrease in the release of TNF-α (p<0.0001) in RPE/choroid compared to control (FIG.20), indicating that AVD-104 suppresses pro-inflammatory TNF-α. [00311] Referring to FIGs.19A and 19B: Retinal degeneration model: The eyes of Siglec- 11 mice were treated with a single IVT dose of the Product (3 mg/ml or 19 mg/ml) or 10% sucrose vehicle, after which BLD (Blue Light Damage) was induced with exposure to 10,000 lux for 4 hours. In both (FIG.19A) ONL thickness and (FIG.19B) total retinal thickness, a 2- way analysis of variance provided evidence of significant loss of thickness between Baseline and Day 7. The Product exhibited a significant, dose-dependent rescue of retinal degeneration AVQ-00425 compared to vehicle (shown in graphs). IVT administration of the Product was not associated with ocular inflammation or toxicity at either dose. [00312] Referring to FIG.20: Ocular tissues collected at Day 8 from both the Product 3 mg/ml and 19 mg/ml were homogenized, and supernatants collected were analyzed by ELISA (R&D Systems) for TNF-α. Data are representative of N-5 RPE/choroid tissues homogenized. RPE-Retinal Pigment epithelium. [00313] 9. Efficacy of the Product in a Laser-Induced Choroidal Neovascularization (CNV) Model in Humanized Siglec 11 Transgenic Mice [00314] This study was completed in BALB/c and C57BL/6 mice, transgenic Siglec-11 humanized mice. It was demonstrated that a single dose of the Product (SF22000208) resulted in clinically meaningful protection from lesion formation and lesion leakage and suppression of C5b9 membrane attack complex. [00315] This in vivo study used laser injury to induce CNV in Siglec-11 humanized mice so that the impact of the Product on retinal damage (quantified here as lesion size and magnitude of vascular leakage) could be examined. In this study, on Day 1, animals received 1 μL IVT injections OU (both eyes): 1 group received 10% sucrose vehicle (control), 1 group received 3 mg/ml AVD-104, and 1 group received 19 mg/ml of the Product. Following this, a 532 nm diode laser was used to create 4 single laser spots OU surrounding the optic nerve. Fluorescein angiography was performed on all animals OU on Day 8. Following euthanasia on Day 8, nine to 10 eyes/group were enucleated and retinas were dissected, incubated with an antibody cocktail, and flat mounted. [00316] On Day 8, fluorescein angiography demonstrated that the control group had the largest mean ± standard deviation (SD) lesion area (5,269.8 ± 2,419.1 μm2) followed by the Product 3 mg/ml group (4,352.7 ± 2,014.7 μm2) and the Product 19 mg/ml group (3,496.0 ± 1,735.1 μm2; FIG.21 and data not shown, discussed below). Flat-mount immunohistochemistry (IHC) staining of isolectin-B4 showed that the control group had the largest mean ± SD lesion area (25,026.8 ± 7,648.7 μm2) followed by the Product 3 mg/ml group (19,573.6 ± 10,369.3 μm2) and the Product 19 mg/ml group (19,818.9 ± 4,915.3 μm2; (FIG.22 and data not shown, discussed below). [00317] Representative images from Day 8 fundus imaging and fluorescein angiography (not shown) were analyzed and showed reduction of lesion size and leakage in dose- dependent manner at Day 8 in CNV Transgenic Mice Model. [00318] With reference to FIG.21, laser-induced CNV model: The eyes of Siglec-11 mice were treated with a single IVT dose of the Product (3 mg/ml or 19 mg/ml) or 10% sucrose AVQ-00425 vehicle, after which CNV was induced with laser injury using a 532 nm diode laser was used to create 4 single laser spots OU surrounding the optic nerve. Fluorescein angiography was performed on all animals OU on Day 8. The Product exhibited a clinically meaningful reduction in lesion area. [00319] With reference to FIG.22, laser-induced CNV model: The eyes of Siglec-11 mice were treated with a single IVT dose of the Product (3 mg/ml or 19 mg/ml) or 10% sucrose vehicle, after which CNV was induced with laser injury using a 532 nm diode laser was used to create 4 single laser spots OU surrounding the optic nerve. Following euthanasia on Day 8, nine to 10 eyes/group were enucleated, retinas were dissected and incubated with an antibody cocktail (anti-C5b-9 and anti-Iba1 antibodies) and then flat mounted. Representative images (acquired on an Olympus Bx63 upright fluorescent microscope equipped with CellSens Software) of Iba1 expression (isolectin-B4, a vascular-specific antibody marker of endothelial cells used for analyzing the vasculature of mouse ocular tissue to quantify the area of neovascularization) within lesions were assessed for each treatment group. [00320] Following euthanasia on Day 8, nine to 10 eyes/group were processed for ocular flatmount IHC to determine C5b-9 and Iba1 expression within lesions (by incubating flatmounts with a corresponding antibody cocktail). The data strongly suggested that a reduction of lesion size correlated to a reduced C5b-9 membrane attack complex. Treatment with the Product was also able to reduce infiltrating macrophages cells, as indicated by reduced staining of the Iba1 marker. Representative images of C5b-9 and Iba1 expression were analyzed and showed reduction of C5b-9 membrane attack complex and Iba1 staining. [00321] 10. Pharmacokinetics and product metabolism in animals [00322] All doses were well tolerated and no ocular or systemic safety concerns were noted in any animals following two in vivo single-dose toxicity studies of the Product in Dutch belted rabbits (N=6 eyes/group). In an MTD study, three Product doses were injected with total solids measuring 0.05 mg/eye, 0.15 mg/eye, and 0.5 mg/eye. These doses were all well tolerated. [00323] In another study conducted in the same rabbit species, with the Product at 2.0 mg/eye, rabbits exhibited