CN110545836A - Treatment of age-related macular degeneration and other ocular diseases with apolipoprotein mimics - Google Patents

Abstract

The present disclosure provides apolipoprotein (apo) mimetics for treating age-related macular degeneration (AMD) and other ocular disorders. The apo mimetics may be peptides/polypeptides that mimic the lipid-cleansing action of, for example, apolipoproteins such as apoA-I and apoE. apo mimetics can exert other beneficial effects, such as reducing inflammation, oxidative stress, and neovascularization. apo mimetics can be used to treat any stage of AMD, including early, intermediate and late stages, as well as any phenotype of AMD, including Geographic Atrophy (GA), including non-central GA and central GA, and Neovascularization (NV), including NV types 1,2 and 3. apo mimetics can be used alone or in combination with other therapeutic agents (e.g., complement inhibitors and/or anti-angiogenic agents) to treat AMD (including atrophic AMD and neovascular AMD) as well as other ocular disorders.

Description

treatment of age-related macular degeneration and other ocular diseases with apolipoprotein mimics

Background

Age-related macular degeneration (AMD) affects about 14-24% of the 65-74 year old population and about 35% of the population over age 75 years old worldwide and results in impaired or lost vision in the center of the visual field (macula) due to retinal damage. It is the leading cause of visual loss and potential blindness in people over the age of 50. The two major forms of AMD are atrophic (non-exudative or "dry") AMD and neovascular (exudative or "wet") AMD. Atrophic AMD is characterized by Geographic Atrophy (GA) in the center of the macula at advanced stages of AMD, and vision can slowly deteriorate for years due to loss of photoreceptors and development of GA. Neovascular AMD is a more severe form of AMD, and is characterized by neovascularization (e.g., choroidal neovascularization) at an advanced stage of AMD, which can rapidly lead to blindness. Neovascular AMD affects over 3000 million patients worldwide and is the leading cause of vision loss in people aged 60 or older-patients may lose central vision in the affected eye within 24 months after the onset of disease if left untreated. Approximately 90% of AMD patients are in dry form, and about 10% develop neovascular AMD. In the united states, there is no approved treatment for atrophic AMD, while approved treatment for neovascular AMD (primarily anti-angiogenic agents) shows efficacy in about 50% of neovascular AMD patients.

Disclosure of Invention

The present disclosure provides apolipoprotein (apo) mimetics for the treatment of AMD and other ocular diseases and disorders. In some embodiments, the apoA-I mimetic and/or apoE mimetic are administered to treat AMD or another ocular disorder. In certain embodiments, the apoA-I mimetic comprises L-4F or D-4F, or is L-4F or D-4F. In some embodiments, the apoE mimetic comprises AEM-28-14, or is AEM-28-14. One or more additional therapeutic agents may be administered in combination with the apo mimetic to treat AMD or another ocular disorder. One or more other therapeutic agents may be selected to target different underlying factors of AMD or other ocular disorders. The apo mimetic can be administered, optionally in combination with another therapeutic agent, to treat AMD, for example, in different stages of AMD (including early, intermediate and late stages) and in different phenotypes of AMD (including geographic atrophy and neovascular AMD), and to prevent or slow the progression of AMD to the next stage.

In addition to apolipoprotein mimics, other therapeutic agents that may be used to treat AMD and other ocular diseases and disorders include, but are not limited to:

1) An anti-dyslipidemic agent;

2) PPAR-alpha agonists, PPAR-delta agonists, and PPAR-gamma agonists;

3) an anti-amyloid agent;

4) an inhibitor of lipofuscin or a component thereof;

5) Visual/photoperiod modifiers and dark adaptation agents;

6) An antioxidant;

7) Neuroprotective agents (neuroprotective agents);

8) Inhibitors of apoptosis and inhibitors of necrosis;

9) Inhibitors of C-reactive protein;

10) Inhibitors of the complement system or components thereof (e.g., proteins);

11) An inflammatory body inhibitor;

12) An anti-inflammatory agent;

13) An immunosuppressant;

14) Modulators of matrix metalloproteinases; and

15) An anti-angiogenic agent.

In addition to AMD, other ocular diseases and disorders that can be treated with an apolipoprotein mimetic, optionally in combination with one or more other therapeutic agents, include, but are not limited to, macular degeneration (e.g., age-related and diabetic maculopathy), macular edema (e.g., diabetic macular edema [ DME ] and macular edema following retinal vein occlusion [ RVO ]), retinopathy (e.g., diabetic retinopathy [ including DME patients ]), RVO (e.g., central RVO and branched RVO), coat's disease (exudative retinitis), uveitis, retinal pigment epithelium detachment, and diseases associated with increased intracellular or extracellular lipid storage or accumulation other than AMD.

Brief Description of Drawings

A better understanding of the features and advantages of the present disclosure will be obtained by reference to the following detailed description that sets forth illustrative embodiments of the disclosure and the accompanying drawings.

Figure 1 shows the role of tissue layers and lipid accumulation involved in the pathology of AMD in the pathogenesis of AMD. And OS: an outer segment of photoreceptors; RPE: the retinal pigment epithelium; RPE-BL: a RPE base layer; ICL: inner collagen layer, EL: elastic layer, OCL: an outer collagen layer; ChC-BL: a ChC basal layer; and (2) ChC: choroidal capillary endothelium; and (3) BLAmd: a base layer deposit; BLinD: a substrate linear deposit; pre-BLinD: a front substrate linear deposit; l: lipofuscin; m: a melanosome; ML: lipofuscin (melanolofuscin); mt: a mitochondrion; circle: lipoprotein particles. Bruch's membrane (BrM) consists of ICL, EL and OCL. BlamD is thickened RPE-BL. The Basal mound (Basal mount) is soft drusen (soft druse) material in BLamD. RPE cells contain melanosomes, lipofuscin, and lipofuscin, which provide signals for color fundus photography, fundus autofluorescence, and optical coherence tomography, for example.

Figure 2 shows the scores of neutral lipids in and on bruch's membrane in and on eyes of injected macaques, which received intravitreal injections of L-4F or placebo (scrambled L-4F) for 6 months, as well as eyes of corresponding non-injected macaques, stained with oil red o (oro). Statistical analysis: 1) paired t-test between the same group of injected and non-injected eyes; 2) unpaired t-tests between injected eyes in the treatment (L-4F) and control (placebo) groups.

figure 3 shows the intensity of esterified cholesterol in bruch's membrane stained with non-lipin (filipin) in the eyes of injected macaques, which received a 6 month intravitreal injection of L-4F or placebo (scrambled L-4F), as well as in the eyes of corresponding non-injected macaques. Statistical analysis: 1) paired t-test between the same group of injected and non-injected eyes; 2) unpaired t-tests between injected eyes in the treatment (L-4F) and control (placebo) groups.

Figure 4 shows the staining intensity of membrane challenge complex (MAC, C5b-9) and choroidal capillaries in bruch's membrane in the eyes of injected macaques, as well as in the eyes of corresponding non-injected macaques, which received intravitreal injections of L-4F or placebo (scrambled L-4F) for 6 months. Statistical analysis: 1) paired t-test between the same group of injected and non-injected eyes; 2) unpaired t-tests between injected eyes in the treatment (L-4F) and control (placebo) groups.

Figure 5 shows the staining intensity of complement factor D in the eyes of injected rhesus monkeys as well as in the eyes of corresponding non-injected rhesus monkeys that received a6 month intravitreal injection of L-4F or placebo (scrambled L-4F). Statistical analysis: 1) paired t-test between the same group of injected and non-injected eyes; 2) unpaired t-tests between injected eyes in the treatment (L-4F) and control (placebo) groups.

Fig. 6 shows the thickness of bruch's membrane measured at the extratemporal macula in the eyes of injected macaques and in the eyes of corresponding non-injected macaques that received a6 month intravitreal injection of L-4F or placebo (scrambled L-4F). Statistical analysis: 1) paired t-test between the same group of injected and non-injected eyes; 2) unpaired t-tests between injected eyes in the treatment (L-4F) and control (placebo) groups.

Detailed Description

while various embodiments of the present disclosure have been described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Many modifications and variations to the embodiments described herein, as well as variations and substitutions to the examples described herein, will be apparent to those skilled in the art without departing from the present disclosure. It should be understood that various alternatives to the embodiments described herein may be employed in practicing the disclosure. It is also to be understood that each embodiment of the present disclosure may be optionally combined with any one or more other embodiments described herein consistent with this example.

Where elements are presented in a list format (e.g., in a markush group), it is to be understood that each possible subgroup of elements is also disclosed, and that any one or more elements can be removed from the list or group.

It should also be understood that, unless explicitly stated to the contrary, in any methods described or claimed herein that include more than one step, the order of the method acts is not necessarily limited to the order of the acts in the method described, but the disclosure encompasses embodiments having the order so defined.

It will also be understood that in general, where embodiments in the specification or claims are referred to as including one or more features, the disclosure also includes embodiments consisting of or consisting essentially of such features.

It is also to be understood that any embodiment of the present disclosure, for example, may be explicitly excluded from the claims any embodiment found in the prior art, whether or not that particular exclusion is recited in the specification.

It is also to be understood that, as appropriate, the present disclosure encompasses all analogs, derivatives, prodrugs, fragments, salts, solvates, hydrates, clathrates, and polymorphs of the compounds/substances disclosed herein. Specific recitation of "analogs", "derivatives", "prodrugs", "fragments", "salts", "solvates", "hydrates", "clathrates", or "polymorphs" of a compound/substance or a group of compounds/substances in a particular instance of the present disclosure is not to be construed as an intentional omission of any such forms in other instances of the present disclosure where the compound/substance or group of compounds/substances is mentioned without recitation of any such forms.

headings are included herein for reference and to aid in locating certain sections. The headings are not intended to limit the scope of the embodiments and concepts described in the sections below those headings, and those embodiments and concepts may have applicability in other sections of the complete disclosure.

All patent documents and all non-patent documents cited herein are incorporated by reference in their entirety to the same extent as if each patent document or non-patent document were specifically and individually indicated to be incorporated by reference in its entirety.

I. Definition of

As used in the specification and the appended claims, the indefinite articles "a" and "an" and "the" may include plural references as well as singular references unless otherwise specified.

the term "exemplary" is used herein to mean "serving as an example, instance, or illustration. Any embodiment characterized as "exemplary" herein is not necessarily to be construed as preferred or advantageous over other embodiments.

the term "about" or "approximately" refers to an acceptable error for a particular value as determined by one of ordinary skill in the art, which depends in part on how the value is measured or determined. In certain embodiments, the term "about" or "approximately" means within one standard deviation. In some embodiments, when a particular error range (e.g., the standard deviation of the mean values given in a chart or data table) is not enumerated, the term "about" or "approximately" means that the range including the stated value as well as ranges encompassed by rounding up or down to the stated value, taking into account the significance value. In certain embodiments, the term "about" or "approximately" means within 20%, 15%, 10%, or 5% of the specified value. The term "about" or "approximately" applies to each of a series of two or more numerical values or a numerical value within the series of two or more numerical ranges provided that the term "about" or "approximately" precedes the first numerical value in the series.

the term "at least" or "greater than" applies to each numerical value in a series of two or more numerical values provided that the term "at least" or "greater than" precedes the first numerical value in the series.

The term "not more than" or "less than" applies to each numerical value in a series of two or more numerical values provided that the term "not more than" or "more than" precedes the first numerical value in the series.

The term "antioxidant" includes, but is not limited to, substances that inhibit the oxidation of other substances, substances that prevent the deterioration of other substances by oxidation, and scavengers of free radical species, reactive oxygen species, hydroxyl radical species, and oxidized lipids and lipid peroxidation products.

The term "apolipoprotein mimetic" encompasses apolipoprotein peptide mimetics and apolipoprotein mimetic peptides.

The term "conservative substitution" refers to the substitution of an amino acid in a polypeptide with a natural or unnatural amino acid that is functionally, structurally or chemically similar. In certain embodiments, the following groups comprise natural amino acids that are conservative substitutions for one another:

1) Glycine (G), alanine (a);

2) Aspartic acid (D), glutamic acid (E);

3) Asparagine (N), glutamine (Q);

4) Arginine (R), lysine (K);

5) Isoleucine (I), leucine (L), methionine (M), valine (V), alanine (a);

6) Phenylalanine (F), tyrosine (Y), tryptophan (W); and

7) Serine (S), threonine (T), cysteine (C).

In other embodiments, the amino acids may be grouped as follows:

1) Hydrophobicity: met (M), Ala (A), Val (V), Leu (L), lie (I), Phe (F), Trp (W);

2) Neutral hydrophilicity: cys (C), Ser (S), Thr (T), Asn (N), Gln (Q);

3) Acidity: asp (D), Glu (E);

4) Alkalinity: his (H), Lys (K), Arg (R);

5) Residues affecting the backbone orientation: gly (G), Pro (P); and

6) Aromatic: trp (W), Tyr (Y), Phe (F), His (H).

In a further embodiment, the following groups comprise natural amino acids that are conservative substitutions for one another:

1) Acidity: asp, Glu;

2) alkalinity: lys, Arg, His;

3) Uncharged polarity: gly, Ser, Thr, Cys, Tyr, Asn, Gin;

4) Aliphatic hydroxyl group-containing or mercapto group-containing: ser, Thr, Cys;

5) An amide-containing compound: asn, Gin;

6) Non-polar: ala, Val, Leu, lie, Met, Pro, Phe, Trp;

7) Hydrophobicity: val, Leu, lie, Phe;

8) aliphatic: ala, Val, Leu, IIe;

9) Aromatic: phe, Trp, Tyr, His; and

10) Small: gly, Ala, Ser, Cys.

The term "pharmaceutically acceptable" means that a substance (e.g., an active ingredient or excipient) that is suitable for use in contact with the tissues and organs of a subject without undue irritation, allergic response, immunogenicity, and toxicity, has a reasonable benefit/risk ratio commensurate therewith, and is effective for its intended use. The "pharmaceutically acceptable" carrier or excipient of the pharmaceutical composition is also compatible with the other ingredients of the composition.

The term "therapeutically effective amount" refers to an amount of a substance that, when administered to a subject, is sufficient to prevent, reduce the risk of developing, delay the onset of, or slow the progression of a medical condition to be treated (e.g., age-related macular degeneration [ AMD ]), or alleviate one or more symptoms or complications of the condition to some extent. The term "therapeutically effective amount" also refers to an amount of a substance sufficient to elicit the biological or medical response of a cell, tissue, organ, system, animal or human that is being sought by a researcher, veterinarian, medical doctor or clinician.

The terms "treat," "treating," and "treatment" include reducing or eliminating a medical condition or one or more symptoms or complications associated with the condition, as well as reducing or eliminating one or more causes of the condition. References to "treatment" of a medical condition (e.g., AMD) include preventing (excluding) the condition or one or more symptoms or complications associated with the condition, reducing the risk of developing the condition or one or more symptoms or complications associated with the condition, delaying the onset of the condition or one or more symptoms or complications associated with the condition, and slowing the progression of the condition or one or more symptoms or complications associated with the condition.

The term "subject" refers to an animal, including mammals, such as primates (e.g., humans, chimpanzees, or monkeys), rodents (e.g., rats, mice, gerbils, or hamsters), rabbits (e.g., rabbits), pigs (e.g., pigs), horses (e.g., horses), canines (e.g., dogs), and cats (e.g., cats). For e.g. mammalian subjects (e.g. human subjects), the terms "subject" and "patient" are used interchangeably herein.

Pathogenesis and pathophysiology of AMD

age-related retinal and choroidal changes progress to age-related macular degeneration (AMD), which includes loss of rod photoreceptors, thinning of the choroid, and accumulation of: lipofuscin in retinal pigment epithelial cells (RPEs) and lipids reported as a component thereof (e.g., A2E [ N-retinylidene-N-retinyl-ethanolamine ]), as well as in the sub-basal RPE (sub-RPE-BL) space and bruch's membrane (BrM, which is part of the choroid). Lipoprotein particles and the reported beta-amyloid (a β) aggregate on BrM to form basal linear deposits (BLinD). BLinD and drusen are thought to develop from the lipid wall formed at BrM. Chronic inflammation is stimulated by the accumulation of lipid walls and abnormal deposits that result, in part, in abnormalities in the proteolytic process that regulates BrM. Abnormal aggregation of material is accompanied by loss of normal extracellular matrix (ECM) maintenance (mediated in part by altered ratios of matrix metalloproteases [ MMPs ] and MMP tissue inhibitors [ TIMPs ]), resulting in BrM changes with concomitant BLinD formation and drusen formation. Drusen are extracellular deposits rich in lipids (e.g., esterified cholesterol [ EC ] and phospholipids) and lipoprotein components (e.g., apolipoprotein B [ apoB ] and/or apoE) and form in the sub-RPE-BL space between the inner collagen layers of RPE-BL and BrM, possibly due to the secretion of Very Low Density Lipoproteins (VLDL) rich in EC by RPE outside the substrate. Esterified cholesterol and phospholipids (in the form of lipoprotein particles of 60-80nm diameter) accumulate throughout adulthood in BrM and eventually accumulate as BLinD at BrM or soft drusen in the sub-RPE-BL space of the older eye. Drusen and BLinD are two forms of the same lesion containing lipoprotein-derived debris (lumps and lamellae, respectively). BrM retain EC-rich, apoB/apoE-containing lipoproteins (e.g., VLDL) secreted by RPE cells, the BrM becoming progressively thicker with age until an oily layer forms on BrM, with lipid oxidation or other modification followed by fusion of the individual lipoproteins to form BLinD over time. Inflammation occurs and BrM is altered by subsequent calcification and rupture, and the accumulation of lipid-containing material leads to neovascularization in the sub-RPE-BL space and breakthrough into the subretinal space, the latent space between the photoreceptors and the RPE. In addition, drusen rich in lipids and BLinD covering BrM in the sub-RPE-BL space block nutrients (including vitamin a) from reaching the photoreceptors (rods and cones) in the retina, causing them to atrophy/regress and eventually die. Other extracellular pathologies associated with AMD include Subretinal Drusen Deposits (SDD), which are compositionally distinct from drusen, contain unesterified (free) cholesterol (UC) and form between the RPE and photoreceptors, possibly due to UC-rich lipoproteins secreted by the RPE at the top. SDD formed in the subretinal space may also lead to sequelae such as inflammation and neovascularization (e.g., type 2 or type 3).

FIG. 1 illustrates the role of tissue layers and lipid accumulation involved in AMD pathology in the pathogenesis of AMD. BrM is composed of three layers: an Inner Collagen Layer (ICL), an Elastic Layer (EL) and an Outer Collagen Layer (OCL). In a healthy eye, the RPE basal layer (RPE-BL) adheres to the ICL of BrM, and there is no space between the RPE-BL and the ICL (the sub-RPE-BL space is the "potential" space). Throughout adulthood, RPE cells divide lipoprotein particles at basal levels (circles in fig. 1), which are dispersed in the ICL and OCL of BrM (leftmost panels in fig. 1). As more lipoprotein particles were secreted and accumulated over the years, they formed pre-BLinD on BrM, a tightly packed ICL (second from left in fig. 1). Over the years secretion and accumulation of more lipoprotein particles resulted in aggregation of lipoprotein particles to form BLinD (lamellar) and soft drusen (bumps) on BrM ICL (two middle panels in fig. 1). The formation of pre-BLinD creates a space between RPE-BL and BrM ICL (sub-RPE-BL space) that increases with the formation of BLinD and soft drusen and the formation of larger amounts. Accumulation of lipid deposits (BLinD and soft drusen) elevates the RPE from BrM ICL (second panel from right in FIG. 1), and if the elevation (sub-RPE-BL space) is sufficient, the RPE-BL can detach from BrM ICL. For example, drusen-like Pigment Epithelial Detachment (PED) can occur due to the formation of soft drusen having a diameter of about 350 microns or greater. As drusen grow, RPE cells become increasingly distant from nutrients and oxygen in the choroidal capillaries. Some of the RPE cells at the top of drusen migrate forward into the sensory neural retina looking for retinal vasculature and the RPE layer ruptures when the RPE cells die, causing the RPE layer to atrophy. In addition, the lipid barrier created by BLinD and soft drusen blocks the exchange of nutrients (including vitamin a) into and waste products out of the choroidal capillaries and RPE cells, which causes the RPE cells to atrophy and then die. Atrophy and death of RPE cells also leads to atrophy and death of photoreceptors, as RPE cells are no longer able to transfer nutrients to photoreceptors. In addition, BLinD on BrM and soft drusen in the sub-RPE-BL space are lipid rich sources that can be oxidized to form oxidized lipids (e.g., oxidized phospholipids) that are highly anti-inflammatory and thus pro-angiogenic. The biomechanically fragile cleavage plane created by BLinD and soft drusen is easily affected by the branching of neovasculature that emanates from the choroid, passes BrM, and infiltrates the sub-RPE-BL space in type 1 Neovascularization (NV) and breaks through to the subretinal space in type 2 NV, as described below. Fluid seepage from the neovasculature in NV types 1 and 2 into the sub-RPE-BL space further causes the volume of the sub-RPE-BL space and elevation of the RPE from BrM and can thereby result in PED.

Chronic inflammatory responses to the above changes include complement-mediated pathways, infiltration by circulating macrophages, and activation of inflammasome and microglia. Activation of the complement cascade results in activation of central component 3(C3) and initiation of the terminal pathway, with component 5(C5) being broken down into C5a and C5 b. The terminal pathway results in the assembly of the Membrane Attack Complex (MAC), for example, in the basal RPE membrane, BrM or choroidal endothelial cell membrane, pores are formed in the lipid bilayer of the membrane by the stepwise association of C5b, C6, C7, C8 and polymerized C9. MAC can lead to dysfunction and death of the RPE, BrM and/or choriocapillaris endothelium, followed by atrophy of the outer retina. In addition, C5a causes a pro-angiogenic effect and, in combination with calcification and rupture of BrM, can cause NV (including choroidal NV (cnv)).

Early stages of AMD, which is atrophic AMD, are characterized by the presence of small amounts of medium-sized drusen and pigmentary abnormalities (e.g., hyperpigmentation or hypopigmentation of the RPE). The intermediate stage of AMD, which is atrophic AMD, is characterized by the presence of at least one large lens, multiple medium-sized drusen, hyperpigmentation or hypopigmentation of the RPE, and Geographic Atrophy (GA) (non-central [ or paracentral ] GA) that does not extend to the center of the macula. GA represents the absence of a continuous colored layer and at least a portion of the RPE cells die. The non-central GA does not hurt the fovea and thus central vision is preserved. However, patients with non-central GA may experience visual disturbances (e.g. a lateral central scotoma) which can impair vision in dim light, reduce contrast sensitivity and impair reading ability. sub-RPE-BL drusen elevate RPE from BrM and thus can cause mild vision loss (including metamorphosis (visual defect, where objects appear distorted)) by interfering with overlapping photoreceptors and slowing down rod-mediated dark adaptation.

The advanced (late) stage of AMD, which remains atrophic AMD, is characterized by the presence of drusen and GA extending to the center of the macula (central GA). Central GA includes macular atrophy. The central GA is involved in the fovea and thus causes a significant loss of central vision and visual acuity. RPE, under retinal atrophy, leads to vision loss through death of photoreceptors. When drusen thicken and the RPE is distant from the choroidal capillaries, RPE atrophy can be caused by a large accumulation of drusen and/or BLinD that results in the death of overlapping RPEs. Drusen may include calcifications in the form of hydroxyapatite and may progress to full calcification, at which stage RPE cells have died. RPE-BL thickens in a fixed manner to form a basal lamellar deposit (BLAmd); RPE cells are therefore located on a thick layer of BLamD. The connections between normal hexagonal RPE cells may be disturbed and individual RPE cells may bunch up, stack up and migrate anteriorly into the sensory nerve retina, where the RPE cells are distant from their nutrient and oxygen supply on the choroidal capillaries. Once RPE cells begin to move forward, the entire RPE layer begins to shrink.

AMD, which becomes the advanced stage of neovascular AMD, is characterized by neovascularization and any potential sequelae thereof, including leakage (e.g., plasma), plasma lipid and lipoprotein deposits, sub-RPE-BL, subretinal and intraretinal fluid, hemorrhage, fibrin, fibrovascular scarring, and RPE detachment. In CNV, new blood vessels grow out of the choriocapillaris and through BrM, which leads to loss of vision through the above mentioned sequelae. There are three types of Neovascularization (NV). Type 1 NV occurs in the sub-RPE-BL space and new blood vessels emanate from the choroid below the macular region. Type 2 NV occurs in the subretinal space above the RPE, and new blood vessels emanate from the choroid and break through to the subretinal space. In both type 1 and type 2 NV, new blood vessels pass through BrM and can branch in the pro-angiogenic cleavage plane created by soft drusen and BLind. NV type 3 (retinal hemangioma hyperplasia) occurs primarily within the retina (within the retina), but can also occur in the subretinal space, and new blood vessels that may coincide with the choroidal circulation emanate from the retina. NV type 3 is the most difficult subtype to diagnose and has the most devastating consequences in terms of photoreceptor damage, but NV type 3 responds well to treatment with anti-VEGF agents. Neovascular AMD patients may also have mixed subtypes of NV, including type 1 plus type 2, type 1 plus type 3, and type 2 plus type 3. The different subtypes of NV in emerging neovascular AMD patients occur roughly as: 40% of type 1, 9% of type 2, 34% of type 3 and 17% of mixed type (for mixed type, 80% of type 1 plus type 2, 16% of type 1 plus type 3 and 4% of type 2 plus type 3). Another form of NV is polypoid vasculopathy, which originates in the choroid and is the most common form of NV in asians, whose eyes usually have few drusen but may have BLinD. In each subtype of NV, RPE can be separated from BrM. For example, leakage of fluid from the neovasculature into the sub-RPE-BL space in type 1 NV can lead to pigment epithelial detachment. The new blood vessels created by NV are fragile, leading to leakage of fluid, blood, and proteins under the macula. Leakage of blood into the subretinal space is particularly detrimental to the photoreceptors, while fluid within the retina represents a poor prognosis of vision. Neovascular bleeding and leakage, followed by fibrosis, if left untreated, can cause irreversible damage to the retina and result in rapid loss of vision.

Modified lipids, including peroxidized lipids, can be strongly pro-inflammatory and thus pro-angiogenic. Thus, modification of lipids (including oxidation) can be an important step leading to the development of NV (including type 1 NV). For example, modified lipids, linoleic acid hydroperoxide and 7-keto cholesterol, may be present in BrM and on BrM and may stimulate NV. NV can be considered as the wound healing process following inflammation.

Both eyes of patients with AMD, whether atrophic or neovascular, are often diseased. However, one of the eyes is typically in a more severe disease state than the other eye.

See, e.g., r.jager et al, n.engl.j.med.,358: 2606-. Age-related eye disease research (AREDS) research group also developed an ophthalmography severity scale for AMD. See, for example, m.davis et al, arch.ophthalmol.,123: 1484-.

For a discussion of The pathogenesis and pathophysiology of AMD, see, e.g., c.a. currio et al, The oil spill in forming Bruch membrane, br.j. ophthalmol.,95(12): 1638-; miller, Age-Related molecular differentiation-modifying the nozzle, am.J. Ophthalmol, 155(1):1-35 (2013); spaide et al, chord neovascularization in age-related macrodepletion-while is the house? Retina,23:595-614 (2003); and S.Bressler et al, Age-Related modular differentiation, Non-neovasular Early AMD, mediate AMD, and Geographic opacity, in Retina, S.Ryan et al, eds., pp.1150-1182, Elsevier (London 2013).

Apolipoprotein mimetics

as noted above, age-related macular degeneration (AMD) is a disease or disorder with a variety of underlying factors. Three major factors of AMD are the formation of lipid-rich deposits in the retina, subretinal space, sub-RPE-BL space and BrM, inflammation and neovascularization. The formation of lipid-containing deposits is one of the first major factors leading to sequelae such as chronic inflammation, non-central and/or central pattern atrophy (GA) of the retina, neovascularization (including CNV), and ultimately loss of central vision or legal blindness. Lipid-scavenging apolipoprotein mimics are useful for treating AMD and its complications, which mimics also have other beneficial properties, such as anti-inflammatory, antioxidant and anti-angiogenic properties.

apolipoprotein peptide mimetics are effective in reducing the accumulation of lipid-rich deposits in the eye. Apolipoprotein (apo) mimetics can modulate (e.g., inhibit) the production of lipoproteins (e.g., VLDL), modulate (e.g., inhibit) cellular uptake of plasma lipids (e.g., cholesterol) and lipoproteins (e.g., VLDL), mediate the clearance or clearance of lipids (e.g., cholesterol and oxidized lipids, such as hydroxysteroids) and lipoproteins (e.g., VLDL) and residues thereof (e.g., low density lipoprotein [ LDL ] and chylomicron residues), and inhibit the formation of lipid-containing lesions. For example, apoE mimetics increase lipid (e.g., cholesterol) efflux, mediate clearance of lipids (e.g., cholesterol) and lipoproteins (e.g., VLDL and chylomicrons), reduce cholesterol and triglyceride levels, reduce the formation of lipid-containing lesions, and have antioxidant and anti-inflammatory properties. As another example, the apoA-I mimetic promotes lipid (e.g., cholesterol) efflux, reduces the formation of lipid-containing lesions (in the eye and intima of arteries), and exhibits antioxidant and anti-inflammatory properties. As another example, the apoA-V mimetic reduces VLDL-Triglyceride (TG) production and stimulates lipoprotein lipase mediated lipolysis of VLDL-TG. As an additional example, the apoC-II mimetic increases lipid (e.g., cholesterol) efflux and activates lipoprotein lipase-mediated lipolysis. The beneficial effect of increased lipoprotein lipase mediated lipolysis may be, for example, reducing the tissue availability of dietary derived lipids, which may affect the upstream source of RPE derived lipoproteins secreted into BrM, the sub-RPE-BL space and the subretinal space.

as an illustrative example, apoA-I mimetics (e.g., those described herein) (e.g., L-4F and D-4F) can solubilize, mobilize, and remove extracellular and potential intracellular lipid deposits that accumulate in the eye. For example, L-4F and D-4F may be able to remove intracellular lipids through LDL-receptors by forming pre- β HDL particles. BrM, which act as a diffusion barrier between the RPE and the choroidal capillaries, promote the formation of basal linear deposits (BLinD) and soft drusen, and are implicated in local inflammation and oxidative stress.

The ApoA-I mimetic (e.g., L-4F) can clear lipid deposits in BrM, thereby remodeling the BrM structure to a normal or healthier state and restoring BrM function, including reducing hydraulic resistance (hydraulic resistance) and increasing the exchange of metabolites and micronutrients between choroidal capillaries and RPE, to improve the health of RPE. In addition, apoA-I mimetics (e.g., L-4F) can promote clearance of lipid, lipoprotein, and lipoprotein components through BrM into the choroidal capillaries and the systemic circulation, and ultimately lead to the liver for its metabolism and excretion into the bile. In addition, the apoA-I mimetic (e.g., L-4F) can reduce local inflammation and oxidative stress by, for example, cleaning lipid deposits from BrM, BLinD, and soft drusen. In addition, apoA-I mimetics (e.g., L-4F) can protect phospholipids from oxidation by, for example, binding a seeding molecule, the seeding molecules are required for the formation of pro-inflammatory oxidized phospholipids such as Ox-PAPC (PAPC is L- α -1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine), POVPC (1-palmitoyl-2- [ 5-oxovaleryl ] -sn-glycero-3-phosphocholine), PGPC (1-palmitoyl-2-glutaryl-sn-glycero-3-phosphocholine) and PEIPC (1-palmitoyl-2- [5, 6-epoxyisopropane E2] -sn-glycero-3-phosphocholine). ApoA-I mimetics (e.g., L-4F) may also have a high affinity for pro-inflammatory oxidized lipids and mediate their removal, which increases the high anti-inflammatory potential of the mimetics. Most AMD-associated lipid deposits are extracellular and suitable for cleaning lipid apoA-I mimics. Thus, the apoA-I mimetic (e.g., L-4F) may be used at any stage of AMD (including early to late stages of AMD) to treat important upstream factors of AMD-accumulation of lipid deposits (such as Blind on BrM and soft drusen in the sub-RPE-BL space) -and to inhibit or reduce downstream factors of AMD (e.g., local inflammation and oxidative stress) by removing these deposits.

in some embodiments, the apolipoprotein mimetic comprises an amphipathic helical domain of an apolipoprotein that binds/associates with a lipid and is capable of removing/cleansing lipids. In certain embodiments, the lipid-binding amphipathic helical domain of the apolipoprotein comprises:

1) A sequence of about amino acids (aa)209 to about aa 219, a sequence of about aa 220 to about aa 241, and a sequence of about aa 209 to about aa 241 of wild type (wt) human apoA-I;

2) wt human apoA-II of sequence from about aa 39 or 40 to about aa 50, from about aa 51 to about aa 71 or 77, from about aa 39 or 40 to about aa 71, and from about aa 39 or 40 to about aa 77;

3) wt human apoC-I of sequence from about aa 7 to about aa 32, sequence from about aa 33 to about aa 53, and sequence from about aa 7 to about aa 53;

4) A sequence of about aa43 to about aa55 of wt human apoC-II;

5) a sequence of about aa40 to about aa67 of wt human apoC-III; and

6) wt human apoE from about aa203 to about aa 266.

In a further embodiment, the apolipoprotein mimetic includes polypeptides (including fusion proteins and chimeras) comprising such a lipid-binding amphipathic helical domain of an apolipoprotein or variant thereof.

Non-limiting examples of apoA-I mimetics include 2F, 3F-1, 3F-2, 3F-14, 4F (e.g., L-4F and D-4F), 4F2, 5A, 5F, 6F, 7F, 18F, 37pA, 4F-P-4F, 4F-IHS-4F, ELK-2K2A2E (or ELK-2A2K2E), FAMP (Fuga apoA-I mimetic), FREL, KRES, apoJ (113-,

CGVLESFKASFLSALEEWTKKLQ-NH2 (monomers, dimers and trimers) (SEQ. ID. NO.1),

DWLKAFYDKVAEKLKE (monomers, dimers and trimers) (SEQ. ID. NO.2),

DWFKAFYDKVAEKFKE (monomers, dimers and trimers) (SEQ. ID. NO.3),

DWFKAFYDKVAEKFKEAF (4F) (monomers, dimers and trimers) (SEQ. ID. NO.4),

DWLKAFYDKVAEKLKEAFPDWLKAFYDKVAEKLKEAF (SEQ. ID. NO.5), DWLKAFYDKVAEKLKEFFPDWLKAFYDKVAEKLKEFF (SEQ. ID. NO.6), DWFKAFYDKVAEKLKEAFPDWFKAFYDKVAEKLKEAF (SEQ. ID. NO.7), DKLKAFYDKVFEWAKEAFPDKLKAFYDKVFEWLKEAF (SEQ. ID. NO.8), DKWKAVYDKFAEAFKEFLPDKWKAVYDKFAEAFKEFL (SEQ. ID. NO.9), DWFKAFYDKVAEKFKEAFPDWFKAFYDKVAEKFKEAF (4F-P-4F) (SEQ. ID. NO.10), and

The corresponding apoA-I mimetics have one or more or all D-amino acids (e.g., D-4F with all D-amino acids) and/or an amino acid sequence in reverse order (e.g., Rev-L-4F and REV-D-4F).

Non-limiting examples of apoE mimetics include Ac-hE18A-NH2(AEM-28) (two-domain [ apoE and apoA-I ] mimetics), Ac- [ R ] hE18A-NH2, AEM-28-14, mR18L, ATI-5261, COG-1410, apoE (130-149) monomers and dimers (including N-acetylated dimers), and apoE (141-155) monomers and dimers (including N-acetylated dimers). Examples of apoC-II mimetics include, but are not limited to, C-II-a.

the present disclosure includes the following apolipoprotein peptide mimetics:

1) apo mimetics in which all amino acid residues have L-type stereochemistry;

2) an apo mimetic in which one or more or all of the amino acid residues have stereochemistry in D-form;

3) an apo mimetic having an amino acid sequence in reverse order and in which all amino acid residues have L-type stereochemistry;

4) an apo mimetic having an amino acid sequence in reverse order and in which one or more or all of the amino acid residues have stereochemistry in D-form; and

5) Multimers of apo mimetics (including dimers and trimers) in which two or more apo mimetic units are linked to each other directly or indirectly, e.g., through a linker or spacer group containing one or more amino acid residues or a group having multiple (e.g., two, three, or more) points of attachment.

The apolipoprotein mimetics described herein may have protecting groups at the N-terminus and/or the C-terminus. In some embodiments, the apo mimetics have an N-terminal protecting group that is an unsubstituted or substituted C2-C10 acyl group (e.g., acetyl, propionyl, butyryl, pentanoyl, or hexanoyl), an unsubstituted or substituted benzoyl group, a benzyloxycarbonyl group, or one or two unsubstituted or substituted C1-C20 or C2-C20 alkyl groups (e.g., one or two methyl, ethyl, propyl, butyl, pentyl, or hexyl groups). In addition, the apo mimetics can have a functional group other than-CO 2H at the C-terminus (e.g., C (o) NH2 or-C (o) NR1R2 amido where R1 and R2 are independently hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, or R1 and R2 and the nitrogen atom to which they are attached form a heterocyclic or heteroaryl ring). The amide group at the C-terminus can be considered to be a protecting group at the C-terminus. Thus, the present invention includes apo mimetics having, for example: having both an N-terminal acetyl group and a C-terminal-C (O) NH2 group.

the present disclosure also encompasses variants of the apolipoprotein mimetics described herein, wherein the variants of the apolipoprotein mimetics may comprise one or more amino acid additions/insertions, deletions and/or substitutions. In other words, the present disclosure includes the following variants: wherein one or more natural and/or unnatural amino acids are added or inserted to any of the apo mimetics described herein, one or more amino acid residues are deleted from any of the apo mimetics described herein, or one or more amino acid residues of any of the apo mimetics described herein are substituted with one or more natural and/or unnatural amino acids (conservative and/or non-conservative substitutions), or any combination or all of the above. An unnatural amino acid can have the same chemical structure as a corresponding natural amino acid but have stereochemistry in the D-form, or it can have a different chemical structure and stereochemistry in the D-form or L-form. Unnatural amino acids can be utilized, for example, to promote alpha-helix formation and/or to increase the stability of the peptide (e.g., against proteolytic degradation). For example, D-4F is resistant to enteropeptidase and is therefore suitable for oral use. Examples of non-natural amino acids include, but are not limited to, proline analogs (e.g., CMePro), phenylalanine analogs [ e.g., Bip2EtMeO, Nal (1), Nal (2), 2FPhe, Tmp, Tic, CMePhe, and CMe2FPhe ], tyrosine analogs (e.g., Dmt and cmeutr), glutamine analogs (e.g., citrulline [ Cit ]), lysine analogs (e.g., homolysine, ornithine [ Orn ], and cmesys), arginine analogs (e.g., homoarginine [ Har ]), C- α -disubstituted amino acids (e.g., Aib, Ac4C, Ac5C, Ac6C, and Deg), and other non-natural amino acids disclosed in US2015/031630 and WO 2014/081872. One or more peptidomimetics may also be used for additions/insertions and/or substitutions. Variants may have protecting groups at the N-terminus and/or C-terminus, such as an acyl group at the N-terminus (e.g., acetyl) and/or an amide group at the C-terminus [ e.g., -C (O) NH2 ]. In some embodiments, the biological or pharmacological activity of a variant of an apo mimetic is enhanced relative to, or substantially similar to (e.g., the relative reduction is no more than about 10%, 20%, or 30%) the biological or pharmacological activity of an apo mimetic having the native amino acid sequence. As a non-limiting example, the invention includes a variant of 4F, designated 4F2, having the sequence DWFKAFYDKV-Aib-EKFKE-Aib-F (seq. id No.11), wherein a11 and a17 are substituted with α -aminoisobutyric acid (Aib). In certain embodiments, 4F2 has the structure Ac-DWFKAFYDKV-Aib-EKFKE-Aib-F-NH2(seq. id No.12), wherein all amino acid residues have the L-form (L-4F2), or one or more or all of the amino acid residues have the D-form.

The variants of apolipoprotein mimetics described herein also include analogues and derivatives of apo mimetics, with alternative or additional further modifications selected from: amino acid additions/insertions, deletions and/or substitutions. As an example, variants of apo mimetics include fusion proteins and chimeras comprising an apolipoprotein-binding amphipathic helical domain or variant thereof (e.g., 4F) linked directly or indirectly (e.g., via a linker) to a heterologous peptide. Heterologous peptides may confer beneficial properties, such as increased half-life. For example, the heterologous peptide can be an Fc domain of an immunoglobulin (e.g., an IgG, such as IgG1), or a modified Fc domain of an immunoglobulin, having, for example, one or more amino acid substitutions or mutations that alter (e.g., reduce) effector functions of the Fc domain. The Fc domain may be modified to have a reduced ability to, for example, bind Fc receptors, activate the complement system, stimulate phagocyte attack, or interfere with the physiological metabolism or function of retinal cells, or any combination or all thereof. The inclusion of an Fc domain in a fusion protein or chimera may allow dimerization of the fusion protein or chimera (e.g., by forming intermolecular disulfide bonds between the two Fc domains), which may enhance the biological or pharmacological activity of the fusion protein or chimera. Alternatively, the lifetime enhancing heterologous peptide may be, for example, a Carboxy Terminal Peptide (CTP) derived from the beta chain of human chorionic gonadotropin, such as CTP-001, CTP-002 or CTP-003 as disclosed in WO 2014/159813. As another example, an apo mimetic (e.g., an apoA-I mimetic (e.g., L-4F) or an apoE mimetic (e.g., AEM-28-14)) can be attached directly or indirectly (e.g., via a linker) to a natural or synthetic polymer (e.g., polyethylene glycol [ PEG ]) at the N-terminus, C-terminus, and/or one or more side chains. PEGylation of apo mimetics (having, for example, about 2-20 or 2-10 PEG units) can increase protease resistance, stability, and half-life, reduce aggregation, increase solubility, and enhance the activity of the apo mimetics. As another example, the apo mimetics can be glycosylated (containing carbohydrate or sugar moieties), such as apoC-III mimetics containing one or more sialic acid residues. As yet another example, the apo mimetic can be phosphorylated. As another example, apo mimetics can be complexed with phospholipids (e.g., L-4F complexed with DMPC [1, 2-dimyristoyl-sn-glycero-3-phosphocholine ] or POPC [ 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine ])).

In addition to or as an alternative to the use of apolipoprotein mimics, substances that increase the level of apolipoprotein (e.g., apoE, apoA-I, apoA-V or apoC-II), e.g., by stimulating its production, may be used. For example, in addition to or as an alternative to using an apoA-I mimetic, a substance that increases apoA-I levels (e.g., 1, 2-dimyristoyl- α -glycero-3-phosphocholine [ DMPC ]) can be administered.

Apolipoprotein peptide mimetics or apolipoprotein mimetic peptides can be prepared according to methods known to those skilled in the art. By way of non-limiting example, apo mimetics and salts thereof can be prepared by sequentially condensing a protected amino acid on a suitable resin support and removing the protecting group, removing the resin support, and purifying the product by methods known in the art. Solid phase synthesis of peptides and salts thereof can be promoted by using, for example, microwaves, and can be automated by using a commercially available peptide synthesizer. Solid phase synthesis of peptides and salts thereof is described, for example, in j.m. palomo, rscadv.,4: 32658-; M.Amblard et al, Biotechnol.,33(3): 239-; and m.stawikowski and g.b.fields, curr.protoc.protein sci., Unit 18.1: Introduction to Peptide Synthesis (2012). Protecting Groups suitable for use in the Synthesis of peptides and salts thereof are described, for example, in P.Wuts and T.Greene, Greene's Protective Groups in Organic Synthesis,4th Ed., John Wiley and Sons (New York 2006). Methods for purifying peptides and salts thereof include, but are not limited to, crystallization, column (e.g., silica gel) chromatography, high pressure liquid chromatography (including reverse phase HPLC), hydrophobic adsorption chromatography, silica gel adsorption chromatography, partition chromatography, supercritical fluid chromatography, reverse flow distribution, ion exchange chromatography, and ion exchange using basic and acidic resins.

Treatment of AMD with apolipoprotein mimics

some embodiments of the present disclosure relate to methods of treating age-related macular degeneration (AMD), comprising administering to a subject in need of treatment a therapeutically effective amount of an apolipoprotein (apo) mimetic. In some embodiments, the apo mimetic is administered to the ocular region, intraocular, ocular, or periocular at a dose of about 0.1 or 0.3mg to about 1.5mg per administration (e.g., per injection), or a total dose of about 0.5 or 1mg to about 10mg over a period of about 6 months.

The apo mimetics are used in substantially pure form. In certain embodiments, the apo mimetics have a purity of at least about 90%, 95%, 96%, 97%, 98%, or 99% (e.g., at least about 95%, or 98%). The apo mimetics can be purified, i.e., substantially free of undesirable chemical or biochemical components resulting from their preparation or isolation, which are not suitable for use in a pharmaceutical formulation, or have a sufficiently low level of such undesirable chemical or biochemical components so as not to hinder the use of the apo mimetics in a pharmaceutical formulation.

Non-limiting examples of apolipoprotein mimics include apoA-I mimics and apoE mimics, including those described elsewhere herein. In some embodiments, the apo mimetic comprises an apoE mimetic, or is an apoE mimetic. In certain embodiments, the apoE mimetic includes AEM-28-14 or a variant or salt thereof, or is AEM-28-14 or a variant or salt thereof.

In a further embodiment, the apo mimetic includes or is an apoA-I mimetic that is either an alternative to an apoE mimetic (e.g., AEM-28-14) or in addition to an apoE mimetic (e.g., AEM-28-14). In certain embodiments, the apoA-I mimetic includes 4F or a variant or salt thereof (e.g., acetate), or is 4F or a variant or salt thereof (e.g., acetate). In some embodiments, all of the amino acid residues of 4F have L-type stereochemistry (L-4F). In other embodiments, one or more or all of the amino acid residues of 4F have D-form stereochemistry (e.g., D-4F with all D-form amino acids). In other embodiments, the apo mimetics have the 4F amino acid sequence in reverse order (e.g., Rev-L-4F or Rev-D-4F). The apo mimetics can have a protecting group at the N-terminus and/or C-terminus, such as an N-terminal acyl group (e.g., acetyl) and/or a C-terminal amide group (e.g., -C (O) NH 2). In certain embodiments, the apo mimetics include L-4F having the structure Ac-DWFKAFYDKVAEKFKEAF-NH2(SEQ. ID. NO.13), or L-4F having the structure Ac-DWFKAFYDKVAEKFKEAF-NH2(SEQ. ID. NO. 13). When folded into the appropriate secondary structure, L-4F is an amphipathic α -helix with opposite polarity and hydrophobic faces and mimicking apoA-I, which is the major apolipoprotein of HDL.

The apoA-I mimetic 4F (including L-4F and D-4F) has anti-dyslipidemic properties. For example, L-4F is capable of binding oxidized and unoxidized lipids with greater affinity than apoA-I itself, and reducing lipid deposition, e.g., in the sub-RPE-BL space and on bruch's membrane (BrM). L-4F is a potent lipid receptor and scavenger that removes extracellular lipids (and potentially intracellular lipids) including neutral lipids, esterified cholesterol and phospholipids from, for example, BrM and sub-RPE-BL spaces, thereby improving, for example, BrM structure (e.g., reducing BrM thickness and normalizing BrM layer arrangement) and BrM function (e.g., reducing BrM hydraulic resistivity and increasing metabolite and micronutrient exchange between RPE and choroidal capillaries, including facilitating multi-molecular complexes carrying these nutrients). Extracellular age-related lipid deposits at, for example, BrM form a hydrophobic diffusion barrier that causes oxidative stress and inflammation in, for example, RPE and retina, and removal of such lipid deposits by L-4F reduces such oxidative stress and inflammation.

L-4F has additional beneficial properties. For example, L-4F exhibits strong anti-inflammatory properties, in part because it binds with high affinity to pro-inflammatory oxidized lipids (e.g., oxidized phospholipids) and fatty acid hydroperoxides and their clean-up of such oxidized lipids. L-4F can also enhance the ability of HDL-cholesterol to protect LDL-cholesterol from oxidation, thereby reducing the formation of pro-inflammatory oxidized lipids. Furthermore, L-4F inhibits complement activation and reduces the levels of complement factor D and membrane attack complexes, which may be other causes of its antioxidant and anti-inflammatory properties, and may be caused by its downstream effects of inhibiting lipid deposition. In addition, L-4F has anti-angiogenic properties. The extracellular lipid-rich deposits in the sub-RPE-BL space provide a biomechanically fragile pro-inflammatory environment into which new blood vessels can enter and proliferate unimpeded by the attachment of the RPE basal layer to the remainder of BrM. Removal of such lipid deposits by L-4F may close or substantially reduce such pro-angiogenic cleavage planes.

In studies conducted on the cynomolgus monkey model for early AMD in humans and as described below, L-4F showed the following potent abilities: clearance of neutral lipids and esterified cholesterol, rejuvenation/normalization of BrM, and reduction of downstream effects of lipid deposition (e.g., complement activation and local inflammation). Although phospholipids were not stained in the study, L-4F also appeared to be effective in removing phospholipids, which are the major source of pro-inflammatory oxidized lipids. It is expected that the results of the cynomolgus studies may be translated to all stages and forms of AMD in humans where extracellular lipid deposits play a pathological role, including early, intermediate and advanced AMD, and including atrophic AMD and neovascular AMD. Drusen are rich in esterified cholesterol and phospholipids, both attributed to the core and surface of lipoproteins secreted by RPE, respectively. Furthermore, since the lipoproteins (both native and modified) in drusen are not bound to structural collagen and elastin fibers, unlike the lipoproteins in BrM, the former are more loosely bound than the latter and are therefore easier to remove. Thus, the substantial reduction in esterified cholesterol and lipid deposits from BrM in the macaque study demonstrates the ability of L-4F to effectively reduce soft drusen and clear lipids (including esterified cholesterol) in ocular tissues including BrM. Despite the active protease of RPE, intravitreally injected L-4F readily passed through RPE and reached BrM in the cynomolgus studies and effectively removed lipid deposits from BrM. Removal of lipid deposits in BrM by L-4F normalized the structure and function of BrM. Furthermore, reducing drusen volume by L-4F may reduce RPE layer elevation from BrM and may thereby reduce visual deformans, and may prevent, delay the onset of or slow the progression of non-central or central pattern atrophy and may thereby improve vision. The reduction in human drusen volume can be easily quantified using Spectral Domain Optical Coherence Tomography (SDOCT) and commercially available software.