moderate inflammation at Day 4, with a mean ocular inflammation score of 11 out of 60 (using the Hackett-McDonald scoring method) and hazy vitreous. By Day 7, in the absence of any treatment, this inflammation reduced significantly to an ocular score of 2, with mild inflammation. Hence, the MTD was determined to be 1 mg/eye. AVQ-00425 [00324] 11. Single Dose Pharmacokinetics Assessment of AVD-104 in Dutch Belted Rabbits [00325] In this study, it was shown that PEG levels were sustained in all ocular tissues tested through the last sampling day. The rank order of exposure was RPE/choroid > retina > AH and VH. T_max for plasma and RPE/ choroid was the last sampling day. [00326] In this study, all rabbits received bilateral IVT injections of the Product (SF22000208) 0.5 μg/eye on Day 0. Terminal blood collection (for plasma) and/or ocular tissues (vitreous, RPE/choroid, and retina) were collected on Days 1, 3, 7, 10, 14, 17, 21, 24, and 28. [00327] Following injection, PEG became detectable in plasma on Day 3 post dose and was sustained through the last time point (Day 24), with concentrations increasing steadily throughout the study period (FIG.23). [00328] Quantitative determination of the Product in rabbit matrices was performed using PEG ELISA kit from Abcam (Cat. No. ab215546). [00329] Briefly, the Polyethylene Glycol (PEG) RabMAb® ELISA Kit operates on the basis of competition between enzyme HRP-conjugated PEG and PEG labeled molecules for a limited number of binding sites on the surface of 96-wells coated with anti-PEG RabMab® antibody. The extent of color development resulting from interaction between HRP and the substrate TMB is inversely proportional to the amount of PEGylated molecules in the sample. For example, the absence of PEGylated molecules in the sample will result in a bright blue color, whereas the presence of PEGylated molecules will result in decreased or no color development. [00330] The PEG content in a batch used for this study was found as 1.6 ng/mL. [00331] Referring to FIG.23, following the Product injection, the highest exposure (Cmax 22.6 ng/mL, AUClast 292 Day*ng/mL) was observed in RPE/choroid. The LLOQ was 0.1 ng/mL. [00332] Similarly, PEG concentration tended to increase in RPE/choroid, with concentrations increasing from Day 7 through Day 28. The highest detectable concentration of PEG was observed in RPE/choroid. Retina, aqueous humor, and vitreous humor levels all remained relatively constant throughout the study period. The extent of exposure in ocular tissues was determined as RPE/choroid > retina > AH and VH (Table 20). [00333] Table 20. Pharmacokinetic parameters (Polyethylene Glycol) in rabbit ocular tissues and plasma AVQ-00425 Table 20 AH, aqueous humor; LLOQ, lower limit of quantitation; RPE, retinal pigment epithelium; VH, vitreous humor. The LLOQ was 0.1 ng/mL. [00334] In the majority of tested tissues, PEG exposure was sustained (AH, VH, retina) or increased (RPE/choroid, plasma) through the last time point. In VH, the exposure reached a maximum on Day 3 with a Cmax of 0.277 ng/mL. [00335] VH half-life value was calculated based on Day 24 and Day 28 post-dose data and is presented in Table 22. The half-life was determined to be in the range of 25 to 40 hours in VH. [00336] Table 22. Half-life (Polyethylene Glycol) in rabbit vitreous humor The LLOQ was 0.1 ng/mL [00337] The lack of elimination phase data does not allow an accurate prediction of PK parameters in other tissues. The mean residence time for PEG was determined for RPE and AH to be 15.7 to 16.8 hours. [00338] 12. The Effect of the Product on Alternative Complement Activation [00339] The complement system is a central effector of the innate immune system, and is activated in response to either pathogen threat or disease-associated pathology. The complement system is an enzymatic cascade that functions to recruit inflammatory cells (via anaphylatoxins C3a, Ba, C5a, C4a), opsonize cells/debris for phagocytosis (via opsonins C3b, C1q, and receptor CR3), and directly lyse cells (via C5b-9). There are three main pathways for complement activation: classical (C1q, C2, C2a, C4, C4a), alternative (CFB, Ba, CFD, CFH, CFP), and lectin (MBL, MASP). All pathways converge at C3, and share a single terminal pathway (C5, C5b-9). Complement proteins that circulate in serum are produced in the liver, but inflammatory cells (macrophages, neutrophils, microglia, astrocytes) also produce and secrete complement proteins. In the retina, there are several sources of AVQ-00425 complement proteins (serum through BBB disruption, local cells, infiltrating cells). Complement proteins and receptors are present in normal retinas, and are increased in many clinical diseases and disease models. The complement system, especially the alternative pathway, is strongly implicated in the onset and progression of AMD. In multiple GWAS and candidate gene studies, variants in C3, C2, CFB, CFH, CFI, and C9 were found to be associated with AMD. In studies that measured complement protein concentration in human aqueous humor samples, C3, C3a, CFB, Ba, CFI, and CFH levels were higher in AMD patients than in control non-AMD patients. Therefore, the in vitro effect of the Product on complement proteins relevant to macrophages and AMD was investigated: central complement protein C3, alternative pathway convertase stabilizers CFD and CFP, and alternative pathway inhibitor CFH. [00340] The Product (SF208) treatment decreases complement protein (and increases complement inhibitor) expression by macrophages in vitro. THP1 cells (human macrophage cell line) were plated in a 96 well plate, and immediately differentiated with PMA for 2d, then rested for 1d, before treatment