By reducing lipid deposits, L-4F can maintain or improve the health of RPE and thus can prevent or prevent RPE atrophy (including non-central or central pattern atrophy). As RPE cells continue to secrete lipoproteins, soft drusen and drusen Pigment Epithelial Detachment (PED) develops over time. The RPE layer on drusen and drusen PEDs becomes rough over time and RPE cells migrate out of the RPE layer (where they are further away from the choroidal capillaries than the apex) and onwards into the sensory nerve retina and thus seek oxygen from the retinal circulation. By removing native and modified lipids from drusen, L-4F can prevent forward migration of RPE cells and thereby can bring RPE cells close enough to the choroidal capillaries that the RPE cells are not energetically and metabolically decompensated and therefore do not atrophy. In addition, removal of lipid deposits from BrM improves transport of micronutrients (including vitamin a) between the choroidal capillaries and the RPE and waste excretion. By reducing drusen and removing the lipid deposits in BrM, L-4F can maintain RPE health and prevent RPE atrophy, and thus can retain photoreceptors and vision. The health of drusen overlying the RPE can be monitored by macular SDOCT.

Reduction of lipid deposits had downstream benefits in rhesus monkey studies, including BrM and a substantial reduction in the number of Membrane Attack Complexes (MACs) present in choroidal capillaries. MAC (C5b-9) is the final product of complement system activation and is established in the BrM-choriocapillaris complex from childhood throughout the life of humans. By reducing the level of MAC, L-4F may improve BrM and the health of the choroidal capillary endothelium, and thus may improve the blood supply to the outer retina and the exchange of micronutrients between the choroidal capillaries and the RPE, and may promote clearance of lipoprotein particles secreted by the RPE into the systemic circulation.

in addition, L-4F can prevent or prevent Neovascularization (NV) by removing lipids. Basal linear deposits and soft drusen are the major sources of potentially pro-inflammatory lipids in the sub-RPE-BL space where NV type 1 (the most common type of NV) occurs. As demonstrated in the cynomolgus studies, the removal of native lipids (including esterified cholesterol in lipoprotein deposits) from ocular tissue by L-4F reduces the amount of native lipids available for modification (e.g., peroxidation). Modified lipids (including peroxidized lipids) can be strongly pro-inflammatory and thus can stimulate NV. L-4F may also scavenge any peroxidized lipids and other formed modified lipids. Furthermore, by reducing the size of drusen, L-4F can prevent RPE cells from migrating from nutrient-transporting choroidal capillaries and thereby preventing them from secreting damage-inducing VEGF, which is a potent stimulator of NV. Furthermore, normalization of BrM inhibits choroidal NV by enhancing the natural barrier between choroidal capillaries and sub RPE-BL space due to BrM normalization by removing lipid deposits from BrM by L-4F. Thus, by virtue of its ability to scavenge native lipids and modified (e.g., oxidized) lipids, L-4F together with an angiogenic agent (including intravitreally injected anti-VEGF agents) can prevent or reduce NV (including type 1 NV), and can improve treatment of neovascular AMD, and reduce the burden of treatment.

In some embodiments, the apo mimetic [ e.g., apoA-I mimetic (e.g., L-4F) and/or apoE mimetic (e.g., AEM-28-14) ] is administered topically at a dose of about 0.1-0.5mg, 0.5-1mg, or 1-1.5mg per administration (e.g., per injection). In further embodiments, the apo mimetic [ e.g., apoA-I mimetic (e.g., L-4F) and/or apoE mimetic (e.g., AEM-28-14) ] is administered topically at a dose of about 0.1-0.3mg, 0.3-0.5mg, 0.5-0.75mg, 0.75-1mg, 1-1.25mg, or 1.25-1.5mg per administration (e.g., per injection). The apo mimetic can also be administered topically at a dose greater than 1.5mg per administration (e.g., per injection), such as up to about 2mg per administration (e.g., per injection) or more. In certain embodiments, an apo mimetic [ e.g., an apoA-I mimetic (e.g., L-4F) and/or an apoE mimetic (e.g., AEM-28-14) ] is administered topically at a dose of about 0.1-0.5mg or 0.5-1mg per administration (e.g., per injection).

In further embodiments, the apo mimetic [ e.g., apoA-I mimetic (e.g., L-4F) and/or apoE mimetic (e.g., AEM-28-14) ] is administered topically at a total or cumulative dose of about 0.5 or 1-5mg or 5-10mg over a period of about 6 months. In some embodiments, the apo mimetic [ e.g., apoA-I mimetic (e.g., L-4F) and/or apoE mimetic (e.g., AEM-28-14) ] is administered topically at a total or cumulative dose of about 0.5 or 1-3mg, 3-5mg, 5-7.5mg, or 7.5-10mg over a period of about 6 months. The apo mimetics may also be administered topically at a total or cumulative dose of greater than 10mg over a period of about 6 months, for example up to about 15mg or more over a period of about 6 months. In certain embodiments, the apo mimetic [ e.g., apoA-I mimetic (e.g., L-4F) and/or apoE mimetic (e.g., AEM-28-14) ] is administered topically at a total or cumulative dose of about 0.5-3mg or 3-5mg over a period of about 6 months.

In still further embodiments, the apo mimetic [ e.g., apoA-I mimetic (e.g., L-4F) and/or apoE mimetic (e.g., AEM-28-14) ] is administered topically at a total or cumulative dose of about 1 or 2-20mg or 5-15mg for an entire or complete treatment regimen. In certain embodiments, for a complete treatment regimen, the apo mimetic [ e.g., apoA-I mimetic (e.g., L-4F) and/or apoE mimetic (e.g., AEM-28-14) ] is administered topically at a total or cumulative dose of about 1-5mg, 5-10mg, 10-15mg, or 15-20 mg. In some embodiments, for a complete treatment regimen, the apo mimetic [ e.g., apoA-I mimetic (e.g., L-4F) and/or apoE mimetic (e.g., AEM-28-14) ] is administered topically at a total or cumulative dose of about 1-3mg, 3-5mg, 5-7.5mg, 7.5-10mg, 10-12.5mg, 12.5-15mg, 15-17.5mg, or 17.5-20 mg. The apo mimetics can also be administered topically at a total or cumulative dose greater than 20mg for a complete treatment regimen, e.g., up to about 25mg, 30mg, 40mg, 50mg, or more for a complete treatment regimen. In certain embodiments, for a complete treatment regimen, the apo mimetic [ e.g., apoA-I mimetic (e.g., L-4F) and/or apoE mimetic (e.g., AEM-28-14) ] is administered topically at a total or cumulative dose of about 1-5mg or 5-10 mg.

In some embodiments, the apo mimetic [ e.g., apoA-I mimetic (e.g., L-4F) and/or apoE mimetic (e.g., AEM-28-14) ] is administered topically to the eye, intraocularly, in the eye, or periocularly. In some embodiments, an apo mimetic [ e.g., an apoA-I mimetic (e.g., L-4F) and/or an apoE mimetic (e.g., AEM-28-14) ] is administered by: injection (e.g., intravitreal, subconjunctival, subretinal, or Tenon's subcapsular injection), eye drops, or implants (e.g., intravitreal, intracameral, subretinal, or Tenon's subcapsular implants). In certain embodiments, the apo mimetic [ e.g., apoA-I mimetic (e.g., L-4F) and/or apoE mimetic (e.g., AEM-28-14) ] is administered by injection (e.g., intravitreal, subconjunctival, subretinal, or sub-tenon's capsule injection). Intravitreally injected apo mimetics can readily reach the target site (e.g., sub-RPE-BL space and BrM) from the vitreous cavity. In doing so, the apo mimics may be distributed in different tissue layers of the eye, such as the sensory neuroretina, BrM, and the choroid. The apo mimetic can have a long duration of action (e.g., at least about 2, 3, or 4 weeks or more) by, for example, continuous and slow resupply or "flushing" from the various tissue layers between the inner and outer retinal layers in which the apo mimetic can be distributed. In a further embodiment, the apo mimetic [ e.g., apoA-I mimetic (e.g., L-4F) and/or apoE mimetic (e.g., AEM-28-14) ] is administered by eye drops. In further embodiments, the apo mimetic [ e.g., apo a-I mimetic (e.g., L-4F) and/or apo e mimetic (e.g., AEM-28-14) ] is administered by implanting or injecting a device or material, such as a micro-device, a bioabsorbable polymeric material, or a bioabsorbable microparticle or nanoparticle, into, for example, the vitreous chamber, the space under the retina, or the aqueous humor, which device or material delivers the apo mimetic in a controlled and/or sustained manner. In other embodiments, an apo mimetic [ e.g., an apoA-I mimetic (e.g., L-4F) and/or an apoE mimetic (e.g., AEM-28-14) ] is administered by injecting or implanting into the eye: a cell (e.g., an RPE cell containing an expression vector including a gene encoding an apo mimetic) or a viral (e.g., adenoviral or lentiviral) vector containing a gene or expression construct (e.g., a plasmid) expressing an apolipoprotein mimetic. This method of delivery would have the following benefits: only a single injection or implantation of the expression construct encoding the apo mimetic in the eye is required. If two or more apo mimetics [ e.g., an apoA-I mimetic (e.g., L-4F) and an apoE mimetic (e.g., AEM-28-14) ] are used, the same expression construct or different expression constructs can express two or more apo mimetics.

In embodiments where the apo mimetic [ e.g., apoA-I mimetic (e.g., L-4F) and/or apoE mimetic (e.g., AEM-28-14) ] is administered topically, intraocularly, or periocularly, the dose per administration, the total dose over a period of about 6 months, and the total dose of the complete treatment regimen are in certain embodiments for each eye administered, and in other embodiments for both eyes. The blood system may allow for a localized administration (e.g., injection) of an apo mimetic into one eye or some amount (e.g., a therapeutically effective amount) of the apo mimetic in one eye to be distributed to the other eye, in which case the dose of the apo mimetic may be optionally adjusted (e.g., increased) in view of the other eye (which may be in a less diseased condition), and may allow for simultaneous treatment of both eyes with the apo mimetic without additional administration (e.g., injection) of the apo mimetic within or in the other eye. For example, intravitreally injected apo mimetics can move as natural fluid flows from the vitreous humor through the retina and RPE to the choroid and across the blood-retinal barrier (maintained by the retinal vascular endothelium and RPE) to two target regions (sub-RPE-BL space and bruch's membrane), from which they can enter the choroidal capillaries and ultimately to the corresponding non-administered eye. Without being bound by theory, some amount of apo mimetic can enter the corresponding unapplied eye via the aqueous humor pathway, which is drained through the trabecular meshwork and Schlemm's canal (Schlemm's canal) that flows into the blood system. Thus, some embodiments relate to a method of treating AMD, comprising administering to a subject in need of treatment a therapeutically effective amount of an apolipoprotein mimic, wherein the apolipoprotein mimic is administered to the ocular region, in or around the eye in one eye and both eyes are therapeutically effective.

In certain embodiments, an apo mimetic [ e.g., an apoA-I mimetic (e.g., L-4F) and/or an apoE mimetic (e.g., AEM-28-14) ] is administered locally to the eye, intraocularly, in the eye, or periocularly at an early stage of treatment, and then the apo mimetic is administered systemically. As a non-limiting example, the initial administration (e.g., the first one to five administrations) of the apo mimetic can be a local administration by injection (e.g., intravitreal, subconjunctival, subretinal, or sub-tenon's capsule injection), and then the apo mimetic can be administered systemically (e.g., orally, parenterally (e.g., subcutaneously, intramuscularly, or intravenously) or topically (e.g., intranasally or pulmonary)). In other embodiments, the apo mimetic is administered only topically (e.g., by injection, eye drops, or implant). In other embodiments, the apo mimetic is administered systemically only.

in some embodiments, the apo mimetic [ e.g., apoA-I mimetic (e.g., L-4F) and/or apoE mimetic (e.g., AEM-28-14) ] dose concentration is administered, whether locally (e.g., by intravitreal injection) or systemically, at a concentration of about 1,2, 3,4, or 5mg/mL to about 12 or 15 mg/mL. If two or more apo mimetics (e.g., apo A-I mimetics and apoE mimetics) are used, they can be administered in the same formulation or in different formulations. In certain embodiments, the apo mimetic [ e.g., apoA-I mimetic (e.g., L-4F) and/or apoE mimetic (e.g., AEM-28-14) ] is administered (e.g., by intravitreal injection) at a dose concentration of about 1-4mg/mL, 4-8mg/mL, 8-12mg/mL, 1-5mg/mL, 5-10mg/mL, or 10-15 mg/mL. In some embodiments, the apo mimetic [ e.g., apoA-I mimetic (e.g., L-4F) and/or apoE mimetic (e.g., AEM-28-14) ] is administered (e.g., by intravitreal injection) at a dosage concentration of about 1-3mg/mL, 3-5mg/mL, 5-7.5mg/mL, 6-8mg/mL, 7.5-10mg/mL, 10-12.5mg/mL, or 12.5-15 mg/mL. The apo mimetics can also be administered at a dosage concentration of greater than 15mg/mL, e.g., up to about 20mg/mL or more, whether locally (e.g., by intravitreal injection) or systemically. In certain embodiments, an apo mimetic [ e.g., an apoA-I mimetic (e.g., L-4F) and/or an apoE mimetic (e.g., AEM-28-14) ] is administered (e.g., by intravitreal injection) at a dosage concentration of about 1-5mg/mL, 5-10mg/mL, or 6-8 mg/mL.

In further embodiments, the apo mimetic [ e.g., apoA-I mimetic (e.g., L-4F) and/or apoE mimetic (e.g., AEM-28-14) ] is administered topically (e.g., by intravitreal injection) in a dosage volume of about 50-150 μ L or 50-100 μ L. In certain embodiments, the apo mimetic [ e.g., apoA-I mimetic (e.g., L-4F) and/or apoE mimetic (e.g., AEM-28-14) ] is administered locally (e.g., by intravitreal injection) at a dose volume of about 50-75 μ L, 75-100 μ L, 100-. In some embodiments, an apo mimetic [ e.g., an apoA-I mimetic (e.g., L-4F) and/or an apoE mimetic (e.g., AEM-28-14) ] is administered topically (e.g., by intravitreal injection) in a dosage volume of about 50 μ L, 75 μ L, 100 μ L, 125 μ L, or 150 μ L. The apo mimetics can also be administered topically (e.g., by injection into, or around the eye) in a dosage volume of greater than 150 μ L, such as up to about 200 μ L, so long as the volume administered does not significantly increase intraocular pressure. In certain embodiments, an apo mimetic [ e.g., an apoA-I mimetic (e.g., L-4F) and/or an apoE mimetic (e.g., AEM-28-14) ] is administered topically (e.g., by intravitreal injection) in a dose volume of about 100 μ L (0.1 mL).

In further embodiments, the apo mimetic [ e.g., apoA-I mimetic (e.g., L-4F) and/or apoE mimetic (e.g., AEM-28-14) ] is administered topically (e.g., by intravitreal injection) once per month (4 weeks) or every 1.5 months (6 weeks). In other embodiments, the apo mimetic [ e.g., apoA-I mimetic (e.g., L-4F) and/or apoE mimetic (e.g., AEM-28-14) ] is administered topically (e.g., by intravitreal injection) once every 2 months (8 weeks), every 2.5 months (10 weeks), or every 3 months (12 weeks). In other embodiments, the apo mimetic [ e.g., apoA-I mimetic (e.g., L-4F) and/or apoE mimetic (e.g., AEM-28-14) ] is administered topically (e.g., by intravitreal injection or intravitreal implantation) once every 4, 5, or 6 months. In some embodiments, the apo mimetic [ e.g., apoA-I mimetic (e.g., L-4F) and/or apoE mimetic (e.g., AEM-28-14) ] is administered locally (e.g., by intravitreal injection) more frequently and/or at higher doses early in the treatment.

In further embodiments, the number of administrations (e.g., intravitreal injections) of the topical administration of the apo mimetic [ e.g., apoA-I mimetic (e.g., L-4F) and/or apoE mimetic (e.g., AEM-28-14) ] is about 15 or less, 12 or less, 9 or less, 6 or less, or 3 or less in total. In certain embodiments, the number of administrations (e.g., intravitreal injections) of the topical administration of the apo mimetic [ e.g., apoA-I mimetic (e.g., L-4F) and/or apoE mimetic (e.g., AEM-28-14) ] is about 3-6, 6-9, 9-12, or 12-15 total. The apo mimetics may also be administered topically (e.g., intravitreal injection) a total of more than 15 administrations, such as up to about 20 or more administrations (e.g., intravitreal injections). In some embodiments, the number of administrations (e.g., intravitreal injections) of the topical administration of the apo mimetic [ e.g., apoA-I mimetic (e.g., L-4F) and/or apoE mimetic (e.g., AEM-28-14) ] is about 15, 14, 13, 12, 11, or 10 total. In other embodiments, the number of administrations (e.g., intravitreal injections) of the topical administration of the apo mimetic [ e.g., apoA-I mimetic (e.g., L-4F) and/or apoE mimetic (e.g., AEM-28-14) ] is about 9, 8, 7, 6, 5, 4, or 3 total. In certain embodiments, the number of administrations (e.g., intravitreal injections) of the topical administration of the apo mimetic [ e.g., apoA-I mimetic (e.g., L-4F) and/or apoE mimetic (e.g., AEM-28-14) ] is about 3-6 or 7-10 total. In embodiments where the apo mimetic is administered topically, intra-ocularly, in-ocularly, or periocularly, the frequency of administration and the total number of administrations (e.g., injections) is in certain embodiments for each eye administered, and in other embodiments for both eyes, since the apo mimetic may also have a therapeutic effect in the corresponding non-administered eye.

the duration/length of treatment with the apolipoprotein mimic for each dose administered, total dose over a period of about 6 months, total dose of the complete treatment regimen, frequency of administration and total number of administrations can be adjusted as needed and can be selected by the treating physician to minimize the treatment burden and achieve the desired results, such as reducing lipid deposits to a desired level (e.g., the presence of small, medium-sized drusen or the absence of any large drusen) and eliminating or reducing geographic atrophy (non-central or central) to a desired level. In some embodiments, a treatment regimen with an apo mimetic [ e.g., an apoA-I mimetic (e.g., L-4F) and/or an apoE mimetic (e.g., AEM-28-14) ] is for about 24 months or less, 18 months or less, 12 months or less, or 6 months or less. In further embodiments, a treatment regimen with an apo mimetic [ e.g., an apoA-I mimetic (e.g., L-4F) and/or an apoE mimetic (e.g., AEM-28-14) ] is for about 18-24 months, 12-18 months, or 6-12 months. Treatment with apo mimetics may also last longer than 24 months (2 years), e.g., up to about 2.5 years, 3 years, 3.5 years, 4 years, or more. In some embodiments, a treatment regimen with an apo mimetic [ e.g., an apoA-I mimetic (e.g., L-4F) and/or an apoE mimetic (e.g., AEM-28-14) ] is for about 24, 21, 18, 15, 12, 9, or 6 months. In certain embodiments, a treatment regimen with an apo mimetic [ e.g., an apoA-I mimetic (e.g., L-4F) and/or an apoE mimetic (e.g., AEM-28-14) ] is for about 6-12 or 12-24 months.

in some embodiments, an apo mimetic [ e.g., an apoA-I mimetic (e.g., L-4F) and/or an apoE mimetic (e.g., AEM-28-14) ] is administered at least during the advanced (late) stage of AMD. In certain embodiments, an apo mimetic [ e.g., an apoA-I mimetic (e.g., L-4F) and/or an apoE mimetic (e.g., AEM-28-14) ] is administered at least during the advanced stages of AMD to treat or slow the progression of central Geographic Atrophy (GA), and/or to prevent or delay the onset of neovascular AMD. In further embodiments, an apo mimetic [ e.g., an apoA-I mimetic (e.g., L-4F) and/or an apoE mimetic (e.g., AEM-28-14) ] is administered at least during the advanced stages of AMD to treat or slow the progression of neovascular AMD.

In further embodiments, the apo mimetic [ e.g., apoA-I mimetic (e.g., L-4F) and/or apoE mimetic (e.g., AEM-28-14) ] is administered at least during the intermediate stage of AMD. In certain embodiments, an apo mimetic [ e.g., an apoA-I mimetic (e.g., L-4F) and/or an apoE mimetic (e.g., AEM-28-14) ] is administered at least during the intermediate stages of AMD to treat or slow the progression of non-central GA, and/or prevent or delay the onset of central GA and/or neovascular AMD. In a further embodiment, an apo mimetic [ e.g., an apoA-I mimetic (e.g., L-4F) and/or an apoE mimetic (e.g., AEM-28-14) ] is administered at least during the initial stages of intermediate-stage AMD to prevent or delay the onset of non-central GA. Intermediate AMD is characterized by a large number of confluent soft drusen, which primarily include esterified cholesterol and phospholipids. Reduction of confluent soft drusen in intermediate AMD using apo mimetics [ e.g., apoA-I mimetics (e.g., L-4F) and/or apoE mimetics (e.g., AEM-28-14) ] can lead to a reduction in the thickness of bruch's membrane ("thinning") and normalization, as well as restoration of the overlying RPE cell layer due to improved exchange of micronutrients and metabolites between choroidal capillaries and RPE. Reduction of confluent soft drusen can be observed by non-invasive techniques such as Spectral Domain Optical Coherence Tomography (SDOCT).

in a further embodiment, an apo mimetic [ e.g., an apoA-I mimetic (e.g., L-4F) and/or an apoE mimetic (e.g., AEM-28-14) ] is administered at least during the early stages of AMD. The apo mimetic may be administered at an earlier stage of AMD (e.g., an early stage or an intermediate stage) to slow or stop the progression of AMD. In some embodiments, an apo mimetic [ e.g., an apoA-I mimetic (e.g., L-4F) and/or an apoE mimetic (e.g., AEM-28-14) ] is administered at least during the early stages of AMD to prevent or delay the onset of non-central GA. In certain embodiments, the apo mimetic is administered to the eye locally, intraocularly, in the eye, or periocularly (e.g., by intravitreal, subconjunctival, subretinal, or sub-tenon's capsule injection or eye drop) at an early stage of AMD. If the apo mimetic [ e.g., apoA-I mimetic (e.g., L-4F) and/or apoE mimetic (e.g., AEM-28-14) ] is administered locally in an invasive manner (e.g., by intravitreal, subconjunctival, subretinal, or sub-tenon's capsule injections), the apo mimetic can be administered at a lower frequency (e.g., once every 3 or 4 months or 6 months), at a lower total frequency of administration (e.g., about 1,2, or 3 injections), or at a higher dose of administration per injection (e.g., about 0.5-1mg or 1-1.5mg per injection), or any combination or all thereof, to minimize the therapeutic burden. The apo mimetics do not require the elimination or removal of all or most of the abnormal lipid deposits from the eye to have a therapeutic or prophylactic effect on AMD. If a threshold amount of abnormal lipids are cleared from the eye, the natural transport mechanisms (including the flux between the choroidal capillary endothelium and the RPE layer) may again function properly and may clear the residual abnormal lipids in the eye. In addition, lipids slowly accumulate in the eye over several years (although fluctuations in drusen volume over a shorter time frame can be detected). Thus, apo mimetics administered less frequently (e.g., every about 3,4, or 6 months of intravitreal injection) and/or administered less total number of times (e.g., about 1,2, or 3 intravitreal injections) may still have a therapeutic or prophylactic effect on early AMD.

In other embodiments, the apo mimetic [ e.g., apoA-I mimetic (e.g., D-4F) and/or apoE mimetic (e.g., AEM-28-14) ] is administered systemically (e.g., orally or parenterally (e.g., intravenously)) during the early stages of AMD. To increase resistance of the apo mimetic peptide to peptidase/protease, variants of apo mimetics containing one or more or all D-amino acids (e.g., D-4F with all D-amino acid residues) can be administered systemically (or by eye drops, as the ocular surface contains the peptidase/protease). Given its systemic distribution and its potential systemic antilipidemic effects (e.g., reduction or removal of atherosclerotic plaques in the systemic vasculature, which may be the primary target of apo mimetics in the systemic circulation (and thus the visceral areas)), the dose of apo mimetics for systemic administration may be much higher than that for local administration (e.g., by intravitreal injection or eye drops). In certain embodiments, the dose of apo mimetic [ e.g., apoA-I mimetic (e.g., D-4F) and/or apoE mimetic (e.g., AEM-28-14) ] for systemic administration is at least about 50, 100, 200, 300, 400, 500, or 1,000 times (e.g., at least about 100 or 500 times) greater than its locally administered dose. In some embodiments, the dose of apo mimetic [ e.g., apoA-I mimetic (e.g., D-4F) and/or apoE mimetic (e.g., AEM-28-14) ] for systemic administration is at least about 50mg, 100mg, 200mg, 300mg, 400mg, or 500mg per day (e.g., at least about 50mg or 100mg per day if administered intravenously, or at least about 200 or 300mg per day if administered orally)). In further embodiments, the apo mimetic, whether administered systemically (e.g., orally or parenterally (e.g., intravenously)) or topically in a non-invasive manner (e.g., via eye drops), is administered to the eye at an early stage of AMD by the attending physician for a period of time (e.g., at least about 3 months, 6 months, 12 months, 18 months, 24 months, or longer) or until the disease has been successfully treated as a result of the selected measurement criteria (e.g., elimination of all or most soft drusen or reduction in volume to a certain level), once, two or more times per day, once every two days, once every three days, once every week, once every two weeks, or once per month (e.g., once per day or once every two days).