with: media control, LPS control (1ug/ml), sucrose vehicle control (1%), LPS + SF208 (0.1mg/ml), LPS + SF208 (0.3mg/ml), LPS + SF208 (1mg/ml). SF208 is a batch SF22000208 of AVD104. Supernatant was collected 1d post- treatment and stored at -20C. Supernatant samples (1:2 sample dilution) were tested for complement protein concentration using Quidel’s MicroVue Multiplex Complement ELISA kits (#A900, #A916) with Quansys’ Q-View imager LS (#104150GR). [00341] Results presented in FIG.24A show that C3, the central protein of all complement pathways, is increased by LPS and decreased by the Product. Results presented in FIG.24B show that Complement Factors D (CFD) and P (CFP), alternative pathway convertase stabilizers, are decreased by the Product. Results presented in FIG.24C show that Complement Factor H (CFH), a potent inhibitor of the alternative pathway, may be slightly increased by the Product. [00342] 13. Summary of the Data and Further Studies [00343] The Product comprises a sialic acid polymer of characteristic length that is intended to interact specifically with inhibitory Siglec receptors on immune cells and repolarize macrophages and microglia to a resting state. The Product is a nanoparticle intended to be administered by IVT injection to patients with AMD (in particular Geographic Atrophy secondary to AMD, and other ophthalmic diseases to address severe chronic “non-resolving” inflammation in 2 ways: (1) reprogramming inflammatory macrophages that modulate the inflammatory pathobiology to a resting state and (2) downregulating the AVQ-00425 complement cascade. In vitro and in vivo studies with the Product show that this approach is safe and has demonstrated signs of efficacy in several preclinical models. [00344] The no-observed-adverse-effect level (NOAEL) was determined at 0.5 mg total solids/eye based on the nonclinical toxicity study in monkeys. The starting dose for human clinical trials will consider all pharmaceutical release criteria and in vivo and in vitro information from toxicology, PK, and pharmacodynamic studies in monkeys and rabbits. The first study will be a single-dose study starting at a subtherapeutic dose and escalating into the pharmacologic or anticipated therapeutic range, as recommended in M3(R2) Nonclinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals (US FDA, Guidance for Industry, 2010). Dose escalation will cease once dose-limiting toxicities (DLTs) are identified in a small group (n=6) of participants. Based on a 60 kg individual, this would correspond to 11 mg systemic exposure and 1.3 mg/eye. However, the planned starting dose in humans will be even lower, at 0.05 mg/eye. [00345] The First in Human (FIH) trial will be divided into 2 parts. Part 1 will be an open- label MTD study, involving a single IVT dose administered to the study eye. Part 2 will consist of 3 randomized, masked groups. The primary objective of Part 1 is to determine the safety and MTD of AVD-104 (Product) after a single dose by IVT injection using a 3+3 design. Eligible participants will have evidence of GA secondary to AMD that meets the inclusion criteria. [00346] In brief, 3 participants will enter Cohort 1 and, if there are no DLTs in the first 28 days, 3 participants will be enrolled in the next higher dose, Cohort 2. Should there be any DLTs in the first 3 participants in any cohort, 3 additional participants will be recruited to that dose. If no more than 1 of 6 participants has a DLT, the dose can be escalated to the next dose level. If 2 or more participants have a DLT, dose escalation will stop and the MTD will be declared as the previous dose. If there are fewer than 2 DLTs at the highest dose, then an additional 6 participants will be dosed at both the mid and high doses such that there are 9 participants dosed at each of these levels to provide more data and confidence in these doses. If 2 or more participants in Cohort 1 have DLTs occur, the next cohort will receive a dose that is reduced by 50% and this will serve as the new lowest dose. After the initial DLT observation period of 28 days, all participants will be followed up for safety until Month 3. [00347] Part 2 will consist of 3 randomized, masked groups: high-dose Product, low-dose Product, and sham injection. If supported by the nonclinical multiple-dose toxicity studies yet to be conducted and by PK data from Part 1, the dosing interval will be increased to bimonthly or longer for all groups. AVQ-00425 [00348] The major inclusion criteria are the presence of GA secondary to AMD, age ≥55 years, and no prior history of treatment for neovascular AMD in the study eye. The ocular media must be sufficiently clear, and pupillary dilation must be adequate to permit quality fundus imaging. The area of GA must be ≥2.5 mm2 and ≤17.5 mm2, with at least 1 lesion ≥1.25 mm2 (0.5 disc areas). In Part 1, participants will be allowed to have central involvement (subfoveal) of the GA and a history of CNV in the fellow eye (not currently active). In Part 2, central involvement of the GA will be exclusionary as well as any history of CNV in either eye. [00349] The major exclusion criteria are the presence of RPE tears, or any other macular pathology such as macular hole, epiretinal membrane, toxic maculopathies, or diabetic retinopathy. Additional exclusion criteria are aphakia, myopia >8 diopters, intraocular surgery except for cataract surgery more than 3 months prior, and a history of corneal transplantation, uveitis, glaucoma, or herpetic infection. The presence of any significant ocular condition that would potentially affect vision in the subsequent 2 years is also exclusionary. [00350] The risks to the participants in this study include the standard risks associated with IVT injections, such as endophthalmitis, retinal tear or detachment, or damage to the lens, all of which can lead to loss of vision or loss of the eye. Risks associated with the study drug include inflammation and loss of retinal function. The nonclinical studies in mice, rabbits, and NHPs indicate that the risk of serious visual loss is low. [00351] The benefits to participants enrolled in the study include more frequent evaluations, which increase the likelihood of detecting a change in their ocular condition. Early detection of any significant visual change in participants with AMD is likely to facilitate a better visual outcome. There is also the possibility that participants who receive the Product will have a better clinical course in relation to their underlying AMD. [00352] V. FURTHER CHARACTERIZATION OF THE BIOLOGICAL ACTIVITIES OF THE PRODUCT [00353] 1. Transcriptomic analysis of AMD eyes. [00354] Transcriptomic analysis was performed to investigate the expression changes of Siglecs in AMD eyes. The GSE135092 dataset, which included RNA-seq data from eyes with a clinical diagnosis of AMD using the AREDS classification and ages ranging from 59 to 98 years, was utilized for this analysis described in Orozco, L.D., et al., “Integration of eQTL and a Single-Cell Atlas in the Human Eye Identifies Causal Genes for Age-Related Macular Degeneration.” Cell Rep, 2020.30(4): p.1246-1259.e6. The dataset consisted of bulk RNA- AVQ-00425 seq data from the retina tissues of the macula and non-macula (peripheral) regions of 129 postmortem donors (106 control and 23 AMD patients). The analysis was conducted using R software described in Team, R.C., “R: A Language and Environment for Statistical Computing.” 2021. Statistical analysis was performed using the Student’s T-test or the Wilcoxon test in the case of non-parametric data. [00355] The results are shown in FIG.26. The results show an increase in the expression of Siglec 7 in patients suffering from AMD as compared to healthy patients. [00356] 2. Determination of the Inhibition of IL-12 Production by the Product [00357] Peripheral Blood Mononuclar Cells (PBMCs, Stem Cell Research, Cat No- 70500.2) were activated to an M1 phenotype (interferon-gamma 50 ng/mL, LPS 10 ng/mL) for 48 hours. Cells were then treated with a serial dose range of the Product (batch SF22000208; 0.01−1 mg/mL) overnight. LPS served as a positive control. Post-treatment supernatants were collected and assayed by ELISA (R&D Systems, DY1270-05) for IL-12. In vitro AVD-104 significantly downregulated the amount of IL-12 in the supernatants from activated macrophages. ****p<0.0001 Dunnett's multiple comparisons test. [00358] The results are presented in FIG.27. [00359] 3. Determination of a Complement Inhibition Activity by the Product in Human Macrophages [00360] Administration of the Product decreases complement protein (and increases complement inhibitor) expression by macrophages in vitro. [00361] PBMCs (Stem Cell Research, Cat No-70500.2) were activated to an M1 phenotype (interferon-gamma 50 ng/mL, LPS 10 ng/mL) for 48 hours. Cells were then treated with a serial dose range of the Product (batch FG2200012; 0.01−3 mg/mL) overnight Supernatant was collected 1day post-treatment and stored at -20 °C. Supernatant samples (1:2 sample dilution) were tested for complement protein concentration using Quidel’s MicroVue Multiplex Complement ELISA kits (#A900, #A916) with Quansys’ Q-View imager LS (#104150GR). [00362] The results are presented in FIGs.28A through 28C and FIGs.29A and 29B. As can be seen, the Product decreases overall complement activity. Specifically, decreased levels of C3a, C5a, and sC5b-9 were demonstrated (FIGs.28A-28C) as well as decreased levels of Ba and Bb (FIGs.29A and 29B). AVQ-00425 [00363] VI. FURTHER CHARACTERIZATION OF THE BIOLOGICAL ACTIVITIES OF THE PRODUCT IN NON-HUMAN PRIMATES [00364] 1. Summary of Findings [00365] The purpose of this study was to determine the potential toxicity of AVD-104 when administered once every two months or once every month by intravitreal injection to cynomolgus monkeys (also referred to as “non-human primates” or “NHP”) for 39 weeks and to assess the reversibility, persistence, or delayed occurrence of toxic effects following an 8- week recovery period. [00366] For this 1-month interim phase report, monkeys were administered a single intravitreal injection of 0 mg/eye AVD-104 (vehicle; 5/sex), 0.5 and 1.0 mg/eye AVD-104 (3/sex/group) and 1.5 mg/eye AVD-104 (5/sex) in the left eye. Right eyes were untreated in the vehicle group or sham injected in AVD-104 groups. [00367] The following parameters and endpoints were evaluated in this 1-month interim report: mortality, clinical observations, body weight, ophthalmology, intraocular pressure (IOP), and cardiovascular safety pharmacology (electrocardiography [ECG], blood pressure, heart rate, and body temperature). Electroretinography (ERG), optical coherence tomography (OCT), clinical pathology, and toxicokinetics results were not included. [00368] By the end of 1-month interim phase, there were no moribund or found dead animals. No test article-related changes in body weights and cardiovascular safety pharmacology parameters were observed by the end of the 1-month interim phase. [00369] The main AVD-104-related findings in males and females administered 1.5 mg/eye consisted of acute, transient, slight or severe aqueous flare (1+ or 4+, respectively) that resolved by the end of the first week following treatment with TOBRADEX® and mydriatics, a secondary IOP decrease in females on Day 7, slight to moderate cell-like opacity in the anterior vitreous chamber (1-2+) from