In certain embodiments, the earlier the AMD stage is targeted, the less frequent and/or less frequent the apo mimetic [ e.g., apoA-I mimetic (e.g., L-4F) and/or apoE mimetic (e.g., AEM-28-14) ] is administered (e.g., by intravitreal injection). Higher doses of apo mimetics may also be administered at earlier stages of the AMD stage. In other words, in certain embodiments, the more advanced the AMD stage is targeted or the more severe the condition of AMD, the more frequent (e.g., by intravitreal injection) administration of an apo mimetic [ e.g., an apoA-I mimetic (e.g., L-4F) and/or an apoE mimetic (e.g., AEM-28-14) ] (which can result in more total number of administrations) and/or higher doses (higher doses per administration and/or higher total doses for the complete treatment regimen). By way of non-limiting example, in intermediate and advanced AMD, including atrophic AMD and neovascular AMD, the apo mimetics may be administered more frequently (e.g., once every 4-12 or 4-8 weeks in intermediate AMD, and once every 4-8 or 4-6 weeks in advanced AMD), more total number of injections (e.g., about 4-8 or more injections in intermediate AMD, and about 8-12 injections in advanced AMD), at higher doses per injection (e.g., up to about 1-1.5mg per injection), or at a greater total dose for a complete treatment regimen (e.g., up to about 10-15mg or more in intermediate AMD, up to about 15-20mg or more in advanced AMD), by injection (e.g., intravitreal, subconjunctival, subretinal, or sub-tenon's capsule injection), or any combination or all thereof, to remove from the eye a greater amount of lipid deposits (including drusen and basal linear deposits) including from the sub-RPE-BL space and bruch's membrane.

In early, intermediate and advanced stages of AMD, as well as atrophic AMD and neovascular AMD, progression and treatment of AMD can be monitored using a variety of methods known in the art (referred to herein as "diagnostic" methods for simplicity). These methods include, but are not limited to, structural SDOCT (which displays drusen and RPE and can quantify drusen overall volume and monitor disease progression), hyperspectral autofluorescence (which can detect fluorophores specific to drusen and basal linear deposits), color fundus photography, quantitative fundus autofluorescence (qAF), and OCT-Fluorescein Angiography (FA), and can examine the following parameters: such as cone-mediated vision (e.g., best corrected visual acuity BCVA, which persists to late stage disease), visual acuity examined with ETDRS charts, contrast sensitivity examined with Pelli-Robson charts, low brightness visual acuity measured with neutral density filters to reduce retinal illuminance, and development of visual object deformation), and rod-mediated vision (e.g., dark adaptation kinetics sensitive to measure macular function tracking disease progression). For example, treatment is expected to stabilize or improve photopic (daylight) vision mediated by cone photoreceptors and scotopic (nighttime) vision mediated by rod photoreceptors. As another example, RPE cell health may be assessed with qAF, where stability of qAF intensity or an increase in qAF intensity may indicate stable RPE health or improved RPE health, as a decrease in qAF intensity may indicate regression of RPE cells. qAF can be used to quantify the area or size of geographic atrophy and thereby monitor the progression of non-central GA or central GA, as done in the MAHALO phase II study on lambertizumab. The health of RPE cells can also be assessed with SDOCT, where the presence of a hyperreflective lesion located vertically above drusen within the retina represents migrating RPE cells, indicating that the RPE layer is disintegrating just before the RPE cells and photoreceptors shrink. Poor health of the RPE may be an indicator of poor visual prognosis in atrophic AMD and neovascular AMD. As another example, OCT-FA can detect the presence of sub-RPE-BL, subretinal or intraretinal fluid, which can indicate active neovascularization and leakage of fluid from the neovascularization.

the use of diagnostic methods allows for monitoring and modulating the course of treatment of early, intermediate or advanced AMD, or atrophic AMD or neovascular AMD, with one or more therapeutic agents (e.g., an apo mimetic, an anti-angiogenic agent, or a complement inhibitor, or any combination or all thereof). For example, an apo mimetic [ e.g., an apoA-I mimetic (e.g., L-4F) and/or an apoE mimetic (e.g., AEM-28-14) ] can be administered by injection (e.g., intravitreal, subconjunctival, subretinal, or sub-tenon's capsule injection) for treating early, intermediate, or advanced AMD, or atrophic AMD or neovascular AMD. During the initial phase of treatment, the apo mimetic can be administered at a certain injection frequency and at a certain dose per injection. If one or more diagnostic methods show a significant improvement in the disease after a significant period of treatment, or show stability of the disease (e.g., SDOCT shows a significant reduction in the volume of soft drusen, or shows stability of the volume of soft drusen after a significant period of treatment), the apo mimetic can be injected less frequently and/or at lower doses each time, or the apo mimetic can be injected less frequently and at higher doses each time, thereby administering a substantially similar total dose over a period of time. On the other hand, if one or more of the diagnostic methods shows worsening of the disease or no change in the disease after the initial treatment phase (particularly disease to a more severe form, such as non-central or central pattern atrophy or neovascular AMD) (e.g., SDOCT shows an increase in the volume of soft verrucous, or no change in the volume of soft verrucous, after the initial phase of treatment), the apo mimetic may be injected more frequently and/or at higher doses each time. Treatment with an apo mimetic can be suspended or discontinued if one or more diagnostic methods show significant improvement in the disease (e.g., SDOCT shows elimination of all or most soft drusen). However, if one or more diagnostic methods show disease recurrence after a period of time (e.g., SDOCT shows appreciable or significant amounts of soft drusen), treatment with the apo mimetic can be resumed (e.g., a treatment regimen that has resulted in a significant improvement). Diagnostic methods may be used to monitor the progression and treatment of AMD to adjust treatment accordingly. Such treatment regimens may be referred to as "on-demand" or "opportunistic" regimens. An on-demand regimen involves a routine outpatient visit (e.g., once every 4, 6, or 8 weeks) so that one or more diagnostic methods can be performed to monitor the progression and treatment of AMD, although therapeutic agents may not be administered during the outpatient visit depending on the results of the diagnostic test.

as another example of treating early, intermediate, or advanced AMD, or atrophic AMD or neovascular AMD by administering an apo mimetic [ e.g., an apoA-I mimetic (e.g., L-4F) and/or an apoE mimetic (e.g., AEM-28-14) ] by injection (e.g., intravitreal, subconjunctival, subretinal, or sub-tenon's capsule injection), the apo mimetic can be administered at an injection frequency (e.g., once a month) during the initial phase of treatment and at each dose. During the second phase of treatment, the apo mimetic may be injected less frequently (e.g., once every 6 or 8 weeks) and the dose per injection is the same as the initial dose per injection or higher so that the total dose administered over a period of time is substantially similar. The second phase of treatment may last for a selected period of time. During the optional third phase of treatment, the apo mimetic may be injected even less frequently (e.g., once every 10 or 12 weeks), and the dose per injection is the same as the initial dose per injection or higher so that the total dose administered over a period of time is substantially similar. The optional third phase of treatment may last for a selected period of time. And so on. Such a treatment regimen may be referred to as a "treatment and extension" regimen. One or more diagnostic methods may be performed to monitor the progression and treatment of AMD during the initial/first phase, the second phase, the optional third phase, and any additional optional treatment phases, and perhaps to adjust the treatment based on the diagnostic test results. For example, if one or more diagnostic methods show a worsening disease (e.g., SDOCT shows an increase in the volume of soft-glass warts), the apo mimetic can be injected more frequently and/or at higher doses per injection. Conversely, if one or more diagnostic methods show stable disease or improved disease (e.g., SDOCT shows stable or reduced volume of soft verruca, the apo mimetic can be injected at a lower frequency and/or at a lower dose per injection, or the apo mimetic can be injected at a lower frequency and at a higher dose per injection, such that a substantially similar total dose is administered over a period of time. Unlike on-demand treatment regimens, treatment and extension regimens do not involve a conventional diagnostic visit, but rather administer the therapeutic agent in a conventional therapeutic visit (the frequency of which is reduced in the second and optional third phases of treatment), even though the therapeutic agent or dose administered may not be medically necessary at the time. Frequent outpatient visits (whether for monitoring and/or treatment) and frequent (e.g., monthly) injections may have negative consequences such as reduced patient compliance, poor medical outcomes (e.g., tachyphylaxis), and increased healthcare costs. A potential advantage of the treatment and extension protocol over the on-demand protocol is that it may reduce the total number of out-patient visits for monitoring and treatment.

as non-limiting examples of treatment and extension regimens, either alone or in combination with another therapeutic agent (e.g., an apo mimetic, e.g., an apoA-I mimetic [ e.g., L-4F ] or an apoE mimetic [ e.g., AEM-28-14]), anti-angiogenic agents (e.g., anti-VEGF agents such as arbepril, bevacizumab or ranibizumab) for the treatment of neovascular AMD can be injected (e.g., intravitreally) every 4, 6 or 8 weeks until maximal effect is achieved, such as substantially complete regression of subretinal fluid and/or intraretinal fluid in the absence of new retinal hemorrhage, or at least two consecutive outpatient visits without further reduction of subretinal fluid and/or intraretinal fluid in OCT-FA in the absence of new retinal hemorrhage. In this case, the anti-angiogenic agent may be injected less frequently (the interval between injections may be extended, for example, by about 2 or 4 weeks). If the disease remains stable, the interval between injections may be extended, for example, by about 2 or 4 weeks once, and the total extension period may reach, for example, about 3,4,5 or 6 months. If the patient's disease exhibits a relatively mild deterioration (e.g., a relatively small amount of subretinal fluid and/or a relatively small increase in intraretinal fluid or amounts thereof reappears), the interval between injections of the anti-angiogenic agent may be shortened, for example, by about 1 or 2 weeks. Frequent injections of the anti-angiogenic agent may be resumed if the disease is severely exacerbated (e.g., once every 4, 6, or 8 weeks). Similar principles apply to treatment and prolongation regimens for the treatment of atrophic AMD or neovascular AMD with any other type of therapeutic agent including, but not limited to, apo mimetics (e.g., apoA-I mimetics, e.g., L-4F or apoE mimetics such as AEM-28-14) and complement inhibitors (e.g., complement factor D inhibitors such as lanreolizumab).

As an alternative to an on-demand regimen or a treatment and extension regimen for treating early, intermediate or advanced AMD, or atrophic AMD or neovascular AMD, a therapeutic agent (e.g., an apo mimetic, an anti-angiogenic agent, or a complement inhibitor) may be administered at substantially the same frequency and at substantially the same dosage each time, for substantially the entire duration of treatment selected by the attending physician or until the results of one or more diagnostic methods indicate that the disease has been successfully treated according to the selected measurement criteria. Such a treatment regimen may be referred to as a "fixed conventional" regimen.

apo mimetics [ e.g., apoA-I mimetics (e.g., L-4F) and/or apoE mimetics (e.g., AEM-28-14) ] can be administered as a composition comprising one or more pharmaceutically acceptable excipients or carriers. If two or more apo mimetics (e.g., apoA-I mimetics and apoE mimetics) are used, they can be administered in the same composition or in different compositions. In some embodiments, a composition containing an apo mimetic [ e.g., an apo a-I mimetic (e.g., L-4F) and/or an apoE mimetic (e.g., AEM-28-14) ] comprises about 75-95% (e.g., about 90%) of the apo mimetic and about 5-25% (e.g., about 10%) of the corresponding apolipoprotein (e.g., apoA-I and/or apoE) or an active portion thereof or domain thereof, by weight or molar concentration, relative to their combined amount. In certain embodiments, a composition containing an apo mimetic [ e.g., an apoA-I mimetic (e.g., L-4F) and/or an apoE mimetic (e.g., AEM-28-14) ] is formulated for injection (e.g., intravitreal, subconjunctival, subretinal, or sub-tenon's capsule injection). Examples of formulations for injection into the eye include, but are not limited to, those described elsewhere herein. In other embodiments, compositions containing an apo mimetic [ e.g., an apoA-I mimetic (e.g., L-4F) and/or an apoE mimetic (e.g., AEM-28-14) ] are formulated as eye drops or implants (e.g., intravitreal, subretinal, or sub-tenon's capsule implants). The use of one or two eye drops or the implantation of one or two implants may avoid potential problems associated with repeated injections.

In a further embodiment, a composition containing an apo mimetic [ e.g., an apoA-I mimetic (e.g., L-4F) and/or an apoE mimetic (e.g., AEM-28-14) ] is configured for sustained release of the apo mimetic. Non-limiting examples of sustained release compositions include those described elsewhere herein. In certain embodiments, the apo mimetic [ e.g., apoA-I mimetic (e.g., L-4F) and/or apoE mimetic (e.g., AEM-28-14) ] is administered by microparticles, such as polymeric microparticles or microparticles that comprise or consist essentially of an apo mimetic. The use of sustained release compositions or such microparticles may reduce the number of potentially invasive procedures (e.g., intravitreal injections) performed to administer the drug and may improve the distribution of the amount of drug delivered to the target site over time.

In some embodiments, a composition containing an apo mimetic [ e.g., an apoA-I mimetic (e.g., L-4F) and/or an apoE mimetic (e.g., AEM-28-14) ] comprises one or more excipients that inhibit peptide/protein aggregation, increase peptide/protein solubility, decrease solution viscosity, or increase peptide/protein stability, or any combination or all thereof. Examples of such excipients include, but are not limited to, those described elsewhere herein. These excipients may improve the injectability of compositions containing apo mimetics. Thus, such excipients enable the use of needles (e.g., injection needles) having a smaller gauge (e.g., less than 30G) when administering (e.g., by intravitreal injection) compositions containing apo mimetics.

Because such excipients inhibit peptide/protein aggregation and increase peptide/protein solubility, they can be used, for example, to increase the concentration of peptide or protein in a solution or suspension. An increase in peptide/protein concentration reduces the volume required to administer a given amount of peptide or protein, which can have a beneficial effect (e.g., lowering intraocular pressure) if the peptide or protein is administered by injection into the eye. Furthermore, an increase in peptide/protein concentration allows for a greater dose of peptide or protein to be administered for a given volume, which may allow for less frequent administration of peptide or protein for a given total dose administered over a period of time. Less frequent administration (e.g., by intravitreal injection) of peptides or proteins can have benefits, such as improved patient compliance and health due to less invasive procedures being performed.

apo mimetics [ e.g., apoA-I mimetics (e.g., L-4F) and/or apoE mimetics (e.g., AEM-28-14) ] can be used alone or in combination with one or more other therapeutic agents to treat AMD. Examples of other therapeutic agents include, but are not limited to, those described elsewhere herein. As described elsewhere herein, one or more additional therapeutic agents may be administered in combination with the apo mimetic at different stages of AMD (e.g., early, intermediate, or late stages of AMD), as well as for the treatment of different phenotypes of AMD (e.g., geographic atrophy or neovascular AMD).

Apolipoprotein mimetics (e.g., apoA-I mimetics [ e.g., L-4F ] and/or apoE mimetics [ e.g., AEM-28-14]) (optionally in combination with one or more other therapeutic agents) can be used to treat any symptom or complication associated with AMD. Examples of such symptoms and complications include, but are not limited to, accumulation of lipids (including neutral lipids and modified lipids) at BrM, thickening of BrM, accumulation of lipid-rich debris, deposition of lipid-rich debris (including basal linear deposits and drusen) between RPE-BL and BrM ICL, formation of a diffusion barrier between RPE and choroidal capillaries, photoreceptor degeneration, geographic atrophy (including non-central and central GA), RPE atrophy, neovascularization (including NV types 1,2 and 3), intraocular leakage, bleeding and scarring, and visual impairment and loss.

As a non-limiting example, some embodiments of the present disclosure relate to methods of preventing, delaying the onset of, slowing the progression of, or reducing the extent of vision impairment or loss associated with AMD, comprising administering to a subject a therapeutically effective amount of an apo mimetic (e.g., an apoA-I mimetic [ e.g., L-4F ] and/or an apoE mimetic [ e.g., AEM-28-14 ]). One or more additional therapeutic agents may optionally be administered. Visual impairment or loss may be associated with atrophic AMD (including non-central and/or central pattern atrophy) or neovascular AMD (including neovascularization of type 1,2 and/or 3).

Class of other therapeutic agents

As mentioned above, AMD has a number of potential factors, including the formation of lipid-containing deposits, the formation of toxic by-products, oxidation, inflammation, neovascularization, and cell death. Multiple agents targeting multiple latent factors of AMD, or having different mechanisms of action, may be used to treat AMD. Therapeutic agents that may optionally be used in combination with the apolipoprotein mimetic to treat AMD include, but are not limited to:

1) An anti-dyslipidemic agent;

2) PPAR-alpha agonists, PPAR-delta agonists, and PPAR-gamma agonists;

3) An anti-amyloid agent;

4) An inhibitor of lipofuscin or a component thereof;

5) visual/photoperiod modifiers and dark adaptation agents;

6) an antioxidant;

7) neuroprotective agents (neuroprotective agents);

8) Inhibitors of apoptosis and inhibitors of necrosis;

9) C-reactive protein (CRP) inhibitors;

10) inhibitors of the complement system or components thereof (e.g., proteins);

11) An inflammatory body inhibitor;

12) An anti-inflammatory agent;

13) An immunosuppressant;

14) Modulators of Matrix Metalloproteinases (MMPs); and

15) An anti-angiogenic agent.

A particular therapeutic agent may exert more than one biological or pharmacological effect and may be classified into more than one class.

The therapeutic agent is used in a therapeutically effective amount. When used in combination with another therapeutic agent (e.g., an apolipoprotein mimetic), the therapeutic agent may be administered substantially simultaneously with the other therapeutic agent (e.g., during the visit by the same physician, or within about 30 or 60 minutes of each other), or before or after the other therapeutic agent is administered. When administered concurrently with another therapeutic agent, the therapeutic agent may be administered in the same formulation as the other therapeutic agent or in a separate formulation.

The formation of lipid-rich deposits is an important upstream cause of AMD, leading to complications (e.g., non-central and central pattern atrophy and neovascularization). One approach to prevent or minimize the accumulation of lipid-rich substances in multiple tracts is to inhibit the production of lipids (e.g., cholesterol and fatty acids) and lipoproteins (e.g., VLDL) by RPE cells, inhibit the uptake of lipids (e.g., cholesterol and fatty acids) and lipoproteins (e.g., VLDL) by RPE cells, inhibit the secretion of lipids (e.g., cholesterol and fatty acids) and lipoproteins (e.g., VLDL) and components thereof (e.g., apoB and apoE) from RPE cells into BrM, sub-RPE-BL space and subretinal space, and eliminate BrM, sub-RPE-BL space and subretinal space of lipids (e.g., cholesterol and oxidized lipids) and lipoproteins (e.g., VLDL) and components thereof (e.g., apoB and apoE). For example, apoB is involved in at least the formation of hepatic VLDL, which is at least the source of plasma LDL. Inhibition of apoB production by RPE cells and inhibition of fatty acid uptake by RPE cells that is useful for lipidating apoB may reduce VLDL production by RPE cells and thus potentially reduce LDL production.

Anti-dyslipidemia agents modulate, among other things, the production, uptake and clearance of lipids, lipoproteins and other substances that play a role in the formation of lipid-containing deposits within the retina, subretinal, sub-RPE-BL space, choroid (e.g., BrM). One class of antilipidemic agents is the fibrates, which activate peroxisome proliferator-activated receptor- α (PPAR- α). Fibrates are hypolipidemic agents that reduce the production of fatty acids and triglycerides, induce lipolysis but stimulate the production of High Density Lipoproteins (HDL), mediate reverse cholesterol transport, increase the removal of LDL from plasma, and stimulate reverse cholesterol transport from the cell to the circulation and ultimately to the liver where cholesterol is metabolized and excreted into the bile. Lecithin-cholesterol acyltransferase [ LCAT ] (a plasma enzyme activated by, for example, apolipoprotein a-I) converts free cholesterol to a cholesteryl ester, which is then sequestered in the core of the HDL particles.) examples of fibrates include, but are not limited to, bezafibrate (benzafibrate), ciprofibrate (ciprofibrate), rofibrate (clinofibrate), clofibrate (clofibrate), clofibrate acid (clofibrate acid), clofibrate (clofibrate), aluminum clofibrate (aluminum clofibrate), clofibrate (clofibrate), ethoxyfibrate (fenofibrate), gemfibrozil (gemfibrozil), chloronicotinate (fibrate), bisfibrate) and analogues, derivatives and salts thereof. Other triglyceride-lowering agents include omega-3 fatty acids, such as docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA).

another class of anti-dyslipidemia agents are HMG-CoA reductase inhibitors (statins). Statins inhibit cholesterol synthesis, reduce the production of VLDL and LDL apoB (or apoB-containing VLDL and LDL), reduce apoB secretion, and lower blood lipid levels. Examples of statins include, but are not limited to, atorvastatin (atorvastatin), cerivastatin (cerivastatin), fluvastatin (fluvastatin), mevastatin (mevastatin), monacolins (monacolins) (e.g., monacolin K [ lovastatin) ], pitavastatin (pitavastatin), pravastatin (pravastatin), rosuvastatin (rosuvastatin), simvastatin (simvastatin), and analogs, derivatives, and salts thereof.

other dyslipidemia agents include acetyl-coa carboxylase (ACC) inhibitors. ACC inhibitors inhibit fatty acid and Triglyceride (TG) synthesis and reduce VLDL-TG secretion. Non-limiting examples of ACC inhibitors include anthocyanidins, avenaculides, benzodioxepines { e.g., 7- (4-propoxy-phenylethynyl) -3, 3-dimethyl-3, 4-dihydro-2H-benzo [ b ] [1,4] dioxepin }, benzothiophenes [ e.g., N-ethyl-N' - (3- { [4- (3, 3-dimethyl-1-oxo-2-oxa-7-azaspiro [4.5] dec-7-yl) piperidin-l-yl ] -carbonyl } -l-benzothiophen-2-yl) urea), bispiperidyl carboxamides (e.g., CP-640186), chloroacetylated biotin, cyclodim, cydodim, Diclofop, haloxyfop, biphenyl-and 3-phenylpyridine, phenoxythiazoles (phenoxythiazoles), for example 5- (3) -acetamido-but-1-ynyl } -2- (4-propoxyphenoxy) thiazole, piperazine oxadiazoles, (4-piperidinyl) -piperazines, salophenes (such as salophen A1. alpha.), spiro-piperidines, spiro-pyrazolidinediones, spiro [ chroman ] -2,4' -piperidin) -4-one, 5- (tetradecyloxy) -2-furancarboxylate (TOFA), thiazolyl phenyl ether, thiophenes [ for example 1- (3- { [4- (3, 3-dimethyl-1-oxo-2-oxa-7-azaspiro [4.5] dec-7-yl) piperidin-1-yl 5- (pyridin-2-yl) -2-thiophen) -3-ethylurea ], and analogs, derivatives and salts thereof.

acyl-CoA cholesterol acyltransferase (ACAT) inhibitors may also be used as anti-dyslipidemic agents. ACAT inhibitors inhibit cholesterol esterification and reduce the production of VLDL and LDL apoB (or apoB-containing VLDL and LDL). Examples of ACAT inhibitors include, but are not limited to, atorvastatin (avasimibe), patimibe (pactimibe), pellitorine (pellitarine), terpendole C, and analogs, derivatives and salts thereof.

Another class of anti-dyslipidemia agents is glucagon-like peptide-1 (GLP-1) receptor agonists. GLP-1 receptor agonists reduce apoB and VLDL particle production and thereby VLDL-apoB and VLDL-TG, lower cellular levels of cholesterol and triglycerides, and reduce or reverse hepatic steatosis (fatty liver) by reducing hepatic lipogenesis. Non-limiting examples of GLP-1 receptor agonists include exenatide (exendin) -4, albiglutide (albic), dulaglutide (dulaglutide), exenatide (exenatide), liraglutide (liraglutide), lixisenatide (lixisenatide), somaglutide (semaglutide), taspoglutide (taspoglutide), CNT0736, CNT03649, and analogs, derivatives, and salts thereof. Because GLP-1, an endogenous ligand for the GLP-1 receptor, is rapidly degraded by dipeptidyl peptidase 4(DPP-4), similar anti-dyslipidemic effects to GLP-1 receptor agonists can be achieved using DPP-4 inhibitors, although efficacy may be low. Non-limiting examples of DPP-4 inhibitors include alogliptin (alogliptin), alogliptin (anagliptin), dologliptin (dutogliptin), gemliptin (gemigliptin), linagliptin (linagliptin), saxagliptin (saxagliptin), sitagliptin (sitagliptin), terliptin (teneligliptin), vildagliptin (vildagliptin), berberine, lupeol (lupeol), and analogs, derivatives, and salts thereof.