Day 6 to Day 28 with a decrease in severity at Day 28, and minimal vitreous haze (0.5+) on Day 28. Cell-like vitreous opacity and vitreous haze could be attributed to inflammatory cells and/or AVD-104 particles from precipitation. [00370] Ophthalmic findings at ≤ 1.0 mg/eye were limited to dose-related vitreal cell-like opacity that was slight at 0.5 mg/eye and slight to moderate at 1.0 mg/eye on Day 7 with partial resolution by Day 28. All ophthalmic findings following a single intravitreal dose of ≤ 1.5 mg/eye were considered non-adverse based on transient occurrence or low severity. AVQ-00425 [00371] 2. Conclusions [00372] In conclusion, administration of AVD-104 at 0.5, 1.0, and 1.5 mg/eye by single unilateral intravitreal injection with a 1-month interim evaluation did not cause any test article-related changes in body weight and cardiovascular safety pharmacology parameters. AVD-104-related non-adverse ophthalmic findings at 1.5 mg/eye included acute, transient, slight or severe aqueous flare that resolved by Day 7, a secondary decrease in IOP at Day 7 and minimal vitreal haze on Day 28. Dose-related slight to moderate vitreal cell-like opacity was observed at ≤ 1.5 mg/eye on Day 7 with partial resolution by Day 28. [00373] Dose-related slight to moderate vitreal cell-like opacity was observed at ≤ 1.5 mg/eye on Day 7 with partial resolution by Day 28. [00374] Fundus photographs and Optical Coherent Tomography (OCT) images were collected and analyzed after the 6^th injection in a Control Group and in a Low Dose Groups (0.5 mg/eye), as well as after the 3^rd injection in the Mid Dose Groups (1 mg/eye) and High Dose Group (1.5 mg/eye). No abnormalities or adverse effects were observed. [00375] Based on the absence of an adverse effects at the NHP dosing of 1.5 mg/eye, a “clinical dosing” in humans was established at 3 mg/eye. [00376] VI. Further Characterization of AVD-104 [00377] 1. AVD-104 Inhibits Binding of Siglec-7 and -9 to Human PANC-1 Cells [00378] AVD-104 binding to Siglecs was evaluated by an ELISA-type binding assay in which the specific binding capability of the AVD-104 to the extracellular domain of Siglecs - 7 and -9 conjugated to a C-terminal Fc tag was evaluated. [00379] A competitive binding assay revealed that binding of Siglec-7 Fc and Siglec-9 Fc proteins to sialic acid-expressing Panc-1 cells was inhibited by AVD-104 (50% reduction of Siglec-9 binding at 0.5 mg/mL and 28% reduction of Siglec-7 binding at 0.25 mg/mL (FIG. 30, the bar marked with a star). This result indicates that AVD-104 bind to Siglec-7/9 Fc, thus inhibiting binding of the latter to Panc-1 cells. [00380] 2. AVD-104 Reduces oxLDL-Mediated Inflammation [00381] The effect of AVD-104 on macrophages activated with either LPS or oxidized (Ox) LDL was evaluated using MTT cell viability assays. The results showed no cytotoxicity effect of AVD-104 when used at a concentration from 1.0 to 0.01mg/mL on OxLDL-treated macrophages (FIG.31A). AVQ-00425 [00382] AVD-104 showed dose-dependent inhibition in TNF-α production in either OxLDL- or LPS-treated macrophages when compared with treatment with 10% sucrose vehicle (dash line) (p<0.05 and p<0.001, one-way ANOVA) (FIG.31B). [00383] VII. Clinical Studies of AVD-104 in Patients Suffering From Geographic Atrophy [00384] As demonstrated in the in vitro and in vivo experiments, AVD-104 has a dual mechanism: it acts in the cellular arm of the innate immune response by binding to Siglecs and repolarizing overactivated macrophages; in the humoral arm, AVD-104 binds complement factor H to downregulate complement overproduction. [00385] The effect of AVD-104 on patients suffering from Geographic Atrophy (GA) has now been further investigated (NCT05839041). [00386] Briefly, AVD-104 was investigated for the treatment of GA secondary to age- related macular degeneration (AMD) in the ongoing clinical trial. Part 1 of the trial was a multicenter, open-label, single-dose safety study with 4 cohorts to investigate the safety, tolerability, and dose limiting toxicity. The study design is graphically shown in FIG.32. [00387] The intermediate results of this study are presented in the tables shown in FIG.33. In this study a Best-Corrected Visual Acuity test (BCVA), was a number of letters of a Shellen chart or its equivalent that a patient was able to read (also referred to as a BCVA score). A baseline measurement was established. A gain or loss was measured as a difference between the baseline BCVA score and the BCVA score at the time of a subsequent measurement. [00388] Initial data indicates that AVD-104 has a potential for a long-term abatement of GA lesion progression from the lesion leading edge. The data collected from patients 4 and 5 of Cohort 2 is presented in FIG.34 shows a significant reduction in the lesion leading edge hyperautofluorescence (hyper-AF) area over a 1-month period. The AVD-104 dosage is indicated in mg/eye. [00389] The hyper-AF (HAF) area and the BCVA score for Patient 5 of Cohort 2 are also shown in FIG.35A and FIG.35B ((BCVA (OS Study Eye): 29 (screen), 28 (baseline), 33 (day 15), 33 (1 month), 33 (2 month); HAF Area: 1.03 mm2 (baseline), 0.66 mm2 (1 month)). [00390] A representative aqueous humor biomarker analysis was also conducted for Patient 5 of Cohort 2. The results of the measurements of IL-6, complement C3a and C4a, and Complement Factor H (CFH) are shown in FIG.36A through FIG.36D. AVQ-00425 [00391] FIG.37 represents a design of the second part of the clinical study of AVD-104 described above. The second part of the trial is a randomized, sham-controlled, active comparator study assessing efficacy in reducing GA lesion growth rates.290 patients are expected to be enrolled, with 250 patients randomized. [00392] In summary, AVD-104 is a new dual mode-of-action treatment for GA. The mechanism of AVD-104 involves repolarizing macrophages and inhibiting complement to target pathobiology in GA. Whereas the available complement inhibitors only address one arm of innate immune response and may deplete complement factors, AVD-104 repolarizes overactivated macrophages and inhibits overamplified complement system. [00393] VIII. Further Results of Clinical Studies of AVD-104 in Patients Suffering From Geographic Atrophy [00394] Further data on the effect of AVD-104 on patients suffering from Geographic Atrophy (GA) investigated during clinical study NCT05839041 (see Part VII, above) was collected. [00395] The study design is graphically shown in FIG.32. Briefly, four cohorts were followed, defined by AVD-104 dose (Cohort 1 - 0.1 mg, Cohort 2 - 0.5 mg, Cohort 3 - 1 mg, and Cohort 4 - 3 mg per eye). The patients in each cohort suffered from bilateral GA. Each patient received treatment for one eye (study eye, SE) but did not receive treatment for the other eye (fellow eye, FE). Furthermore, in certain instances, the data collected during the study was processed separately for the categories of “all lesions” and “excluding large lesions,” where a “large lesion” was considered to be a lesion having the area of 15.5 mm² or above. [00396] The autofluorescence data (GA lesion area, mm²) obtained by combining the results for Cohorts 3 and 4 is shown in FIG.38A (percent change of area of lesion from baseline) and FIG.38B (mean change of area of lesion from baseline). These data demonstrate that AVD-104 slows the growth of the GA lesions when comparing to the fellow eye that also had GA. [00397] The collected autofluorescence data permitted cross-study comparison to the standard-of-care (SoC) medications, such as IZERVAY and SYFOVRE. Specifically, mean change of lesion areas as a function of time for cohorts 3 and 4 was plotted against similar data for the clinical studies involving the Standard of Care (SoC) medications. The results, excluding large lesions and out-of-window (late) measurements, are presented in FIG.39 (Syfovre Trials OAK and Derby) and FIG.40 (Iservay). It should be noted for the data AVQ-00425 presented in FIGs.39 and 40, that AVD-104 was administered as a single injection at baseline, Syfovre was administered as 3 injections (every month treatment), and Izervay was administered as 3 injections (every month treatment) The SoC data excludes lesions larger than 17.5 mm². No patients in the present study had lesions sized between 15.5 mm² and 17.5 mm². The lesions in this study were larger than the average lesion in the Syfovre and Izervay published series so they should actually have a larger increase in area than the comparators. Even though AVD-104 was given as only a single injection compared to three monthly injections of the comparators the growth of GA lesions in the AVD-104 treated eyes was less than that seen in eyes treated with either Izervay or Syfovre. [00398] Peri-Lesional Hyper Auto-Fluorescence data (cohorts pooled, excluding out-of- window assessments) is presented in FIG.41. The margin area of GA lesions called the junctional zone is where the inflammatory activity is greatest and this is demonstrated by hyper-autofluorescence (hyper-AF). This area of hyper-AF increased in the fellow eyes and substantially decreased in AVD-104 treated eyes showing the positive affect of AVD-104 in reducing inflammation. [00399] Best-Corrected Visual Acuity score (BCVA) was determined for the patients in each cohort. The BCVA score is the number of letters of an ETDRS chart that a patient was able to read. A baseline measurement was established. A gain or loss was measured as a difference between the baseline BCVA score and the BCVA score at the time of a subsequent measurement. The score was assessed by ETDRS Visual Acuity test. [00400] The BCVA score (mean change from baseline) for all cohorts is presented in FIG. 42. There is a clear dose response showing participants that received the higher doses in Cohorts 3 and 4 had visual gain over the course of the study. The natural history of GA is a loss of 1-2 letters over a 3-month period. [00401] The BCVA score gains and losses for all cohorts are presented in Table 18 (study eye) and Table 19 (Fellow Eye). The majority of patients had stable or improved BCVA score in the study eye; the majority of patients had a reduction in the BVCA score in the fellow eye. AVQ-00425 Table 18 Table 19 [00402] The analysis of the numbers of patients who lost or gained letters in the BCVA testing is further presented in FIG.43 for all cohorts. This chart shows that the visual gains were not driven by just one or two participants and the majority of participants maintained or improved on BCVA testing. [00403] A similar analysis of BCVA testing as shown in FIG.43 is presented in FIG 44A and FIG.44B for the combined cohorts 3 and 4. [00404] The collected BCVA data permitted cross-study comparison to the standard-of- care (SoC) medication, SYFOVRE PM and lampalizumab (Chroma & Spectri Trails at 4qw and 6qw). Specifically, mean change of BCVA as a function of time for cohorts 3 and 4 was plotted against similar data for the clinical studies involving SYFOVRE PM and lampalizumab. The results are presented in FIG.45A and FIG.45B. It should be noted for the data presented in FIGs.45A and 45B, that AVD-104 was administered as a single injection at baseline, Syfovre was administered as 3 injections (every month treatment), and lampalizumab was administered either every 4 weeks or every 6 weeks. These graphs provide perspective that patients treated with either