Additional anti-dyslipidemia agents include inhibitors of the Microsomal Triglyceride Transfer Protein (MTTP), which is expressed in RPE cells. MTTP catalyzes the assembly of cholesterol, triglycerides and apoB with chylomicrons and VLDL. MTTP inhibitors inhibit apoB-containing chylomicron and VLDL synthesis and inhibit secretion of these lipoproteins. Examples of MTTP inhibitors include, but are not limited to, microRNAs (e.g., miRNA-30c), improtapide (implitapide), lomitapide (lomitapide), delactapide (dirlotapede), mitratapide (mitratapide), CP-346086, JTT-130, SLx-4090, and analogs, derivatives and salts thereof. Systemic administration of MTTP inhibitors can lead to liver steatosis (e.g., accumulation of triglycerides in the liver), which can be avoided by: such as topical administration of an MTTP inhibitor, use of a non-systemically absorbed MTTP inhibitor (e.g., SLx-4090), or co-administration with a GLP-1 receptor agonist, or any combination or all thereof. Another option to avoid liver steatosis is to use miRNA-30 c. One region of the miRNA-30c sequence, which reduces MTTP expression and apoB secretion, while the other region reduces fatty acid synthesis, has no detrimental effect on the liver.

Other classes of anti-dyslipidemia polynucleotides include antisense polynucleotides targeting apoB mRNA, including apoB48 and apoB 100. ApoB is important in the formation of VLDL and subsequent LDL. Antisense polynucleotides complementary in whole or in part (e.g., at least about 50%, 60%, 70%, 80%, 90%, or 95%) to apoB mRNA are used to block translational expression of apoB and thus produce VLDL and LDL. Examples of antisense polynucleotides targeting the mRNA of apoB include, but are not limited to, milbemesen (mipomensen). Other anti-dyslipidemia antisense polynucleotides include those targeting miRNA-33a and miRNA-33 b. miRNA-33a and miRNA-33b inhibit the expression of the ATP-binding cassette transporter ABCA1 (cholesterol efflux regulator protein [ CERP ]), which ABCA1 mediates efflux of cholesterol and phospholipids. Use of antisense polynucleotides complementary in whole or in part (e.g., at least about 50%, 60%, 70%, 80%, 90%, or 95%) to miRNA-33a and/or miRNA-33b increases reverse cholesterol transport and HDL production and reduces VLDL-TG and fatty acid production. Increasing expression of ABCA1 also has a protective effect on the angiogenesis of AMD.

In addition, cholesterol transfer protein (CETP) inhibitors may be useful as anti-dyslipidemic agents. CETP transfers cholesterol from HDL to VLDL and LDL. CETP inhibitors increase HDL levels, decrease VLDL and LDL levels, and increase reverse transport of cholesterol from the cell to the circulation and ultimately to the liver, where it is metabolized and excreted into the bile. Examples of CETP inhibitors include, but are not limited to, anacetrapib, dalcetrapib, etacetrapib, torcept, AMG 899(TA-8995), and analogs, derivatives, and salts thereof.

other anti-dyslipidemic agents that increase the efflux of cellular lipids (e.g., cholesterol) include Liver X Receptor (LXR) agonists and Retinoid X Receptor (RXR) agonists. LXR heterodimerizes with the obligate partner RXR. The LXR/RXR heterodimer can be activated with an LXR agonist or an RXR agonist. Activation of LXR/RXR heterodimers decreases fatty acid synthesis and increases the efflux of lipids (e.g., cholesterol) from cells into the circulation and ultimately to the liver where they are metabolized and excreted into the bile. Non-limiting examples of LXR agonists include endogenous ligands (e.g., oxysterols (e.g., 22(R) -hydroxycholesterol, 24(S) -hydroxycholesterol, 27-hydroxycholesterol, and cholesterol acid)), and synthetic agonists (e.g., acetyl-podocarpic acid dimer, hypocholenamide (hypocholelamide), N-dimethyl-3 β -hydroxy-cholenamide (N, N-dimethyl-3 β -hydroxy-cholenamide, DMHCA), GW3965, T0901317), and analogs, derivatives, and salts thereof. Non-limiting examples of RXR agonists include endogenous ligands (e.g., 9-cis-retinoic acid), and synthetic agonists (e.g., bexarotene (bexarotene), AGN 191659, AGN 191701, AGN 192849, BMS649, LG100268, LG100754, LGD346), and analogs, derivatives, and salts thereof.

PPAR-alpha agonists and PPAR-gamma agonists are also useful in the treatment of AMD. The hypolipidemic effect of PPAR-alpha activating fibrates is as described above. Fibrates also reduce the expression of Vascular Endothelial Growth Factor (VEGF) and VEGF receptor 2(VEGFR2), which VEGF and VEGFR2 play an important role in the development of neovascularization, including CNV. Examples of PPAR-alpha agonists include, but are not limited to, fibrates and perfluoroalkanoic acids (e.g., perfluorooctanoic acid and perfluorononanoic acid). Thiazolidinediones (thiazolidinediones) that activate PPAR- γ also have an anti-dyslipidemic effect. Like LXR, PPAR- γ also heterodimerizes with RXR. Thiazolidinediones lower lipid levels (e.g., fatty acids and triglycerides), increase HDL levels (mediating reverse cholesterol transport), and increase the efflux of lipids (e.g., cholesterol) from cells into the circulation and ultimately to the liver where they are metabolized and excreted into the bile. Like fibrates, thiazolidinediones also inhibit VEGF-induced angiogenesis. Examples of PPAR-gamma agonists include, but are not limited to, thiazolidinediones (e.g., ciglitazone, rosiglitazone, pioglitazone, rifagllitazone, rosiglitazone, troglitazone), rhodanine, berberine, honokiol, perfluorononanoic acid, and analogs, derivatives and salts thereof.

Other dyslipidemic PPAR modulators include PPAR-delta agonists. PPAR-delta agonists increase HDL levels, decrease VLDL levels, and increase expression of cholesterol efflux transporters (e.g., ABCA 1). Non-limiting examples of PPAR-delta agonists include GFT505 (PPAR-alpha/delta dual agonist), GW0742, GW501516, Sodelglitazar (GW677954), MBX-8025, and analogs, derivatives and salts thereof.

Anti-dyslipidemia agents also include apolipoprotein peptide mimetics, which are described elsewhere herein.

Another method of increasing cholesterol efflux from cells is to increase the levels of cardiolipin in the inner mitochondrial membrane. Increasing cardiolipin content can also prevent or reduce mitochondrial dysfunction. Non-limiting examples of agents that increase the level of cardiolipin in the inner mitochondrial membrane are elaiopeptide (elaiprentide) (MTP-131), cardiolipin peroxidase inhibitors, and mitochondrial targeting peptides.

If systemic administration of an anti-dyslipidemia agent that increases lipid efflux (e.g., reverse cholesterol transport) results in, or is at risk of, liver steatosis or abnormal lipid levels in the blood can be avoided or treated by, for example, topical administration of an anti-dyslipidemia agent to the eye, co-use of a substance that reduces or reverses liver steatosis, or co-use of a substance that reduces lipid levels in the blood, or any combination or all thereof. Examples of agents that reduce or reverse hepatic steatosis include, but are not limited to, agents that reduce hepatic lipogenesis, such as GLP-1 receptor agonists, which may be administered for this purpose, e.g., systemically. A non-limiting example of a substance that reduces the level of lipids in the blood is a statin, which may be administered systemically for this purpose.

Other compounds that bind and neutralize and/or promote the clearance of lipids and toxic lipid byproducts (e.g., oxidized lipids) may also be used. For example, cyclodextrins have a hydrophilic exterior but a hydrophobic interior and can therefore form water-soluble complexes with hydrophobic molecules. Thus, cyclodextrins (including α -cyclodextrin (6-membered sugar ring molecules), β -cyclodextrin (7-membered sugar ring molecules), γ -cyclodextrin (8-membered sugar ring molecules) and derivatives thereof (e.g., methyl- β -cyclodextrin)) can form water-soluble inclusion complexes with lipids (e.g., cholesterol) and toxic lipid by-products (e.g., oxidized lipids), and thus can neutralize their action and/or facilitate their removal.

Another anti-dyslipidemia agent is an Endoplasmic Reticulum (ER) modulator that restores proper ER function, including but not limited to, azramide (Azoramide). ER plays an important role in lipid metabolism. ER dysfunction and chronic ER stress are associated with a number of pathologies, including obesity and inflammation. Almiramine increases the ability of ER proteins to fold and activate the ability of ER chaperones to protect cells from ER stress.

AMD has been reported to be associated with apoE and extracellular deposits of amyloid-beta (A β) (included in drusen). A β deposits are reported to be involved in inflammatory events. Thus, anti-amyloid agents (e.g., inhibitors of a β formation or aggregation into plaques/deposits, and promoters of a β clearance) may potentially be useful in the treatment of AMD. Examples of anti-amyloid agents (e.g., anti-a β agents) include, but are not limited to, anti-a β antibodies (e.g., bapineuzumab, sorafezumab, GSK933776, RN6G [ PF4382923], AN-1792, 2H6, and deglycosylated 2H6), anti-apoE antibodies (e.g., HJ6.3), apoE mimetics (e.g., AEM-28), cystatin c, berberine, L-3-n-butylphthalide, T0901317, and analogs, derivatives, fragments, and salts thereof.

Elevated levels of other toxic by-products are also associated with AMD. For example, elevated levels of toxic aldehydes (e.g., 4-Hydroxynonenal (HNE) and Malondialdehyde (MDA)) are present in patients with AMD, particularly atrophic AMD patients. Substances that inhibit the formation of toxic aldehydes, bind to them and reduce their levels, or promote their decomposition or cleaning (e.g., the aldehyde trap NS2) may be used to treat AMD.

In addition, lipofuscin and its components (e.g., A2E) are reported to accumulate in RPE with age as a by-product of the visual cycle. Lipofuscin diyne A2E was reported to inhibit lysosomal degradation functions and cholesterol metabolism in RPE, induce the complement system and mediate blue light-induced apoptosis, and thus was associated with atrophy and cell death of RPE cells. Thus, inhibitors of lipofuscin or its components (e.g., A2E), including inhibitors of their formation or accumulation and promoters of their decomposition or clearance, can potentially be used to treat AMD. Examples of inhibitors of lipofuscin or components thereof (e.g., A2E) include, but are not limited to, isotretinoin, which inhibits the formation of A2E and the accumulation of lipofuscin pigment; soraprazan, which promotes the release of lipofuscin from RPE cells; and retinol binding protein 4(RBP4) antagonists (e.g., Al120 and compound 43[ cyclopentyl fused pyrrolidine ]), which inhibit the formation of lipofuscin dihydrovoxels such as A2E.

Another possible way to prevent or reduce the accumulation of lipofuscin diterpenoids (e.g. A2E) is to interfere with the visual/photoperiod in photoreceptors. For example, the visual/photoperiod modulator fenretinide (fenretinide) reduces serum levels of retinol and RBP4 and inhibits retinol binding to RBP4, which reduces photoperiod retinoid levels and stops accumulation of lipofuscin bidihydroglycosides (e.g., A2E). Other visual/photoperiod modulators include, but are not limited to, inhibitors of the trans-cis-retinol isomerase RPE65 (e.g., emixustat [ ACU-4429] and retinoic acid amines) that reduce the amount of retinol available and its downstream byproduct A2E by inhibiting the conversion of all-trans retinol to 11-cis retinol in RPE. Treatment with a periodicity modulator can slow the rate of rod-mediated dark adaptation in a patient. To accelerate the rate of dark adaptation, a dark adaptation agent may be applied. Non-limiting examples of dark-adaptation agents include carotenoids (e.g., carotenes, such as beta-carotene), retinoids (e.g., all-trans retinol [ vitamin a ], 11-cis retinol, all-trans retinal [ vitamin a aldehyde ], 11-cis retinal, all-trans retinoic acid [ retinoic acid ] and esters thereof, 9-cis-retinoic acid [ alitretinoic acid ] and esters thereof, 11-cis retinoic acid and esters thereof, 13-cis-retinoic acid [ isotretinoin ] and esters thereof, etretinate (etretinate), acitretin (acitretin), adapalene (adapalene), bexarotene, and tazarotene (tazarotene)), and analogs, derivatives, and salts thereof.

Oxidative events play an important role in the pathogenesis of AMD. For example, accumulation of peroxidized lipids can lead to inflammation and neovascularization. To prevent AMD, delay the onset of AMD, or slow the progression of AMD, antioxidants may be administered. In addition, antioxidants can have neuroprotective effects by preventing or reducing toxicity in the retina and interfering with cell death pathways. For example, the mitochondrially targeted electron scavenger, XJB-S-131, inhibits oxidation of cardiolipin, a mitochondrial specific polyunsaturated phospholipid, and thus reduces cell death (including in the brain). Another example is that crocin (crocin) and crocetin (crocetin), carotenoids found in saffron, can protect cells from apoptosis. As yet another example, xanthophylls (e.g., lutein and zeaxanthin) may protect the RPE from the development of drusen-like lesions, loss of macular pigment, and photo-induced apoptosis of photoreceptors. As yet another example, carnosic acid, a dihydroxybiphenylene diterpene found in rosemary and sage, can up-regulate antioxidant enzymes, protect retinal cells from hydrogen peroxide toxicity, and increase the thickness of the outer nuclear layer. As another example, curcuminoids (e.g., curcumin) found in turmeric may up-regulate heme oxygenase-1, thereby protecting RPE cells from hydrogen peroxide-induced apoptosis. As a further example, zinc increases the activity of catalase and glutathione peroxidase, thereby protecting RPE cells and photoreceptors from hydrogen peroxide and t-butyl hydroperoxide, and protecting photoreceptors and other retinal cells from caspase-mediated cell death. As yet another example, cyclopentenone prostaglandins (e.g., cyclopentenone 15-deoxy- Δ -prostaglandin J2[15d-PGJ2], a ligand of PPAR- γ) can protect RPE cells from oxidative damage by, for example, upregulation of glutathione (an antioxidant) synthesis. Cyclopentenone prostaglandins also have anti-inflammatory properties.

Non-limiting examples of antioxidants include anthocyanins, apolipoprotein mimetics (e.g., apoA-I mimetics and apoE mimetics), benzenediol abietanediterpenes (e.g., carnosic acid), carnosine, carotenoids (e.g., carotene [ e.g., beta-carotene ], xanthophylls [ e.g., lutein, zeaxanthin, and meso-zeaxanthin ], and carotenoids in saffron [ e.g., crocin and crocetin ]), curcuminoids (e.g., curcumin), cyclopentenone prostaglandins (e.g., 15d-PGJ2), flavonoids (e.g., flavonoids in Ginkgo biloba (Ginkgo biloba) [ e.g., myricetin (myricetin) and quercetin (quercetin) ], isoprenoid flavonoids (e.g., isoxanthohumol (isoxanthohumol)), retinoids (stilbenoids), stilbenoids (e.g., resveratrol (resveratrols)), (resveratrol), Uric acid, vitamin a, vitamin B1 (thiamine), vitamin B2 (riboflavin), vitamin B3 (niacin), vitamin B6 (such as pyridoxal, pyridoxamine, 4-pyridoxic acid, and pyridoxine), vitamin B9 (folic acid), vitamin B12 (cobalamin), vitamin C, vitamin E (such as tocopherol and tocotrienol), selenium, zinc (such as zinc monocysteine), inhibitors and scavengers of lipid peroxidation and its byproducts (e.g., vitamin E [ e.g., alpha-tocopherol ], tirapazad, NXY-059, and XJB-5-131), activators of nuclear factor (erythrocyte-derived 2) like 2(NFE2L2 or NRF2) (e.g., OT-551), superoxide dismutase (SOD) mimetics (e.g., OT-551), and analogs, derivatives, and salts thereof.

Antioxidants can be provided, for example, by dietary supplements such as AREDS or AREDS2 formulations, preparations, Saffron 2020TM or, if the supplement contains a relatively high level of zinc (e.g., zinc acetate, zinc oxide, or zinc sulfate), copper (e.g., copper oxide or copper sulfate) can optionally be co-administered with zinc to prevent copper-deficient anemia associated with high zinc intake. Saffron 2020TM contains Saffron, resveratrol, lutein, zeaxanthin, vitamins A, B2, C and E, zinc and copper. Comprises acetyl-L-carnitine, omega-3 fatty acids and coenzyme Q10. Exemplary age-related eye disease research (AREDS) formulations include beta-carotene, vitamin C, vitamin E, zinc (e.g., zinc oxide), and copper (e.g., copper oxide). An exemplary AREDS2 formulation comprises:

1) Beta-carotene, vitamin C, vitamin E and zinc; or

2) Vitamin C, vitamin E, zinc and copper; or

3) vitamin C, vitamin E and zinc; or

4) Beta-carotene, vitamin C, vitamin E, omega-3 fatty acids, zinc and copper; or

5) Beta-carotene, vitamin C, vitamin E, lutein, zeaxanthin, zinc and copper; or

6) beta-carotene, vitamin C, vitamin E, lutein, zeaxanthin, omega-3 fatty acids, zinc and copper.

Exemplary formulations include:

1) vitamin a, vitamin C, vitamin E, zinc and copper; or

2) Vitamin a, vitamin B2, vitamin C, vitamin E, lutein, zeaxanthin, zinc, copper and selenium.

An exemplary formulation comprises:

1) vitamin C, vitamin E, lutein, zeaxanthin, zinc and copper; or

2) vitamin C, vitamin E, lutein, zeaxanthin, omega-3 fatty acids, zinc and copper; or

3) Vitamin A, vitamin C, vitamin E, lutein, zeaxanthin, zinc, copper and selenium.

Other neuroprotective agents (neuroprotective agents) may be administered to treat AMD, either in lieu of or in addition to antioxidants. Neuroprotective agents can be used, for example, to promote the health and/or growth of cells in the retina, and/or to prevent cell death, regardless of the initiating event. For example, ciliary neurotrophic factor (CNTF) rescues photoreceptors from degeneration. As another example, glatiramer acetate reduces retinal microglial toxicity (and inflammation). Examples of neuroprotective agents include, but are not limited to, berberine, glatiramer acetate, alpha 2-adrenergic receptor agonists (e.g., apraclonidine (apraclonidine) and brimonidine (brimonidine)), serotonin 5-HT1A receptor agonists (e.g., AL-8309B and azanaphthalenones [ e.g., buspirone (buspirone), gepirone (gepirone) and tandospirone (tandospirone) ], neuroprotective (neuroprotectant) classes (e.g., neuroprotective A, B and D1), endogenous neuroprotective agents (e.g., carnosine, CNTF, glial cell-derived neurotrophic factor (GDNF) family (e.g., GDNF, artemin, neurturin and persephin), and neurotrophins (e.g., brain-derived neurotrophic factor [ BDNF ], neurotrophin [ NT-3] and neurotrophin [ 4-urotropin ], such as prostaglandin-4 analogs [ UF ], and analogs, derivatives, fragments and salts thereof.

In addition, other neuroprotective agents useful in the treatment of AMD include substances that prevent retinal-related cells (e.g., RPE cells and photoreceptors) from dying by apoptosis (programmed cell death) and/or necrosis (characterized by cell swelling and rupture). For example, Nucleoside Reverse Transcriptase Inhibitors (NRTI) block RPE cell death by inhibiting P2X 7-mediated inflammatory activation of caspase-1 by NLRP3 and reduce geographic atrophy and CNV. If apoptosis is reduced (e.g., by inhibiting caspases), necrosis may be increased to compensate for the reduction in apoptosis, and thus an effective strategy to prevent or reduce retinal-related cell death may involve inhibiting both apoptosis and necrosis. Non-limiting examples of apoptosis inhibitors include the following: caspase (e.g., caspase family [ e.g., Q-VD (OMe)) -OPh (SEQ. ID. NO.14), Boc-D-FMK (SEQ. ID. NO.15), Z-VAD (SEQ. ID. NO.16) and Z-VAD-FMK (SEQ. ID. NO.17) ], caspase-1 [ e.g., Z-YVAD-FMK (SEQ. ID. NO.18), caspase-2 [ e.g., Z-VDVAD-FMK (SEQ. ID. NO.19) ], caspase-3 [ e.g., Q-DEVD-OPh (SEQ. ID. NO.20), Z-DEVD-FMK (SEQ. ID. NO.21) and Z-DQMD-FMK (SEQ. ID. NO.22) ], caspase-4 [ e.g., Z-VD-FMK (SEQ. ID. FMK.23), caspase-5 [ e.g., Z-WEMD-FMK (SEQ. ID. NO. 24.25) ], caspase-4 [ e.g., caspase-24. ID. NO.25 Caspase-8 [ e.g., Q-IETD-OPh (seq. id No.26) and Z-IETD-FMK (seq. id No.27) ], caspase-9 [ e.g., Q-LEHD-OPh (seq. id No.28) and Z-LEHD-FMK (seq. id No.29) ], caspase-10 [ e.g., AEVD-FMK (seq. id No.30) ], caspase-12 [ e.g., Z-ATAD-FMK (seq. id No.31) ], and caspase-13 [ e.g., ed-FMK (seq. id No.32) ], inflammatory body inhibitors, P2X7, which mediate NLRP3 activation of inhibitors of caspase-1 (e.g., NRTI, such as abacavir (abacavir) [ ABC ], lamivudine (lamivudine) [3TC ], stavudine (stavudine) [ d4T1, me-d4T, and zidovudine (zidovudine) [ AZT ]), neuroprotective agents, and analogs, derivatives, and salts thereof. Examples of necrosis inhibitors include, but are not limited to, caspase inhibitors, inhibitors of receptor-interacting protein (RIP) kinase (e.g., necroptosis inhibitors (necrostatins), such as necroptosis inhibitors 1,5, and 7), Necrox compounds (e.g., Necrox-2 and Necrox-5), Nec-1, and analogs, derivatives, and salts thereof.

Elevated levels of C-reactive protein (CRP) are found in the blood and eyes of patients with AMD. Elevated CRP levels can increase VEGF production and thereby lead to neovascularization. In addition, CRP is involved in the pathogenesis of inflammation and inhibits cholesterol efflux by down-regulating the cholesterol efflux proteins ABCA1 and ABCG 1. In addition, monomeric CRP can bind to complement protein C1q and subsequently activate the classical complement pathway, which in tandem with the alternative complement pathway can lead to the formation of Membrane Attack Complexes (MAC) and ultimately to cell lysis. Thus, CRP inhibitors that reduce CRP levels (e.g., by reducing production or increasing breakdown or clearance) or reduce CRP activity may be used to treat AMD. Examples of CRP inhibitors include, but are not limited to, DPP-4 inhibitors, thiazolidinediones, stilbenes, statins, epigallocatechin-3-gallate (EGCG), CRP-i2, and analogs, derivatives, and salts thereof.

The complement system of the innate immune system is involved in the pathogenesis of AMD. For example, variants of the CFH gene that result in Complement Factor H (CFH) deficient or deficient (deficiency) are closely associated with the risk of AMD. In addition, the alternative complement pathway can be activated by accumulation of apolipoproteins (e.g., apoE) and lipofuscin or components thereof (e.g., A2E). In addition, the membrane attack complex (MAC, C5b-9) has been documented on choroidal vessels, bruch's membrane (BrM) and RPE and is associated with abnormal RPE cells, suggesting that complement-mediated cell lysis may accelerate RPE dysfunction and death in AMD. In addition, there was significant MAC accumulation in BrM of the aged macula and in the choroidal capillary endothelium. The complement system also plays an important role in inflammatory and oxidative events. For example, the anaphylatoxins C3a, C4a, and C5a mediate inflammation and the production of cytotoxic oxygen radicals. For example, binding of C3a and C5a to the C3a and C5a receptors, respectively, results in an inflammatory response, such as stimulation of mast cell mediated inflammation through histamine release. Activation of the complement cascade and local inflammation involves, for example, drusen formation, which is a hallmark of atrophic AMD leading to neovascular AMD. In addition, the complement system is involved in neovascularization (including CNV). For example, activation of the complement system can lead to the formation of MAC in the choriocapillaris endothelium, which is destroyed by MAC which can lead to hypoxia and thus CNV. In addition, some complement components (e.g., C5a) exhibit pro-angiogenic properties-e.g., C5a receptors mediate increased VEGF secretion in RPE cells. In addition, MAC releases pro-angiogenic molecules (e.g., PDGF and VEGF).