Syfovre or lampalizumab [00405] lose vision over time whereas the AVD-104 treated participants actually gained vision. AVQ-00425 [00406] FIG.46 is a bar plot showing the BCVA score change for each patient in each cohort at 3 months (each bar represents one patient). This waterfall plot again demonstrates that the majority of participants in Cohorts 3 and 4 had improvement in their vision. [00407] Certain patients in the study were tested using the multifocal electroretinogram (mfERG) using the equipment and methods designed by Diagnosys LLC according to the manufacturer’s protocol. [00408] The Multifocal ERG (mfERG) test measures an electrical signal across the macula as indicating visual function. This test divides the macula into multiple hexagonal regions. The stimulus is a pseudo-random sequence of black and white hexagons that alternate many times per second. A standard ERG electrode setup is used to record the signal, and mathematical extraction is used to create the multifocal waveforms. A typical multifocal waveform consists of a peak (P1), both preceded by and followed by a trough (N1 and N2, respectively). MfERG responses are primarily derived from cone on- and off- bipolar cells, with additional contributions from cone photoreceptors. The main cellular components of the mfERG response are On- and Off- bipolar cells; cone photoreceptors also contribute to a lesser degree. Hence mfERG can be readily utilized to distinguish between macular and generalized retinal dystrophies, as well as to localize retinal defects. [00409] The data obtained in this clinical study demonstrated excellent intertest reliability. Three of 6 patients in phase I demonstrated increases above normal variability (≥20%) in P1 voltage at month 2, and 5 of 6 fellow eyes were within normal variability (≤20%) at month 3. At month 3, mean BCVA change from baseline among eyes treated with AVD-104 reached +6.0 letters. All subjects had very poor responses within the area of severe RPE loss (area of GA on FAF imaging). Three subjects (50% of those examined) had significant improvements in the peri-lesion waveforms (with continued severe depression of the waveforms within the area of atrophy). These improvements in peri-leison waveforms generally lasted two months, with a return to baseline poor response by month 3. [00410] Evaluation of eyes that were dosed with AVD-104 showed that a majority of improved mfERG responses occurred in regions adjacent to GA lesions. These data indicate with completely objective evidence that AVD-104 is able to improve the function of remaining photoreceptors where GA is not complete. [00411] IX. A Phase 2 Study of Intravitreal AVD-104 in Diabetic Macular Edema [00412] Patients suffering from diabetic macular edema will be investigated during clinical study NCT06181227. AVQ-00425 [00413] This is a phase 2 study to determine the safety and preliminary efficacy of intravitreal injections of AVD-104 in reducing macular edema associated with diabetic retinopathy. The primary objective is to evaluate the tolerability and treatment effect of intravitreal injections (IVT) of AVD-104 in participants with diabetic macular edema (DME). Participants will receive either three intravitreal injections of low-dose AVD-104 (1.0 mg) each 28 days apart or two intravitreal injections of AVD-104 at a high-dose (2.0 mg) 56 days apart. Serial optical coherence tomography (OCT), ultra wide-field fluorescein angiography, and OCT-angiography (OCT-A) will be performed to evaluate the treatment effect on central subfield thickness (CST) and areas of non-perfusion. All participants will be followed-up for safety until day 84. There will be a planned enrollment up to 30 participants. [00414] Inclusion Criteria: • Diagnosis of diabetes mellitus (type 1 or 2), as defined by the World Health Organization and/or American Diabetes Association • Decreased visual acuity (VA) due to DME, with BCVA letter score of 75-20 letters on ETDRS-like charts (20/32-20/320 Snellen equivalent) • DME represented by macular thickening on SD-OCT involving the center of the macula: CST ≥325 μm [00415] Exclusion Criteria: • Any IVT anti-vascular endothelial growth factor (VEGF) treatment within 3 months before randomization • Any history of pan-retinal photocoagulation (PRP) treatment • Any use of Iluvien® (Alimera Sciences, Inc., Alpharetta, GA) in the last 3 years; or Ozurdex® (Abbvie, Chicago, IL) or Xipere (Bausch & Lomb, Vaughan, Ontario, Canada) in the last 6 months • History of macular laser photocoagulation • Any signs of high-risk proliferative diabetic retinopathy (PDR) [00416] Arms and Interventions are described in Table 21, below. AVQ-00425 Table 21 [00417] While this invention has been particularly shown and described with references to example embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the scope of the invention encompassed by the appended claims.

Claims