Alternatively or in addition to inhibition of the alternative complement pathway, inhibition of the lectin complement pathway (and/or the classical complement pathway) may be beneficial in the treatment of atrophic AMD and/or neovascular AMD. For example, inhibition of mannan-binding lectin serine proteases (or mannose-related serine proteases [ MASP ]) (e.g., MASP-1, -2, or-3) using, for example, an antibody or fragment thereof (e.g., OMS721, an anti-MASP-2 antibody) can inhibit the amplification of complement activation and its sequelae (e.g., inflammation). In the lectin pathway, MASP cleaves C2 and C4 to form C2aC4b (a C3-convertase). At the boundary between the lectin and the alternative pathway, C3-convertase cleaves C3 into C3a and C3 b. C3b binds to C2aC4b to form a C5 convertase, which C5 convertase cleaves C5 into C5a and C5 b. Together, C5b, C6, C7, C8, and C9 form a Membrane Attack Complex (MAC) that can lead to cell lysis by cell swelling and rupture. For example, complement factors H and I inactivate C3b and down regulate the alternative pathway, thereby inhibiting inflammation. By inhibiting the formation of the C3 convertase C2aC4b, MASP inhibitors may be useful in the treatment of atrophic AMD and/or neovascular AMD.

thus, inhibitors of the complement system or components thereof (e.g., proteins and factors) (e.g., CFB, CFD, C2, C2a, C2b, C4, C4a, C4b, C3-convertases [ e.g., C2aC4b and C3bBb ], C3, C3a, C3b, C3a receptor, C3[ H2O ], C3[ H2O ] Bb, C5-convertases [ e.g., C2aC3bC4b and C3 bbc3b ], C5, C5a, C5b, C5a receptor, C6, C7, C8, C9, and MAC [ C5b-9]) can be used for treatment of AMD. As an illustrative example, lanreolizumab is an antigen binding fragment (Fab) of a humanized monoclonal antibody that targets Complement Factor D (CFD), the rate-limiting enzyme involved in Alternative Complement Pathway (ACP) activation. CFD cleaves CFB into protein active factor Bb. Bb binds to spontaneously hydrolyzed C3[ C3(H2O) ] which leads to the formation of the C5-convertase C3bBbC3 b. Hyperactivity of ACP is associated with the development of AMD, including Geographic Atrophy (GA). Lanbolizumab inhibits complement activation and inflammation, and can be used to treat or slow the progression of AMD (including GA). Atrophic AMD patients with complement factor i (cfi) mutations appear to show a more positive response to treatment with lanreolizumab. In a phase II trial of MAHALO, patients receiving 10mg of lanborlizumab in one eye intravitreally for 18 months per month showed approximately 20% reduction in the area of geographic atrophy of the injected eye, based on fundus autofluorescence, compared to patients receiving placebo. A subset of patients who were CFI biomarker positive and received 10mg of lanborlizumab monthly intravitreal injection for 18 months showed an approximately 44% reduction in geographic atrophy area. CFI, a C3b/C4b inactivator, modulates complement activation by cleaving cell-bound C3b and C4b or liquid phase C3b and C4 b.

Non-limiting examples of inhibitors of the complement system or components thereof include sCR1 (soluble form of complement receptor 1[ CR1] that promotes degradation of C3bBb and inhibits the classical and alternative complement pathways), TT30 (fusion protein containing the domain of complement receptor 2[ CR2] and CFH (which inhibits the alternative pathway), anti-CFB antibodies and fragments thereof (e.g., TA106), anti-CFD antibodies and fragments thereof (e.g., lanbolilizumab [ FCFD4514S ]), C3 complement inhibin (compstatin) and derivatives thereof (e.g., POT-4[ AL-78898A ]) (inhibits C3 and MAC formation), mycophenolic acid-glucosamine conjugates (down-regulator of C3), soluble form of a protein or fragment thereof that is a C3 inhibitor (e.g., CR1, decay accelerating factor [ DAF MCP ]) and membrane cofactor protein [ or CD46]), 3E7 (anti-C3 b/iC3 b), anti-C5 antibodies (e.g., fragments thereof), eculizumab [ inhibits C5 and MAC formation ] and LFG316), anti-C5 aptamers (e.g., ARC1905 (C5 cleavage inhibitor)), other C5 inhibitors (e.g., Coversin), C5a receptor antagonists (e.g., JPE-1375, JSM-7717, PMX-025, Ac-F [ OPdChaWR ] { PMX-53}, and anti-C5 aR antibodies and fragments thereof [ e.g., nougat mab (neutrazimab) ]), apoA-I mimetics (e.g., L-4F (complement activation inhibitor)), CD59 and modified CD59 with glycolipid anchors (inhibitor of MAC), tandospirone (reduce complement deposition), zinc (inhibitor of complement activation and MAC deposition), and analogs, derivatives, fragments, and salts thereof.

inflammation is also a significant contributor to the pathogenesis of AMD. For example, the inflammatory response may be involved in the formation of drusen and may upregulate the expression of VEGF and other pro-angiogenic factors that cause neovascularization, including CNV. Inflammation may be mediated by the cellular immune system (e.g., dendritic cells) and/or the humoral immune system (e.g., complement system). Inflammation may also be mediated by inflammatories, which are components of the innate immune system. For example, the accumulation of substances in BrM (e.g., lipoprotein-like particles, lipids, and possibly lipofuscin or components thereof [ e.g., A2E ]) can activate the NLRP3 inflammasome, resulting in a chronic inflammatory response. In addition, assembly of inflammasomes (e.g., NLRP3) in response to cellular stress signals activates caspases (e.g., caspase-1), which leads to inflammation (e.g., by producing proinflammatory interleukin-1 β) and ultimately to cell death of, for example, RPE cells.

Many of the substances mentioned in this disclosure have anti-inflammatory properties in addition to one or more properties to the description. Other anti-inflammatory agents include, but are not limited to, hydroxychloroquine (hydroxychloroquine), corticosteroids such as fluocinolone acetonide and triamcinolone acetonide (triamcinolone acetonide), steroids with little glucocorticoid activity such as anecortave (anecortave) [ anecortave acetate ]), non-steroidal anti-inflammatory drugs such as non-selective cyclooxygenase [ COX ]1/COX-2 inhibitors [ e.g., aspirin ] and COX-2 selective inhibitors [ e.g., coxibs (coxibs) ], mast cell stabilizers, and inflammatory body inhibitors. Examples of inflammatory body inhibitors (e.g., inhibitors of their assembly or function) include, but are not limited to, NLRP3(NALP3) inhibitors (e.g., interleukin-4 [ IL-4], omega-3 fatty acids, anthraquinones (anthraquinones) [ e.g., chrysophanol (chrysophanol) ], sesquiterpene lactones (sesquiterpene lactone) [ e.g., parthenolide) ], sulfonylureas [ e.g., glyburide (glyburide) ], triterpenes (triterpenes) [ e.g., asiatic acid (asiatic acid) ] and vinylsulfones [ e.g., Bay 11-7082]), NLRP3/AIM2 inhibitors (e.g., diarylsulfonylureas [ e.g., nlcp-456,773 ]), NLRP1 inhibitors (e.g., Bcl-2, and Bcl-1 region inhibitors, NLRP B), and analogs thereof) (e.g., chrysophanol-B), NLRP B), and analogs thereof), Fragments and salts.

Non-limiting examples of corticosteroids (not including mineralocorticoids) include hydrocortisone (hydrocortisone) types (e.g., cortisone (cortisone), hydrocortisone [ cortisol (cortisol) ], prednisolone (prednisone), methylprednisolone (methylprednisone), prednisone (prednisone), and tixocortol), betamethasone (betamethasone) types (e.g., betamethasone (betamethasone), dexamethasone (dexamethasone), and fluocortolone), halogenated steroids (halometasone) (e.g., alclomethasone (alclomethasone), beclomethasone (beclomethasone), clobetasol (clobetamethasone), clobetasone (clobetasone), clobetamethasone), and related substances (e.g., flunisolone), triamcinolone (flusone), and related substances (e.g., halometasone), amcinonide, budesonide, ciclesonide, desonide, fluocinolone acetonide [ fluocinolone acetonide ], halcinonide, triamcinolone and triamcinolone, carbonates, such as prednisolone, and analogs, derivatives and salts thereof.

examples of non-steroidal anti-inflammatory drugs (NSAIDs) include, but are not limited to:

Acetic acid derivatives, such as aceclofenac (aceclofenac), bromfenac (bronfnac), diclofenac (diclofenac), etodolac (etodolac), indomethacin (indomethacin), ketorolac (ketorolac), nabumetone (nabumetone), sulindac (sulindac), sulindac sulfide (sulindac sulfide), sulindac sulfone (sulindac sulfone), and tolmetin (tolmetin);

Anthranilic acid derivatives (fenamic acids), such as fluorobenzoic acid (flufenamic acid), meclofenamic acid (meclofenamic acid), mefenamic acid (mefenamic acid), and tolfenamic acid (tolfenamic acid);

enolic acid derivatives (oxicams), such as droxicam (droxicam), isoxicam (isoxicam), lornoxicam (lornoxicam), meloxicam (meloxicam), piroxicam (piroxicam) and tenoxicam (tenoxicam);

Propionic acid derivatives, such as fenoprofen (fenoprofen), flurbiprofen (flurbiprofen), ibuprofen (ibuprofen), dexibuprofen (dexibuprofen), ketoprofen (ketoprofen), dexketoprofen, loxoprofen (loxoprofen), naproxen (naproxen), and oxaprozin (oxaprozin);

salicylates, such as diflunisal (diflunisal), salicylic acid, acetylsalicylic acid (aspirin), choline trisalicylate (choline magnesium trisalicylate), and salsalate (salsalate);

COX-2 selective inhibitors, such as aliskirib (apricoxib), celecoxib (celecoxib), etoricoxib (etoricoxib), felicoxib (firocoxib), floroxib (flerocoxib) (e.g., floroxib A-C), lumiracoxib (lumiracoxib), mevalonxib (mavacoxib), parecoxib (parecoxib), rofecoxib (rofecoxib), temacoxib (tillmacoxib) (JTE-522), valdecoxib (devacoxib), 4-O-methyl and magnolol (4-O-methonokiol), niflumic acid (niflumuric acid), DuP-697, 00649, GW406381, NS-40398, SC-58125, benzothieno [3,2-d ] pyrimidin-4-one sulfonamide thio derivatives (benzothiazino [3,2-d ] pyrimidin-4-one sulfonimide thio-derivatives), and COX-2 inhibitors from Tribulus terrestris;

other classes of NSAIDs, such as anilinopyridinecarboxylic acid (aniloforbic acid) such as lonicin (clonixin), sulfonanilide (sulfenides) such as nimesulide (nimesulide), a dual inhibitor of lipoxygenase such as 5-LOX and cyclooxygenase such as COX-2 (e.g., chebulagic acid, linclolone, 2- (3,4, 5-trimethoxyphenyl) -4- (N-methylindol-3-yl) thiophene and di-tert-butylphenol compounds [ e.g., DTPBHZ, DTPINH, DTPNHZ and DTPSAL ]); and

analogs, derivatives and salts of the above.

in non-central and central pattern atrophy, mast cells degranulate in the choroid, releasing histamine and other inflammatory mediators. Mast cell stabilizers block calcium channels necessary for mast cell degranulation, stabilize mast cells, and thereby prevent the release of histamine and other immune mediators. Examples of mast cell stabilizers include, but are not limited to, β 2-adrenergic receptor agonists, cromoglycic acid (cromoglicanic acid), ketotifen (ketotifen), methylxanthines (methyxanthines), nedocromil (nedocromil), olopatadine (olopatadine), omalizumab (omalizumab), perosis (pemirolast), quercetin, tranilast (tranilast), and analogs, derivatives, and salts thereof. Examples of short-acting β 2-adrenergic agonists include, but are not limited to, bitolterol, fenoterol, albuterol, isoproterenol, levansalinol, levansalbuterol, calcitonin, procalcitonine, pirbuterol, procaterol, ritodrine, salbutamol, terbutaline, derivatives and salts thereof. Non-limiting examples of long-acting beta 2-adrenergic agonists include arformoterol (arformoterol), bambuterol (bambuterol), clenbuterol (clenbuterol), formoterol (formoterol), salmeterol (salmeterol), and analogs, derivatives, and salts thereof. Examples of ultralong-acting beta 2-adrenergic agonists include, but are not limited to, carmoterol (carmoterol), indacaterol (indacaterol), milveterol (milveterol), olodaterol (olodaterol), vilanterol (vilanterol), and analogs, derivatives, and salts thereof.

in summary, examples of anti-inflammatory agents include, but are not limited to, hydroxychloroquine, anti-amyloid agents, antioxidants, apolipoprotein mimics (e.g., apoA-I mimics and apoE mimics), C-reactive protein inhibitors, complement inhibitors, inflammatory body inhibitors, neuroprotective agents (e.g., glatiramer acetate), corticosteroids, steroids with little glucocorticoid activity (e.g., anecortave), non-steroidal anti-inflammatory drugs (NSAIDs), mast cell stabilizers, cyclopentenone prostaglandins, anti-angiogenic agents (e.g., anti-VEGF/VEGFR agents), and immunosuppressive agents.

Other therapeutic agents that may be used to treat atrophic AMD and/or neovascular AMD include immunosuppressive agents. The immunosuppressant may have anti-inflammatory properties. Examples of immunosuppressive agents include, but are not limited to, inhibitors of interleukin-2 (IL-2) signaling, production, or secretion (e.g., antagonists of IL-2 receptor alpha subunit [ e.g., basiliximab and daclizumab ], mTOR inhibitors [ e.g., rapamycin (sirolimus)), polypemide (deforolimus) (ridaforolimus), everolimus (everolimus), temsirolimus (temsirolimus), temsirolimus (limulus) (biolimus a9) and zokitamulus (zotarolimus) ], and calcineurin inhibitors [ e.g., cyclosporine (cyclosporine), pimecrolimus (pimecrolimus) and tacrolimus) ], and tumor necrosis factor (e.g., TNF-alpha) inhibitors (e.g., adalimumab (adalimumab), certolizumab (certolizumab), tacrolimus (tacrolimus)), and tacrolimus (e-a), and non-limited use of the inhibitors of edalimumab, and potential for the use of tacrolimus (e). Immunosuppressive agents may reduce the number or frequency of administration of anti-angiogenic agents (e.g., the number or frequency of injections of anti-VEGF/VEGFR agents) in the treatment of neovascular AMD.

Matrix Metalloproteinases (MMPs) degrade extracellular matrix (ECM) proteins and play important roles in cell migration (dispersion and adhesion), cell proliferation, cell differentiation, angiogenesis and apoptosis. For example, as AMD progresses to the advanced stage, elevated MMP levels denature bruch's membrane (BrM), ECM, and a portion of the choroid. Endothelial cells migrate along the ECM to the site of injury, proliferate, form endothelial vessels, and mature into new blood vessels that are produced by capillaries in the choroid and grow through the ruptured BrM. In addition, the disruption in BrM may allow endothelial cells to migrate into the sub-RPE-BL space and form leaky and tortuous immature vessels and may extend into the subretinal space. The end result is the development of neovascularisation (including CNV) and neovascular AMD. MMPs can also cleave peptide bonds of cell surface receptors, releasing pro-apoptotic ligands (e.g., FAS). MMP inhibitors are useful, for example, in inhibiting angiogenesis and apoptosis, and in treating neovascular AMD (including neovascularization of type 1,2, and/or 3) or atrophic AMD (including non-central and/or central pattern atrophy). For example, doxycycline reduces the loss of photoreceptors. Non-limiting examples of MMP inhibitors include tissue inhibitors of metalloproteinases (e.g., TIMP 1,2, 3, and 4), tetracyclines (e.g., doxycycline, incyclidine, and minocycline), dichloromethylene diphosphonic acid (dichloromethylene diphosphonic acid), batimastat (batimastat), cimastat (cipimastat), ilomastat (ilomastat), marimastat (marimastat), marimastat (tanomastat), MMI-166, MMI-270, Ro 28-2653, RS-130830, Reg No. (CAS N) 56-97-5, 46N 29-84, CRN-556052, CRN-593-3893-68, CRN-3932, CRN-3873, CRN-3873-3-3873, and analogs, derivatives, fragments and salts thereof.

Other types of cell migration inhibitors may be used instead of or in addition to MMP inhibitors. For example, rho kinase (ROCK) inhibitors, including ROCK1 and ROCK2 inhibitors, block cell migration, including endothelial cell migration at the early stages of neovascularization. Examples of ROCK inhibitors include, but are not limited to, fasudil (fasudil), neratidil (netarssuldil), rapasudil (ripassail), GSK-429286A, RKJ-1447, Y-27632, and Y-30141.

in some cases, it may be desirable to use an MMP activator rather than an MMP inhibitor. Mediated by MMPs and TIMPs, BrM undergoes constant turnover. BrM thicken progressively with age, partly due to elevated TIMP levels and resulting in reduced ECM turnover. BrM, the thickening of the ECM with age may result in BrM retaining the lipoproteins secreted by the RPE, ultimately leading to the formation of BLinD and drusen. Accumulation of lipid-rich BLinD and basal lamellar deposits (BlamD, which is excess extracellular matrix in thickened RPE-BL) prolongs the diffusion distance between choroidal capillaries and RPE. MMP activators can be used to achieve increased BrM turnover and decreased BrM thickening, but not to the extent that BrM becomes so denatured that new blood vessels can grow through BrM. Examples of MMP activators include, but are not limited to, bassein (extracellular matrix metalloproteinase inducer [ EMMPRIN ] or CD147), concanavalin (concanavalin) a, cytochalasin (cytochalasin) D, and analogs, derivatives, fragments, and salts thereof. Similarly, matrix metalloproteases can be used to reduce the thickness of the BLamD persisting at BrM.

Angiogenesis is a potential mechanism for neovascularization (including types 1,2, and 3), which can occur at advanced stages of AMD to cause neovascular AMD and severe loss of vision if left untreated. Neovascular AMD is characterized by vascular growth and fluid leakage in the choroid, sub-RPE-BL space, subretinal space, and the neural retina. Vascular leakage is more responsible for the neovascular AMD-associated vision loss than for the growth of neovessels. Vascular Endothelial Growth Factor (VEGF) plays a key role in the pathogenesis of neovascular AMD. VEGF is a potent secreted endothelial mitogen that stimulates the migration and proliferation of endothelial cells and increases the permeability of new blood vessels, resulting in leakage of fluids, blood, and proteins therefrom. In addition, VEGF increases levels of MMPs, which further denatures ECM. In addition, VEGF enhances the inflammatory response. However, VEGF or its receptor is not the only potential target for anti-angiogenic agents. For example, targeting integrins associated with receptor tyrosine kinases with integrin (integrin) inhibitors (e.g., ALG-1001) inhibits the generation and growth of new blood vessels and reduces permeability (leakage) of blood vessels. Angiogenesis may also be inhibited by inhibiting other targets, including but not limited to kinases (e.g., tyrosine kinases, such as receptor tyrosine kinases) and phosphatases (e.g., tyrosine phosphatases, such as receptor tyrosine phosphatases).

anti-angiogenic agents are useful for preventing or reducing neovascularization (including types 1,2, and 3), and reducing permeability/leakage of blood vessels. For example, interleukin-18 (IL-18) eliminates VEGF from the eye, thereby inhibiting the formation of damaging blood vessels behind the retina. Non-limiting examples of anti-angiogenic agents include inhibitors of VEGF (e.g., squalamine, PAN-90806, anti-VEGF antibodies and fragments thereof (e.g., bevacizumab rabizumab ESBA1008 and ESBA903), anti-VEGF aptamers (e.g., pegaptanib), anti-VEGF-designed ankyrin repeat proteins [ DARPins ] (e.g., peipibi (abipolar) AGN-150998 or MP0112]), soluble VEGFR [ e.g., VEGFR1], and soluble fusion proteins containing one or more extracellular domains of one or more VEGFRs [ e.g., VEGFR1 and VEGFR2] (e.g., aflibercept (aflibercept) and combasicept (conbercept)), VEGF receptor (VEGFR) inhibitors (e.g., axitinib (axitinib), pazopanib (pazopanib), sorafenib (sorafenib), sunitinib (sutinib), X-82, VEGFR-X-gfr), anti-VEGF-derived antibodies and platelet-derived inhibitors such as PDGF (337210), platelet-growth factor (PDGF) and/or fragment thereof (PDGF) and antibodies (e.g., PDGF 38), and platelet-derived antibodies (PDGF) and/or antibodies thereto, anti-PDGF aptamers (e.g., E10030), anti-PDGF antibodies and fragments thereof, and soluble PDGFR) or receptor (PDGFR) inhibitors thereof (e.g., axitinib, pazopanib, sorafenib, sunitinib, X-82, and anti-PDGFR antibodies and fragments thereof [ e.g., REGN2176-3]), inhibitors of Fibroblast Growth Factor (FGF) (e.g., squalamine, anti-FGF antibodies and fragments thereof, anti-FGF aptamers, and soluble FGFR) or receptor (FGFR) inhibitors thereof (e.g., anti-FGFR antibodies and fragments thereof), inhibitors of angiogenin (e.g., anti-angiogenin antibodies and fragments thereof (e.g., nesvacumab [ REGN910] and REGN910-3), and soluble angiogenin receptors) or receptor inhibitors thereof (e.g., anti-angiogenin receptor antibodies and fragments thereof, inhibitors of integrins (e.g., ALG-1001, JSM-6427, and anti-integrin antibodies and fragments thereof), Anecortave (anecortave acetate), angiostatin (e.g. angiostatin K1-3), α v β 3 inhibitors (e.g. etalizumab), apoA-I mimetics (e.g. L-4F and L-5F), berberine, bleomycin (bleomycin), borrelidin (borrelidin), carboxyamidotriazole (carboxycyanidetriazole), chondrogenic angiogenesis inhibitors (e.g. chondroregulatin I and troponin I), castanospermine (castanospermine), CM101, inhibitors of the complement system, cyclopropene fatty acids (e.g. sterculic acid), α -difluoromethylornithine (diflorothionine), endostatin (eostellatin), everolimus, fumagillin (fumagillin), interleukin-12, troconazole-12F, interleukin-12 (trozosin), Rituximide (linomide), MMP inhibitors, 2-methoxyestradiol, Pigment Epithelium Derived Factor (PEDF), platelet factor-4, PPAR-alpha agonists (such as fibrates), PPAR-gamma agonists (such as thiazolidinediones), prolactin, anti-angiogenic siRNA, sphingosine-1-phosphate inhibitors (such as Senecilomab (sonepcizumab)), squalene, staurosporine (staurosporine), angiostatic steroids (such as tetrahydrocortisol) plus heparin, stilbenes, suramin, SUS416, Taquinimod (tasquinimod), Tecagan (tecogalan), tetrathiomolybdate (tetrathiomorphobdate), thalidomide (thalidomide) and its derivatives (such as lenalidomide (lenalidomide) and pomalidomide (pomidomide)), thiabendazole (thiabendazole), platelet response protein (thrombospondin (such as thrombospondin 1), TNFat-1, TNFa-A470), Nippodamide (TNFa A), and analogs, derivatives, fragments and salts thereof.

One or more anti-angiogenic agents may be administered at an appropriate time to prevent or reduce the risk of developing pathologies that may result in severe loss of vision. In certain embodiments, one or more anti-angiogenic agents are administered prior to the occurrence of scarring (fibrosis) or substantial occurrence thereof.

The anti-angiogenic agents described herein may have additional beneficial properties. For example, the anti-PDGF aptamer E10030 may also have an anti-fibrotic effect by reducing subretinal fibrosis, which may lead to central vision loss in about 10-15% of neovascular AMD patients.

In some embodiments, two or more anti-angiogenic agents targeting different angiogenic mechanisms are used to inhibit neovascularization (including types 1,2, and 3), reduce permeability/leakage of blood vessels, and treat neovascular AMD. In certain embodiments, the two or more anti-angiogenic agents comprise an anti-VEGF/VEGFR agent (e.g., aflibercept, bevacizumab, or ranibizumab) and a substance that targets a different angiogenic mechanism. In some embodiments, the two or more anti-angiogenic agents comprise an anti-VEGF/VEGFR agent and an anti-PDGF/PDGFR agent, such as bevacizumab or ranibizumab and E10030, or aflibercept and REGN 2176-3. E10030 blocks PDGF-B binding to native receptors on pericytes, causing pericytes to dissect from newly formed abnormal blood vessels. Without protection, endothelial cells are very susceptible to anti-VEGF agents. Due to this ability to exfoliate pericytes, E10030 may have an effect on immature and more mature vessels later in the disease process. In further embodiments, the two or more anti-angiogenic agents comprise an anti-VEGF/VEGFR agent and an anti-angiopoietin/angiopoietin receptor agent, such as aflibercept and neffersumab or REGN 910-3.

Alternatively, anti-angiogenic agents targeting different angiogenic mechanisms may be used to treat, for example, neovascular AMD. For example, bispecific antibodies or darpins targeting VEGF/VEGFR and PDGF/PDGFR, or bispecific antibodies or darpins targeting VEGF/VEGFR and angiopoietin/angiopoietin receptors may be used.

AMD can also be treated with other types of therapy, including Laser Photocoagulation Therapy (LPT), photodynamic therapy (POT), and Radiotherapy (RT). LPT employs, for example, an argon (Ar) laser, a micro-pulsed laser, or a nanosecond laser, or any combination thereof, and can reduce or eliminate drusen in patients with atrophic AMD or neovascular AMD. Laser surgery can also be used to destroy abnormal blood vessels in the eye, and is generally appropriate if the abnormal blood vessels grow less extensively and are not close to the fovea. PDT utilizes laser light in combination with a compound (e.g., verteporfin) that, when activated by light of a particular wavelength, damages target cells without damaging normal cells. Steroids may optionally be administered in PDT. PDT is commonly used to treat polypoidal neovascularisation, the most common form of neovascularization in asian populations. Examples of RT include, but are not limited to, external beam irradiation, focal radiation (e.g., delivered intravitreally, vitreally, or transpupillary) (e.g., strontium 90[90Sr ] X-rays delivered vitreally at a dose of 15Gy or 24 Gy), and radiation that binds an anti-VEGF/VEGFR agent (e.g., 90Sr X-rays combined with bevacizumab at a single 24Gy dose, or combined with ranibizumab at 16Gy X-rays delivered vitreally). PDT or RT may be provided to reduce neovascularization (e.g., CNV) and limit vision loss or improve vision in neovascular AMD patients. In some embodiments, LPT, PDT or RT, or any combination or all thereof, is provided to a patient with neovascular AMD who is not sufficiently responsive to treatment with an anti-angiogenic agent (e.g., an anti-VEGF/VEGFR agent).

in addition, cell replacement therapies and stem cell-based therapies, such as stem cell-derived Retinal Pigment Epithelial (RPE) cells, may be used to treat AMD. As illustrative examples, apolipoprotein mimics [ e.g., apoA-I mimics (e.g., L-4F) and/or apoE mimics (e.g., AEM-28-14) ] may be used in combination with RPE cell replacement to treat, for example, advanced stages of AMD, including central geographic atrophy and neovascular AMD. RPE cells may atrophy and die due to rampant lipid deposition on the sub-RPE-BL space and BrM. Removal of lipid deposits from the sub-RPE-BL spaces and BrM normalized BrM structure and function and improved transport of micronutrients (including vitamin a) into and waste products out of the choroidal capillaries to the RPE, and thereby improved RPE cell health. Thus, advanced stage AMD patients can be first treated with lipid-clearing apo mimetics [ e.g., apoA-I mimetics (e.g., L-4F) and/or apoE mimetics (e.g., AEM-28-14) ] and then receive RPE cell replacement (e.g., by one or more injections or implants in, for example, the space under the retina). The RPE cells may be, for example, stem cell-derived RPE cells (e.g., human embryonic stem cells [ hESC ], human neural stem cells [ hNSC ], bone marrow stem cells, and induced pluripotent stem cells [ iPSC ] (including autologous stem cells)), or RPE cells obtained from translocation of the whole retina. Removal of lipid deposits in the eye by apo mimetics can produce beneficial effects, such as reducing local inflammation, oxidative stress, and complement activation, which can help prevent or prevent RPE cell atrophy and death.

As an example of RPE cell replacement therapy, RPE cells may be introduced as a thin layer on a polymer or other suitable carrier material that allows the cells to interdigitate with the remaining photoreceptors and restore important phagocytosis and vitamin a transfer functions among other functions. Lipid-scavenging apo mimetics [ e.g., apoA-I mimetics (e.g., L-4F) and/or apoE mimetics (e.g., AEM-28-14) ] improve the circulation of nutrient ingress and waste egress through BrM and thereby improve the health of cells in the surrounding area. Optionally in combination with a substance (e.g., matrix metalloproteinase) that reduces the thickness of the basal lamina deposit (BLamD) still on BrM, the apo mimetic helps to prepare a suitable graft bed for a thin layer of RPE cells, which benefits from a clear path from the choroidal capillaries to the graft scaffold.

As another example of RPE cell replacement therapy, cells may be introduced into the eye by non-surgical methods. Bone marrow cells can be reprogrammed to settle on the RPE layer and stay between native RPE cells. apo mimetics [ e.g., apoA-I mimetics (e.g., L-4F) and/or apoE mimetics (e.g., AEM-28-14) ] that increase transport of nutrients into and waste out through BrM and thereby improve the health of cells in the RPE layer, optionally in combination with a substance (e.g., matrix metalloprotease) that reduces the thickness of BLamD remaining on BrM.

RPE regeneration may also be implemented. For example, free-floating cells (e.g., umbilical cord cells) can be injected to provide trophic support for existing cells (e.g., neurons and RPE cells). Lipid-clearing apo mimetics [ e.g., apoA-I mimetics (e.g., L-4F) and/or apoE mimetics (e.g., AEM-28-14) ] improve the circulation of nutrient ingress and waste egress across BrM and thereby improve the health of cells in the region of the choroidal drainage tract. Optionally in combination with a substance (e.g., matrix metalloproteinase) that reduces the thickness of BLamD still at BrM, the apo mimetic helps to prepare a suitable dispersed bed for the injected cells.

In addition, AMD can be treated by cell replacement therapy of the choroidal capillaries. For example, the choriocapillaris endothelium may be replaced with choroidal capillary endothelial cells derived from stem cells.

Loss of vessels (dropout)/loss of choroidal capillaries and reduction of choroidal blood flow may occur early in the pathogenesis of AMD. In early AMD, the vascular density of choroidal capillaries is inversely related to the density of sub-RPE-BL deposits (e.g. drusen and BLinD), and the number of "ghost" vessels (remnants of previously healthy capillaries) is positively related to the sub-RPE-BL deposit density. Activation of the complement system and formation of MAC in choroidal capillaries, which can be inhibited by the use of complement inhibitors (e.g., inhibitors of MAC formation, deposition or function), can cause loss of vascular endothelial cells. Endothelial dysfunction may also be caused by the following causes: 1) the reduction in the amount of nitric oxide, which may be due to high levels of dimethylarginine (interfering with L-arginine stimulated nitric oxide synthesis), may be corrected by the use of substances that increase the level of nitric oxide (e.g., a stimulator of nitric oxide synthesis or an inhibitor of dimethylarginine formation; 2) an increase in reactive oxygen species that can impair nitric oxide synthesis and activity, and can be inhibited by the use of antioxidants (e.g., scavengers of reactive oxygen species); and 3) inflammatory events that can be inhibited by an agent that inhibits endothelial inflammatory events (e.g., an apoA-I mimetic, such as Rev-D-4F). Reduction of Choroidal Blood Flow (CBF) may be improved by the use of CBF-increasing substances such as CBF promoters (e.g., MC-1101) or vasodilators (e.g., hyperpolarization-mediated [ calcium channel blockers, e.g., adenosine ], cAMP-mediated [ e.g., prostacyclin ], cGMP-mediated [ e.g., nitric oxide ], inhibition of phosphodiesterases [ PDEs ] [ e.g., moxivirine or sildenafil { a PDE5 inhibitor } ], or inhibition of complement polypeptides that cause smooth muscle contraction [ e.g., C3a, C4a, and C5a ]). Increasing CBF may prevent BrM from cracking. To treat vascular loss and/or reduce CBF, at least one or more therapeutic agents that maintain or improve the health of the endothelium and/or blood flow to the ocular vasculature, including the therapeutic agents described herein, may be administered early in AMD.

In some embodiments, an apolipoprotein mimetic (e.g., apoA-I mimetic [ e.g., L-4F ] and/or apoE mimetic [ e.g., AEM-28-14]) is used in combination with one or more additional therapeutic agents for the treatment of AMD. In certain embodiments, the apo mimetic and one or more additional therapeutic agents have a synergistic effect.

Treatment of AMD with apolipoprotein mimetics and anti-angiogenic agents

Some embodiments of the present disclosure relate to methods of treating AMD, comprising administering to a subject in need of treatment a therapeutically effective amount of an apolipoprotein (apo) mimetic, whether or not the apo mimetic is administered to the ocular region, intraocular, in, or periocular at a dose of about 0.1 or 0.3mg to about 1.5mg per administration (e.g., per injection), or a total dose of about 0.5 or 1mg to about 10mg over a period of about 6 months, and a therapeutically effective amount of an antiangiogenic agent. All embodiments relating to treatment of AMD with apolipoprotein mimics are also applicable to treatment of AMD with apo mimics and anti-angiogenic agents, the embodiments being described in section IV and elsewhere herein.

Examples of apolipoprotein mimics (including apoA-I mimics and apoE mimics) include, but are not limited to, those described elsewhere herein. In some embodiments, the apo mimetic comprises an apoA-I mimetic or is an apoA-I mimetic. In certain embodiments, the apoA-I mimetic includes 4F or a variant or salt thereof (e.g., acetate), or is 4F or a variant or salt thereof (e.g., acetate). In some embodiments, all of the amino acid residues of 4F have the L-form (L-4F). In other embodiments, one or more or all of the amino acid residues of 4F have the D form (e.g., D-4F with all amino acid residues in the D form). 4F may have a protecting group at the N-terminus (e.g., an acyl group such as acetyl) and/or a protecting group at the C-terminus (e.g., an amide group such as-C (O) NH 2). In certain embodiments, the apoA-I mimetic comprises L-4F having the structure Ac-DWFKAFYDKVAEKFKEAF-NH2(SEQ. ID. NO.13), or L-4F having the structure Ac-DWFKAFYDKVAEKFKEAF-NH2(SEQ. ID. NO. 13). In further embodiments, the apo mimetic comprises an apoE mimetic, or is an apoE mimetic. In certain embodiments, the apoE mimetic includes AEM-28-14 or a variant or salt thereof, or is AEM-28-14 or a variant or salt thereof.

Examples of anti-angiogenic agents include, but are not limited to, those described elsewhere herein. In some embodiments, the anti-angiogenic agent comprises or is an agent that inhibits the action of vascular endothelial growth factor (anti-VEGF agent), including but not limited to VEGF-A, VEGF-B and Placental Growth Factor (PGF). Non-limiting examples of anti-VEGF agents include those described elsewhere herein. In certain embodiments, the anti-VEGF agent comprises or is aflibercept bevacizumab or ranibizumab, or any combination or all thereof. In further embodiments, the anti-angiogenic agent comprises a substance that inhibits the action of platelet derived growth factor (anti-PDGF agent) or is a substance that inhibits the action of platelet derived growth factor (anti-PDGF agent) including but not limited to PDGF-A, PDGF-B, PDGF-C, PDGF-D and PDGF-A/B. Non-limiting examples of anti-PDGF agents include those described elsewhere herein. In certain embodiments, the anti-PDGF agent comprises or is E10030

In some embodiments, whether the apo mimetic is administered topically at a dose of about 0.1 or 0.3mg to about 1.5mg per administration (e.g., per injection), or is administered topically at a total dose of about 0.5 or 1mg to about 10mg over a period of about 6 months, the anti-angiogenic agent (e.g., anti-VEGF agent) is administered less frequently than conventional or recommended dosing frequency, and/or at a dose that is less than conventional or recommended dose, for the anti-angiogenic agent in the absence of treatment with the apo mimetic [ e.g., apoA-I mimetic (e.g., L-4F) and/or apoE mimetic (e.g., AEM-28-14) ]. In some embodiments, the conventional or recommended dosing frequency is at least about 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, or 6-fold (e.g., at least about 2-fold) less frequent (e.g., by intravitreal injection) administration of the anti-angiogenic agent (e.g., anti-VEGF agent) without treatment with an apo mimetic [ e.g., an apoA-I mimetic (e.g., L-4F) and/or an apoE mimetic (e.g., AEM-28-14) ], as compared to the conventional or recommended dosing frequency of the anti-angiogenic agent. In certain embodiments, the anti-angiogenic agent (e.g., an anti-VEGF agent) is administered topically to the eye, intraocularly, or periocularly (e.g., by intravitreal injection) once every 2, 3,4,5, or 6 months. In further embodiments, treatment with an apo mimetic [ e.g., an apoA-I mimetic (e.g., L-4F) and/or an apoE mimetic (e.g., AEM-28-14) ] reduces the total number of administrations (e.g., total number of injections) of an anti-angiogenic agent (e.g., an anti-VEGF agent). In certain embodiments, the anti-angiogenic agent (e.g., anti-VEGF agent) is administered (e.g., by intravitreal injection) no more than about 20, 18, 15, 12, or 10 times. In further embodiments, the conventional or recommended dose is for an anti-angiogenic agent (e.g., an anti-VEGF agent) to be administered (e.g., by intravitreal injection) at a dose that is at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, or 80% (e.g., at least about 20%), or about 10-30%, 30-50%, or 50-70% less than an apo mimetic [ e.g., apoA-I mimetic (e.g., L-4F) and/or apoE mimetic (e.g., AEM-28-14) ] without treatment with an apo mimetic (e.g., an apo a-I mimetic (e.g., L-4F) and/or an apo e mimetic (e.g., AEM-28-14) ].

Treatment of AMD with an apo mimetic [ e.g., an apoA-I mimetic (e.g., L-4F) and/or an apoE mimetic (e.g., AEM-28-14) ] and an anti-angiogenic agent (e.g., an anti-VEGF agent) can have a synergistic effect. For example, treatment with an apo mimetic (e.g., an apoA-I mimetic and/or an apoE mimetic) can enhance the efficacy of an anti-angiogenic agent, and/or vice versa. For example, L-4F can significantly reduce lipid deposition of bruch's membrane (BrM) and structurally remodel BrM to a normal or healthier state, thereby reducing the sensitivity of BrM to: invasion of new blood vessels that grow out of the choroid, through BrM, and into the sub-RPE-BL space and the subretinal space in type 1 and type 2 Neovascularization (NV). As another example, the ability of L-4F to reduce inflammation (an important stimulus of NV), by inhibiting, for example, activation of the complement system and formation of pro-inflammatory oxidized lipids, can reduce the number of administrations (e.g., by injection) required and/or the dose of anti-angiogenic agent. Synergy between the apo mimetic (e.g., apo a-I mimetic and/or apo e mimetic) and the anti-angiogenic agent may allow, but does not require, for example, that the anti-angiogenic agent be administered at a frequency and/or dose that is lower than a conventional or recommended dosing frequency and/or dose that is lower than a conventional or recommended dose for the anti-angiogenic agent without treatment with the apo mimetic (e.g., apo a-I mimetic and/or apo e mimetic).

Administration of lower doses of anti-angiogenic agents can have benefits, such as better safety due to fewer side effects. Administration (e.g., by intravitreal injection) of anti-angiogenic agents at a lower frequency may also have benefits, such as greater/better patient comfort, convenience, compliance, and health due to less invasive procedures being performed. Frequent administration can burden both the care provider and the patient due to frequent out-patient visits for testing, monitoring, and treatment. In addition, anti-angiogenic agents (e.g., anti-VEGF agents) may become less effective when used repeatedly, a phenomenon known as tachyphylaxis. In addition, risks of intravitreal injections include elevated intraocular pressure, bacterial and sterile endophthalmitis, cataract formation, hemorrhage, and retinal detachment, and repeated injections can result in retinal thinning and pattern atrophy.

In certain embodiments, the anti-angiogenic agent comprises or is aflibercept and is administered at 2mg once per 2 months intravitreal injection after 2mg once per month administration for 3 months prior to treatment compared to the conventional or recommended dose and frequency of administration of aflibercept for the case of no treatment with an apo mimetic [ e.g., an apoA-I mimetic (e.g., L-4F) and/or an apoE mimetic (e.g., AEM-28-14) ], aflibercept is administered at a dose of about 1-1.5mg or 1.5-2mg once per 3 months, 4 months, 5 months, or 6 months (e.g., by intravitreal injection), optionally after about 1-1.5mg or 1.5-2mg once per month for the first 1 month, 2 months or 3 months, or about 1-1.5mg or 1.5-2mg once every 6 weeks for the first 1.5 or 3 months, and about 1-1.5mg or 1.5-2mg once every 3 months, 4 months, 5 months, or 6 months (e.g., by intravitreal injection). It is estimated that the intravitreal half-life of aflibercept is about 9.0 days.

In other embodiments, the anti-angiogenic agent comprises or is aflibercept, and the conventional or recommended dosing frequency is for aflibercept administered (e.g., by intravitreal injection) at a dose of about 1-1.25mg, 1.25-1.5mg, or 1.5-1.75mg without treatment with an apo mimetic [ e.g., apoA-I mimetic (e.g., L-4F) and/or apoE mimetic (e.g., AEM-28-14) ] at a frequency substantially similar or the same as the conventional or recommended dosing frequency for aflibercept.

In a further embodiment, the anti-angiogenic agent comprises or is ranibizumab and is administered by intravitreal injection at 0.5mg once a month compared to the conventional or recommended dose and frequency of administration of ranibizumab for administration (e.g., by intravitreal injection) once every 2 months, 3 months, 4 months, 5 months, or 6 months at a dose of about 0.2-0.3mg, 0.3-0.4mg, or 0.4-0.5mg (e.g., by intravitreal injection) without treatment with an apo mimetic [ e.g., apoA-I mimetic (e.g., L-4F) and/or apoE mimetic (e.g., AEM-28-14) ], optionally once a month before 1,2, or 3 months at a dose of about 0.2-0.3mg, 0.3-0.4mg, or 0.4-0.5mg once a month, or ranibizumab is administered (e.g., by intravitreal injection) once every 2 months, 3 months, 4 months, 5 months, or 6 months at a dose of about 0.2-0.3mg, 0.3-0.4mg, or 0.4-0.5mg after administration once every 6 weeks at a dose of about 0.2-0.3mg, 0.3-0.4mg, or 0.4-0.5mg for the first 1.5 or 3 months. It is estimated that the intravitreal half-life of ranibizumab is about 7.1 days.

In other embodiments, the anti-angiogenic agent comprises or is ranibizumab, and the ranibizumab is administered (e.g., by intravitreal injection) once per month at a dose of about 0.2-0.3mg or 0.3-0.4 mg.

In further embodiments, the anti-angiogenic agent comprises or is bevacizumab and is administered by intravitreal injection about 1.25mg once a month compared to bevacizumab for the treatment of AMD, for example, once a2 month, 3 month, 4 month, 5 month, or 6 month dose (e.g., by intravitreal injection) of bevacizumab at about 0.5-0.75mg, 0.75-1mg, or 1-1.25mg once a2 month, 3 month, 4 month, 5 month, or 6 month without treatment with apo mimetics [ e.g., apoA-I mimetics (e.g., L-4F) and/or apoE mimetics (e.g., AEM-28-14) ], optionally once a month monthly dose of about 0.5-0.75mg, 0.75-1mg, or 1-1.25mg for the first 1,2, or 3 months, or once a monthly dose of about 0.5-0.75mg, 0.75-1mg or 1-1.25mg for the first 1.5 or 3 months, After a dose of 0.75-1mg or 1-1.25mg is administered once every 6 weeks, bevacizumab is administered (e.g., by intravitreal injection) once every 2 months, 3 months, 4 months, 5 months, or 6 months at a dose of about 0.5-0.75mg, 0.75-1mg, or 1-1.25 mg. It is estimated that the intravitreal half-life of bevacizumab is about 9.8 days.

In other embodiments, the anti-angiogenic agent comprises or is bevacizumab, and bevacizumab is administered (e.g., by intravitreal injection) once a month at a dose of about 0.5-0.75mg or 0.75-1 mg.

In some embodiments, the duration/length of treatment with the anti-angiogenic agent (e.g., anti-VEGF agent) is no more than about 36, 30, 24, 18, or 12 months. In certain embodiments, the duration of treatment with the anti-angiogenic agent (e.g., anti-VEGF agent) is no more than about 24, 18, or 12 months. In further embodiments, the duration of treatment with the anti-angiogenic agent (e.g., anti-VEGF agent) is about 6-12, 12-18, or 18-24 months.

In some embodiments, an anti-angiogenic agent (e.g., an anti-VEGF agent) is administered to treat or slow the progression of neovascular (wet) AMD, including Neovascular (NV) types 1,2, and 3 and including when there is evidence of active neovascular formation. The presence of sub-RPE-BL, subretinal or intraretinal fluid (which may indicate active neovascularization and fluid leakage in new blood vessels) may be detected by techniques such as OCT-fluorescence angiography. In certain embodiments, an anti-angiogenic agent (e.g., an anti-VEGF agent) is administered when the presence of subretinal or intraretinal fluid is detected. Anti-angiogenic agents (e.g., anti-VEGF agents) may also be used when sub-RPE-BL fluid is detected, although pigment epithelial detachment caused by sub-RPE-BL fluid may remain stable for a relatively long period of time and anti-angiogenic therapy may not be required. In further embodiments, an anti-angiogenic agent (e.g., an anti-VEGF agent) is administered at least at an advanced stage of AMD to prevent, delay the onset, or slow the progression of neovascular AMD. In certain embodiments, an anti-angiogenic agent (e.g., an anti-VEGF agent) is administered (e.g., by intravitreal injection) less frequently and/or at a lower dose for preventing, delaying the onset of, or slowing the progression of neovascular AMD, as compared to treating or slowing the progression of neovascular AMD.

With respect to apo mimetics, in certain embodiments, an apo mimetic [ e.g., an apo a-I mimetic (e.g., L-4F) and/or an apo e mimetic (e.g., AEM-28-14) ] is administered (e.g., by intravitreal injection) locally to the eye, intraocularly, or periocularly at a dose of about 0.1 or 0.3-1.5mg, 0.1-0.5mg, 0.5-1.5 mg, 1-1.5mg, 0.1-0.3mg, 0.3-0.5mg, 0.5-0.75mg, 0.75-1mg, 1-1.25mg, or 1.25-1.5mg (e.g., about 0.1-0.5mg, or 0.5-1mg) per administration (e.g., per injection). The apo mimetic can also be administered topically at a dose of greater than 1.5mg per administration, e.g., up to about 2mg or more per administration (e.g., per injection). In further embodiments, the apo mimetic [ e.g., apo A-I mimetic (e.g., L-4F) and/or apo E mimetic (e.g., AEM-28-14) ] is administered topically (e.g., by intravitreal injection or by sustained release composition) at a total dose of about 0.5 or 1-10mg, 0.5 or 1-5mg, 5-10mg, 0.5 or 1-3mg, 3-5mg, 5-7.5mg, or 7.5-10mg (e.g., about 0.5-3mg or 3-5mg) over a period of about 6 months, wherein the duration/length of treatment with the apo mimetic can be, for example, about 6-12, 12-18, or 18-24 months or longer. The apo mimetics may also be administered topically at a total dose of greater than 10mg over a period of about 6 months, for example up to about 15mg or more over a period of about 6 months. In still further embodiments, for a complete/complete treatment regimen using an apo mimetic, the apo mimetic [ e.g., apoA-I mimetic (e.g., L-4F) and/or apoE mimetic (e.g., AEM-28-14) ] is administered topically at a total dose of about 1 or 2-20mg, 5-15mg, 1-5mg, 5-10mg, 10-15mg, 15-20mg, 1-3mg, 3-5mg, 5-7.5mg, 7.5-10mg, 10-12.5mg, 12.5-15mg, 15-17.5mg, or 17.5-20mg (e.g., about 1-5mg or 5-10 mg). The apo mimetics can also be administered topically at a total dose greater than 20mg for a complete treatment regimen, e.g., up to a total dose of about 25mg, 30mg, 40mg, 50mg, or more for a complete treatment regimen.

In embodiments where the apo mimetic [ e.g., apoA-I mimetic (e.g., L-4F) and/or apoE mimetic (e.g., AEM-28-14) ] is administered topically, intraocularly, or periocularly, the dose per administration, the total dose over a period of about 6 months, and the total dose for the entire treatment regimen is in certain embodiments for each eye administered, and in other embodiments for both eyes. The blood system may allow for a localized administration (e.g., injection) of an apo mimetic into one eye or some amount (e.g., a therapeutically effective amount) of the apo mimetic in one eye to be distributed to the other eye, in which case the dose of the apo mimetic may be optionally adjusted (e.g., increased) in view of the other eye (which may be in a less diseased condition), and may allow for simultaneous treatment of both eyes with the apo mimetic without additional administration (e.g., injection) of the apo mimetic within or in the other eye. For example, intravitreally injected apo mimetics can cross the blood-retinal barrier to reach two target regions (i.e., the sub-RPE-BL space and bruch's membrane), from which they can enter the choroidal capillaries and ultimately to the corresponding unadministered eye. Without being bound by theory, some amount of apo mimetic can enter the corresponding unapplied eye by the aqueous humor pathway, which is drained through the trabecular meshwork and schlemm's canal into the blood system. Accordingly, some embodiments relate to a method of treating AMD, comprising administering to a subject in need of treatment a therapeutically effective amount of an apolipoprotein mimic and a therapeutically effective amount of an anti-angiogenic agent, wherein the apolipoprotein mimic is administered to the ocular region, in or around the eye in one eye and both eyes have a therapeutic effect.

In further embodiments, the apo mimetic [ e.g., apoA-I mimetic (e.g., L-4F) and/or apoE mimetic (e.g., AEM-28-14) ] is administered topically (e.g., by intravitreal injection) once per month (4 weeks) or every 1.5 months (6 weeks). In other embodiments, the apo mimetic [ e.g., apoA-I mimetic (e.g., L-4F) and/or apoE mimetic (e.g., AEM-28-14) ] is administered topically (e.g., by intravitreal injection) once every 2 months (8 weeks), every 2.5 months (10 weeks), or every 3 months (12 weeks). In other embodiments, the apo mimetic [ e.g., apoA-I mimetic (e.g., L-4F) and/or apoE mimetic (e.g., AEM-28-14) ] is administered topically (e.g., by intravitreal injection or by a sustained release composition) once every 4, 5, or 6 months. In further embodiments, the apo mimetic [ e.g., apoA-I mimetic (e.g., L-4F) and/or apoE mimetic (e.g., AEM-28-14) ] is administered topically for a total of about 15 or less, 12 or less, 9 or less, 6 or less, or 3 or less (e.g., 3-6 or 7-10) administrations (e.g., injections). A total of more than 15 administrations (e.g., injections) of the apo mimetic can also be topically administered, such as up to about 20 or more administrations (e.g., injections). In embodiments where the apo mimetic is administered topically, intra-ocularly, in-ocularly, or periocularly, the frequency of administration and the total number of administrations (e.g., injections) is in certain embodiments for each eye administered, and in other embodiments for both eyes, since the apo mimetic may also have a therapeutic effect in the corresponding non-administered eye.