AVQ-00425 CLAIMS What is claimed is: 1. A polysialic (PSA)-polymer conjugate compound represented by the structural formula (I): or a pharmaceutically acceptable salt thereof, wherein: P is a poly(lactide-co-glycoclide)-poly(ethylene glycol) copolymer (PLGA- PEG); and p is an integer from 4 to 200. 2. The compound of Claim 1, wherein P is a PLGA(10k)-PEG(5k). 3. The compound of Claim 1 represented by the following structural formula (II): (II), wherein: y is an integer from 1 to 1000, x is an integer from 1 to 1000, and m is an integer from 1 to 450. AVQ-00425 4. The compound of Claim 3, wherein y is an integer from 1 to 500, x is an integer from 1 to 500, and m is an integer from 1 to 250. 5. The compound of Claim 4, wherein: x is an integer from 90 to 140; y is an integer from 10 to 75; and m is an integer from 90 to 140. 6. The compound of any one of Claims 1-5, wherein the value of p is selected from any one of the following ranges: from 10 to 20, from 20 to 30, from 30 to 40, from 40 to 50, and from 50 to 60. 7. The compound of any one of Claims 1-5, wherein the value of p is selected from any one of the following ranges: from 17-200, from 17 to 100, from 17 to 60, from 17 to 25, from 20 to 100, from 20 to 60, from 20 to 30, from 22 to 100, from 22 to 60, from 22 to 30, and from 22 to 25. 8. The compound of any one of Claims 1-7, wherein the value of p is 22. 9. The compound of any one of Claims 1-7, wherein P is a PLGA(10k)-PEG(5k), and p is 15-25. 10. A particle, comprising the compound of any one of Claims 1-9 or a pharmaceutically acceptable salt thereof. 11. The particle of Claim 10, wherein the particle is a nanoparticle. 12. The particle of any one of Claims 10 or 11, wherein the weight of the PSA per unit weight of the particle is from 1µg/mg to 1000 µg/mg. 13. The particle of any one of Claims 10-12, wherein the weight of the PSA per unit weight of P is from 10 to 75 µg/mg. AVQ-00425 14. The particle of any one of Claim 10-13, wherein an average particle size is from 80 nm to 120 nm. 15. A pharmaceutical composition comprising the particle of any one of Claims 10-14 in a pharmaceutically acceptable carrier or diluent. 16. The pharmaceutical composition of Claim 15, wherein the composition is aqueous and further comprises sucrose. 17. A method of treating a subject suffering from an ophthalmic disease, comprising: administering to the subject a therapeutically effective amount of the compound of any one of Claims 1-9, the particle of any one of Claims 10-14, or the pharmaceutical composition of any one of Claims 15-16. 18. The method of Claim 17, wherein the ophthalmic disease is Age-related Macular Degeneration (AMD). 19. The method of Claim 18, wherein the age-related macular degeneration is dry age- related macular degeneration. 20. The method of Claim 18, wherein the age-related macular degeneration is wet age- related macular degeneration. 21. The method of Claim 17, wherein the ophthalmic disease is geographic atrophy secondary to AMD. 22. The method of Claim 17, wherein the ophthalmic disease is retinitis pigmentosa. 23. The method of Claim 17, wherein the ophthalmic disease is diabetic macular edema. 24. The method of any one of Claims 17-23, wherein the administering is intravitreal. 25. A method of preparing a polysialic (PSA)-polymer conjugate compound represented by represented by the structural formula (I): AVQ-00425 or a pharmaceutically acceptable salt thereof, the method comprising: reacting a polymer represented by structural formula (III) , with a PSA precursor represented by the structural formula (IV) under the condition sufficient to form the compound represented by the structural formula (I), wherein: P is a poly(lactide-co-glycoclide)-poly(ethylene glycol) copolymer (PLGA- PEG); and p is an integer from 4 to 200. 26. The method of Claim 25, wherein P is a PLGA(10k)-PEG(5k). AVQ-00425 27. The method of Claim 25, wherein the compound represented by the structural formula (I) is represented by structural formula (II): (II), wherein: y is an integer from 1 to 1000, x is an integer from 1 to 1000, and m is an integer from 1 to 450. 28. The method of Claim 27, wherein y is an integer from 1 to 500, x is an integer from 1 to 500, and m is an integer from 1 to 250. 29. The method of Claim 28, wherein: x is an integer from 90 to 140; y is an integer from 10 to 75; and m is an integer from 90 to 140. 30. The method of any one of Claims 25-29, wherein the value of p is selected from any one of the following ranges: from 10 to 20, from 20 to 30, from 30 to 40, from 40 to 50, and from 50 to 60. 31. The method of any one of Claims 25-29, wherein the value of p is selected from any one of the following ranges: from 17-200, from 17 to 100, from 17 to 60, from 17 to 25, from 20 to 100, from 20 to 60, from 20 to 30, from 22 to 100, from 22 to 60, from 22 to 30, and from 22 to 25. 32. The method of any one of Claims25-30, wherein P is a PLGA(10k)-PEG(5k), and p is 15-25. AVQ-00425 33. The method of any one of Claims 25-32, further comprising the step of preparing the compound represented by the structural formula (IV), the method comprising: reacting a compound represented by the structural formula (V) with a compound represented by the structural formula (VI) (VI), under the conditions sufficient to prepare the compound represented by the structural formula (IV). 34. A method of increasing the Best-Corrected Visual Acuity(BCVA) score in a subject in need thereof, comprising: administering to the subject a therapeutically effective amount of the compound of any one of Claims 1-9, the particle of any one of Claims 10-14, or the pharmaceutical composition of any one of Claims 15-16. 35. The method of Claim 34, wherein the subject’s BCVA score gain is 1-4 letters. 36. The method of Claim 34, wherein the subject’s BCVA score gain is 5-9 letters. 37. The method of Claim 34, wherein the subject’s BCVA score gain is 10-14 letters. 38. The method of Claim 34, wherein the subject’s BVCA score gain is greater than or equal to 15 letters. AVQ-00425 39. A compound represented by the structural formula (IV): or a pharmaceutically acceptable salt thereof, wherein p is an integer from 17 to 200. 40. The compound of Claim 39, wherein the value of p is selected from any one of the following ranges: from 17 to 100, from 17 to 60, from 17 to 25, from 20 to 100, from 20 to 60, from 20 to 30, from 22 to 100, from 22 to 60, from 22 to 30, and from 22 to 25. 41. The compound of Claim 39, wherein p is 22.