In some embodiments, an apo mimetic [ e.g., an apoA-I mimetic (e.g., L-4F) and/or an apoE mimetic (e.g., AEM-28-14) ] is administered at least during the advanced stages of AMD to treat or slow the progression of neovascular AMD, including NV types 1,2, and 3. In further embodiments, an apo mimetic [ e.g., an apoA-I mimetic (e.g., L-4F) and/or an apoE mimetic (e.g., AEM-28-14) ] is administered at least at an advanced stage of AMD to treat or slow progression of central Geographic Atrophy (GA), and/or to prevent or delay onset of neovascular AMD. In additional embodiments, an apo mimetic [ e.g., an apoA-I mimetic (e.g., L-4F) and/or an apoE mimetic (e.g., AEM-28-14) ] is administered at least during the intermediate stages of AMD to treat or slow the progression of non-central GA, and/or prevent or delay the onset of central GA and/or neovascular AMD.

In some embodiments, an apo mimetic [ e.g., an apoA-I mimetic (e.g., L-4F) and/or an apoE mimetic (e.g., AEM-28-14) ] and/or an anti-angiogenic agent (e.g., an anti-VEGF agent) is administered locally to the eye, within the eye, in the eye, or around the eye. Potential routes, sites and topical administration are described elsewhere herein. In some embodiments, the apo mimetic [ e.g., apoA-I mimetic (e.g., L-4F) and/or apoE mimetic (e.g., AEM-28-14) ] and/or anti-angiogenic agent (e.g., anti-VEGF agent) is administered by injection (e.g., intravitreal, subconjunctival, subretinal, or sub-tenon's capsule injection), eye drops, or implants (e.g., intravitreal, subretinal, or sub-tenon's capsule implants). In certain embodiments, the apo mimetic [ e.g., apoA-I mimetic (e.g., L-4F) and/or apoE mimetic (e.g., AEM-28-14) ] and the anti-angiogenic agent (e.g., anti-VEGF agent) are administered by injection (e.g., intravitreal, subconjunctival, subretinal, or sub tenon's capsule injection). In further embodiments, an apo mimetic [ e.g., an apoA-I mimetic (e.g., L-4F) and/or an apoE mimetic (e.g., AEM-28-14) ] and/or an anti-angiogenic agent (e.g., an anti-VEGF agent) is administered by a sustained release composition. Non-limiting examples of sustained release compositions include those described elsewhere herein.

In certain embodiments, the apo mimetic [ e.g., apoA-I mimetic (e.g., L-4F) and/or apoE mimetic (e.g., AEM-28-14) ] is administered locally to the eye, intraocularly, in the eye, or periocularly at an early stage of treatment, and then the apo mimetic is administered systemically. As non-limiting examples, the initial administration (e.g., the first one to five administrations) of the apo mimetic can be by injection locally (e.g., intravitreal, subconjunctival, subretinal, or sub-tenon's capsule injection) and then the apo mimetic can be administered systemically, e.g., orally, parenterally (e.g., subcutaneously, intramuscularly, or intravenously), or topically (e.g., intranasally or pulmonary). In other embodiments, the apo mimetic is administered topically only. In other embodiments, the apo mimetic is administered systemically only.

The apo mimetic [ e.g., apoA-I mimetic (e.g., L-4F or a variant or salt thereof) and/or apoE mimetic (e.g., AEM-28-14 or a variant or salt thereof) ] and the anti-angiogenic agent (e.g., an anti-VEGF agent, such as aflibercept, bevacizumab, and/or ranibizumab) may be administered either in the same pharmaceutical composition or in separate pharmaceutical compositions, wherein the compositions further comprise one or more pharmaceutically acceptable excipients or carriers. If the apo mimetic (e.g., apoA-I mimetic and/or apoE mimetic) and the anti-angiogenic agent are administered via the same composition, such composition may be prepared in advance or may be prepared by combining the apo mimetic and the anti-angiogenic agent into the same formulation shortly or just prior to administration (e.g., by injection) of the formulation. Administration of an apo mimetic (e.g., an apoA-I mimetic and/or an apoE mimetic) and an anti-angiogenic agent in the same composition reduces the number of potentially invasive procedures (e.g., intravitreal injections) performed on a patient compared to separate administration of the therapeutic agent, which may have the following benefits: such as improved patient compliance and health due to less invasive procedures.

In certain embodiments, a composition comprising an apo mimetic [ e.g., an apoA-I mimetic (e.g., L-4F) and/or an apoE mimetic (e.g., AEM-28-14) ] comprises about 75-95% (e.g., about 90%) and about 5-25% (e.g., about 10%) by weight or molar concentration of the corresponding apolipoprotein (e.g., apoA-I and/or apoE) or active portions thereof or domains thereof, relative to their combined amount, whether or not an anti-angiogenic agent (e.g., an anti-VEGF agent) is present.

In some embodiments, a composition comprising an apo mimetic [ e.g., an apoA-I mimetic (e.g., L-4F) and/or an apoE mimetic (e.g., AEM-28-14) ] and/or a composition comprising an anti-angiogenic agent (e.g., an anti-VEGF agent), whether the same composition or separate compositions, comprises one or more excipients that inhibit peptide/protein aggregation, increase peptide/protein solubility, decrease solution viscosity, or increase peptide/protein stability, or any combination or all thereof. Examples of such excipients include, but are not limited to, those described elsewhere herein, and the use of these excipients may have benefits as described elsewhere herein. For example, such excipients may improve the injectability of the composition and thus may allow for injection using needles having smaller gauges. Furthermore, the use of these excipients can reduce the volume required to administer a given amount of peptide or protein, and thus can lower intraocular pressure if the peptide or protein is administered by injection into the eye. Furthermore, the use of such excipients may allow for the administration of a larger dose of peptide or protein for a given volume, which may allow for less frequent administration of peptide or protein for a given total dose administered over a period of time.

In some embodiments, an anti-angiogenic agent (e.g., an anti-VEGF agent) is administered at a dose that is higher than a conventional or recommended dose (e.g., by intravitreal injection) and at a frequency that is lower than a conventional or recommended dosing frequency for the anti-angiogenic agent in the absence of treatment with an apo mimetic [ e.g., an apoA-I mimetic (e.g., L-4F) and/or an apoE mimetic (e.g., AEM-28-14) ]. In certain embodiments, the conventional or recommended dose is for administration (e.g., by intravitreal injection) of the anti-angiogenic agent (e.g., anti-VEGF agent) at a dose that is at least about 10%, 20%, 30%, 50%, 75%, 100%, 150%, or 200% (e.g., at least about 30%), or about 10-30%, 30-50%, 50-100%, 100-150%, or 150-200% (e.g., about 50-100%) higher than the conventional or recommended dose of the anti-angiogenic agent in the absence of treatment with an apo mimetic [ e.g., apoA-I mimetic (e.g., L-4F) and/or apoE mimetic (e.g., AEM-28-14) ]. In further embodiments, the conventional or recommended dosing frequency is at least about 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, or 6-fold (e.g., at least about 2-fold) less frequent (e.g., by intravitreal injection) than administration of the anti-angiogenic agent (e.g., anti-VEGF agent) without treatment with an apo mimetic [ e.g., apoA-I mimetic (e.g., L-4F) and/or apoE mimetic (e.g., AEM-28-14) ].

In certain embodiments, the anti-angiogenic agent comprises or is aflibercept and is administered as an intravitreal injection at 2mg every 2 months after 2mg once a month for 3 months prior to treatment and at 2mg once a month as compared to the conventional or recommended dose and frequency of administration of aflibercept for administration (e.g., by intravitreal injection) once every 3 months, optionally at about 2.2 to 2.5mg, 2.5 to 3mg, 3 to 3.5mg, or 3.5 to 4mg once every 3 months, 4 months, 5 months, or 6 months (e.g., by intravitreal injection) at a dose of about 2.2 to 2.5mg, 2.5 to 3mg, 3 to 3.5mg, or 3.5 to 4mg without treatment with an apo mimetic (e.g., apoA L-4F mimetic (e.g., AEM-28-14) and/or a dose of aflibercept, After a dose of 2.5-3mg, 3-3.5mg, or 3.5-4mg is administered once a month, or after about 2.2-2.5mg, 2.5-3mg, 3-3.5mg, or 3.5-4mg is administered once every 6 weeks for the first 1.5 or 3 months, aflibercept is administered once every 3 months, 4 months, 5 months, or 6 months (e.g., by intravitreal injection) at a dose of about 2.2-2.5mg, 2.5-3mg, 3-3.5mg, or 3.5-4 mg.

In other embodiments, the anti-angiogenic agent comprises or is ranibizumab and is administered by intravitreal injection at 0.5mg once a month compared to a conventional or recommended dose and frequency of administration of ranibizumab that is about 0.55-0.75mg, 0.75-1mg, 1-1.25mg, or 1.25-1.5mg once every 2 months, 3 months, 4 months, 5 months, or 6 months (e.g., by intravitreal injection) at a dose not treated with an apo mimetic [ e.g., apoA-I mimetic (e.g., L-4F) and/or apoE mimetic (e.g., AEM-28-14) ], optionally about 0.55-0.75mg, 0.75-1mg, 1-1.25mg, or 1.25-1.5mg once a month prior to 1,2 months, 3 months, or 6 months, or ranibizumab is administered (e.g., by intravitreal injection) once every 2 months, 3 months, 4 months, 5 months, or 6 months at a dose of about 0.55-0.75mg, 0.75-1mg, 1-1.25mg, or 1.25-1.5mg, after once every 6 weeks at a dose of about 0.55-0.75mg, 0.75-1mg, 1-1.25mg, or 1.25-1.5mg for the first 1.5 or 3 months.

In other embodiments, the anti-angiogenic agent comprises or is bevacizumab and is administered by intravitreal injection about 1.25mg once a month compared to bevacizumab for the treatment of AMD, for a conventional or recommended dose and frequency of administration of bevacizumab at about 1.4-1.75mg, 1.75-2mg, 2-2.5mg, or 2.5-3mg once every 2 months, 3 months, 4 months, 5 months, or 6 months (e.g., by intravitreal injection) without treatment with an apo mimetic [ e.g., apoA-I mimetic (e.g., L-4F) and/or apoE mimetic (e.g., AEM-28-14) ], optionally at a dose of about 1.4-1.75mg, 1.75-2mg, 2-2.5mg, or 2.5-3mg once a month or once every 3 months after one month or 3.5 months of administration After a month of administration at a dose of about 1.4-1.75mg, 1.75-2mg, 2-2.5mg, or 2.5-3mg once every 6 weeks, bevacizumab is administered (e.g., by intravitreal injection) at a dose of about 1.4-1.75mg, 1.75-2mg, 2-2.5mg, or 2.5-3mg once every 2 months, 3 months, 4 months, 5 months, or 6 months.

One or more of the other therapeutic agents described herein can be used in combination with an apo mimetic [ e.g., an apoA-I mimetic (e.g., L-4F) and/or an apoE mimetic (e.g., AEM-28-14) ] and an anti-angiogenic agent (e.g., an anti-VEGF agent) for the treatment of AMD. In some embodiments, the additional therapeutic agent comprises or is the following: an anti-dyslipidemia agent (e.g., a statin such as atorvastatin), an antioxidant (e.g., a vitamin, safranine carotenoid and/or zinc) or a complement inhibitor (e.g., a C5 inhibitor (such as ARC1905 or LFG316), or a complement factor D inhibitor (such as lanreolizumab)), or any combination or all thereof. The use of apo mimetics [ e.g., apoA-I mimetics (e.g., L-4F) and/or apoE mimetics (e.g., AEM-28-14) ] can enhance the efficacy of one or more other therapeutic agents, e.g., improve altered intraliposomal balance, reduce oxidative stress, and/or reduce inflammation. In certain embodiments, the additional therapeutic agent comprises ARC1905 or LFG316, or is ARC1905 or LFG 316.

In some embodiments, an apo mimetic [ e.g., an apoA-I mimetic (e.g., L-4F) and/or an apoE mimetic (e.g., AEM-28-14) ] and an anti-angiogenic agent (e.g., an anti-VEGF agent) are used in combination with an anti-inflammatory agent (e.g., an NSAID (e.g., bromfenac) and/or a corticosteroid (e.g., triamcinolone)) or an immunosuppressive agent (e.g., an IL-2 inhibitor (e.g., daclizumab or rapamycin) or a TNF-a inhibitor (e.g., infliximab)) to treat neovascular AMD. Inflammation is a stimulator of NV, and thus anti-inflammatory agents or immunosuppressive agents can inhibit NV. Thus, the use of anti-inflammatory agents or immunosuppressive agents can reduce the number or frequency of administration (e.g., injection) of anti-angiogenic agents. In further embodiments, an apo mimetic [ e.g., an apoA-I mimetic (e.g., L-4F) and/or an apoE mimetic (e.g., AEM-28-14) ] and an anti-angiogenic agent (e.g., an anti-VEGF agent) are used in combination with a neuroprotective agent (e.g., an endogenous neuroprotective agent (e.g., CNTF)). The use of neuroprotective agents can prevent or reduce the degeneration of retinal cells (e.g., photoreceptors).

In some embodiments, the additional therapeutic agent is administered at least during the advanced stages of AMD. In further embodiments, the additional therapeutic agent is administered at least during the intermediate stage of AMD. In still further embodiments, the additional therapeutic agent is administered at least at an early stage of AMD. In certain embodiments, the additional therapeutic agents administered at least during the early stages of AMD include or are the following: an anti-dyslipidemic agent that reduces lipid production (e.g., a statin) and optionally an antioxidant (e.g., a vitamin, safranine carotenoid and/or zinc) and/or an anti-inflammatory agent (e.g., an NSAID), and the additional therapeutic agent is administered systemically (e.g., orally) or topically (e.g., via eye drops).

apo mimetics [ e.g., apoA-I mimetics (e.g., L-4F) and/or apoE mimetics (e.g., AEM-28-14) ] in combination with anti-angiogenic agents (e.g., anti-VEGF agents such as aflibercept, bevacizumab or ranibizumab, and/or anti-PDGF agents such as E10030) can also be used to treat other ocular diseases and disorders in addition to AMD. Non-limiting examples of other ocular diseases or conditions that may be treated with such a combination include: diabetic macular Degeneration (DMP) (including partially ischemic DMP), Diabetic Macular Edema (DME) (including clinically significant DME [ CSME ], focal DME and diffuse DME), diabetic retinopathy (including in DME patients), Retinal Vein Occlusion (RVO), central RVO (including central RVO with cystoid macular edema [ CME ]), branched RVO (including branched RVO with CME), macular edema following RVO (including central RVO and branched RVO), Irvine-gas syndrome (post-operative macular edema), and uveitis (including post-CME onset uveitis). The beneficial properties of apo mimetics [ e.g., apoA-I mimetics (e.g., L-4F) and/or apoE mimetics (e.g., AEM-28-14) ] (e.g., their strong anti-inflammatory properties) can increase the effectiveness of anti-angiogenic agents (e.g., anti-VEGF agents) to treat these ocular diseases and conditions. Embodiments that involve the use of apo mimetics [ e.g., apoA-I mimetics (e.g., L-4F) and/or apoE mimetics (e.g., AEM-28-14) ] in combination with an anti-angiogenic agent (e.g., an anti-VEGF agent) to treat AMD are also applicable to the use of the combination to treat other ocular diseases and conditions.

treatment of AMD with apolipoprotein mimics and complement inhibitors

Other embodiments of the present disclosure relate to methods of treating AMD, comprising administering to a subject in need of treatment a therapeutically effective amount of an apolipoprotein (apo) mimetic and a therapeutically effective amount of a complement inhibitor, whether or not the apo mimetic is administered to the ocular region, intraocular, in, or periocular at a dose of about 0.1 or 0.3mg to about 1.5mg per administration (e.g., per injection), or about 0.5 or 1mg to about 10mg in total over a period of about 6 months. All embodiments relating to treatment of AMD with apolipoprotein mimics are also applicable to treatment of AMD with apo mimics and complement inhibitors, and are described in section IV and elsewhere herein.

Examples of apolipoprotein mimics (including apoA-I mimics and apoE mimics) include, but are not limited to, those described elsewhere herein. In some embodiments, the apo mimetic comprises an apoA-I mimetic or is an apoA-I mimetic. In certain embodiments, the apoA-I mimetic includes 4F or a variant or salt thereof (e.g., acetate), or is 4F or a variant or salt thereof (e.g., acetate). In some embodiments, all of the amino acid residues of 4F have the L-form (L-4F). In other embodiments, one or more or all of the amino acid residues of 4F have the D form (e.g., D-4F with all amino acid residues in the D form). 4F may have a protecting group at the N-terminus (e.g., an acyl group such as acetyl) and/or a protecting group at the C-terminus (e.g., an amide group such as-C (O) NH 2). In certain embodiments, the apoA-I mimetic comprises L-4F having the structure Ac-DWFKAFYDKVAEKFKEAF-NH2(SEQ. ID. NO.13), or L-4F having the structure Ac-DWFKAFYDKVAEKFKEAF-NH2(SEQ. ID. NO. 13). In further embodiments, the apo mimetic comprises an apoE mimetic, or is an apoE mimetic. In certain embodiments, the apoE mimetic includes AEM-28-14 or a variant or salt thereof, or is AEM-28-14 or a variant or salt thereof.

Non-limiting examples of complement inhibitors include those described elsewhere herein. In some embodiments, the complement inhibitor comprises lanreolizumab, LFG316, or ARC1905 or lanreolizumab, LFG316, or ARC1905, or any combination or all thereof. In certain embodiments, the complement inhibitor comprises, or is, lanebolizumab. In some embodiments, the subject has a mutation in a gene encoding Complement Factor I (CFI), which may be a biomarker that has a more positive response to treatment with lanreolizumab. CFI, a C3b/C4b inactivator, modulates complement activation by cleaving cell-bound C3b and C4b or liquid phase C3b and C4 b.

In some embodiments, an apo mimetic [ e.g., an apoA-I mimetic (e.g., L-4F) and/or an apoE mimetic (e.g., AEM-28-14) ] and a complement inhibitor (e.g., lanebolizumab) are administered for the treatment of Geographic Atrophy (GA). In some embodiments, an apo mimetic [ e.g., an apoA-I mimetic (e.g., L-4F) and/or an apoE mimetic (e.g., AEM-28-14) ] and a complement inhibitor (e.g., lanreolizumab) are administered for preventing central GA, delaying the onset of central GA, or slowing central GA progression. In certain embodiments, an apo mimetic [ e.g., an apoA-I mimetic (e.g., L-4F) and/or an apoE mimetic (e.g., AEM-28-14) ] and a complement inhibitor (e.g., lanreolizumab) are administered at least during the late (late) stage of atrophic (dry) AMD to treat or slow the progression of central GA, and/or to prevent or delay the onset of neovascular AMD. In further embodiments, the apo mimetic [ e.g., apoA-I mimetic (e.g., L-4F) and/or apoE mimetic (e.g., AEM-28-14) ] and complement inhibitor (e.g., lanreolizumab) ] are administered at least during the intermediate stage of AMD to treat or slow the progression of non-central GA, and/or to prevent or delay the onset of central GA and/or neovascular AMD. In additional embodiments, an apo mimetic [ e.g., an apoA-I mimetic (e.g., L-4F) and/or an apoE mimetic (e.g., AEM-28-14) ] and a complement inhibitor (e.g., Lanbolizumab) are administered at least at the early stage of AMD or the initial stage of intermediate stage AMD to prevent or delay the onset of non-central GA. In certain embodiments, a complement inhibitor (e.g., lanreolizumab) and/or an apo mimetic [ e.g., an apoA-I mimetic (e.g., L-4F) and/or an apoE mimetic (e.g., AEM-28-14) ] is administered less frequently and/or at a lower dose for preventing or delaying the onset of non-central or central GA than for treating or slowing the progression of central GA.

in certain embodiments, treatment with an apo mimetic [ e.g., an apoA-I mimetic (e.g., L-4F) and/or an apoE mimetic (e.g., AEM-28-14) ] and a complement inhibitor (e.g., lanreolizumab) slows the progression of central GA and/or non-central GA (e.g., reduces the rate of GA progression, or reduces GA lesion area or size) by at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, or 80% (e.g., at least about 20% or 40%), or about 20-40%, 40-60%, or 60-80%. In further embodiments, treatment with an apo mimetic [ e.g., an apoA-I mimetic (e.g., L-4F) and/or an apoE mimetic (e.g., AEM-28-14) ] and a complement inhibitor (e.g., Landolizumab) ] slows the progression of central GA and/or non-central GA (e.g., reduces the rate of GA progression, or reduces GA lesion area or size) by at least about 10%, 20%, 30%, 50%, 100%, 150%, 200%, or 300% (e.g., at least about 20% or 30%), or about 10-30%, 30-50%, 50-100%, 100-200%, or 200-300% (e.g., about 50-100%) more than treatment with a complement inhibitor without treatment with the apo mimetic.

Treatment of AMD (including central and non-central GAs) with an apo mimetic [ e.g., an apoA-I mimetic (e.g., L-4F) and/or an apoE mimetic (e.g., AEM-28-14) ] and a complement inhibitor (e.g., Lanbolizumab) can have a synergistic effect. For example, treatment with an apo mimetic (e.g., an apoA-I mimetic and/or an apoE mimetic) can enhance the efficacy of a complement inhibitor, and/or vice versa. For example, L-4F can clear the lipid barrier on bruch's membrane, which improves the exchange of nutrients (including vitamin a) from the choroidal capillaries to RPE cells and photoreceptors, thereby reducing the death of RPE and photoreceptor cells. As another example, the ability of L-4F to reduce inflammation may reduce the number of administrations (e.g., by injection) required and/or the dose of complement inhibitor. Synergy between the apo mimetic (e.g., apo a-I mimetic and/or apo e mimetic) and the complement inhibitor may allow, but does not require, for example, administration of the complement inhibitor at a frequency and/or dose that is lower than conventional or recommended dosing frequency or dose for the complement inhibitor without treatment with the apo mimetic. Administration of lower doses of complement inhibitors can have benefits, such as better safety due to fewer side effects. As described elsewhere herein, administration of complement inhibitors (e.g., by intravitreal injection) at a lower frequency can have significant benefits to patients and care providers.

In some embodiments, whether the apo mimetic is administered locally at a dose of about 0.1 or 0.3mg to about 1.5mg per administration (e.g., per injection), or locally at a total dose of about 0.5 or 1mg to about 10mg over a period of about 6 months, the complement inhibitor (e.g., lanreolizumab) is administered less frequently than conventional or recommended dosing frequency, and/or at a dose less than conventional or recommended dose, for the complement inhibitor in the absence of treatment with the apo mimetic [ e.g., apoA-I mimetic (e.g., L-4F) and/or apoE mimetic (e.g., AEM-28-14) ]. In some embodiments, the conventional or recommended dosing frequency is at least about 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, or 6-fold (e.g., at least about 2-fold) less frequent (e.g., by intravitreal injection) administration of a complement inhibitor (e.g., lanreolizumab) in the absence of treatment with an apo mimetic [ e.g., an apoA-I mimetic (e.g., L-4F) and/or an apoE mimetic (e.g., AEM-28-14) ], as compared to the conventional or recommended dosing frequency of the complement inhibitor. In certain embodiments, the complement inhibitor (e.g., lanebolizumab) is administered topically to the eye, intraocularly, or periocularly (e.g., by intravitreal injection) once every 2, 3,4, 5, or 6 months (e.g., every 2 months). In further embodiments, treatment with an apo mimetic [ e.g., an apoA-I mimetic (e.g., L-4F) and/or an apoE mimetic (e.g., AEM-28-14) ] reduces the total number of administrations (e.g., the total number of injections) of a complement inhibitor (e.g., Lanbolizumab). In certain embodiments, the complement inhibitor (e.g., lanebolizumab) is administered locally (e.g., by intravitreal injection) no more than about 20, 18, 15, 12, or 10 times. In further embodiments, the conventional or recommended dose is for a complement inhibitor (e.g., lanreolizumab) to be administered at a dose that is at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, or 80% (e.g., at least about 20%), or about 10-30%, 30-50%, or 50-70% less than that of a complement inhibitor (e.g., by intravitreal injection) without treatment with an apo mimetic [ e.g., an apoA-I mimetic (e.g., L-4F) and/or an apoE mimetic (e.g., AEM-28-14) ].

In certain embodiments, the complement inhibitor comprises or is ranibizumab, and is administered once per month by intravitreal injection at about 10mg compared to the conventional or recommended dose and frequency of administration of ranibizumab for the absence of treatment with an apo mimetic [ e.g., apoA-I mimetic (e.g., L-4F) and/or apoE mimetic (e.g., AEM-28-14) ], administration of ranibizumab at a dose of about 4-6mg, 6-8mg, or 8-10mg once per 2 months, 3 months, 4 months, 5 months, or 6 months (e.g., by intravitreal injection), optionally after once per month administration at a dose of about 4-6mg, 6-8mg, or 8-10mg for the first 1 month, 2 months, or 3 months, or about 4-6mg, 6-8mg, or 8-10mg once every 6 weeks for the first 1.5 or 3 months, and about 2 months, 3 months, 4 months, 5 months, or 6 months for the Lanbollizumab (e.g., by intravitreal injection).

In other embodiments, the complement inhibitor comprises or is landolizumab, and the landolizumab is administered (e.g., by intravitreal injection) once per month (4 weeks) or 1.5 months (6 weeks) at a dose of about 3-5mg, 5-7mg, or 7-9 mg.

In some embodiments, the duration of treatment with the complement inhibitor (e.g., lanebolizumab) does not exceed about 36, 30, 24, 18, or 12 months. In certain embodiments, the duration of treatment with a complement inhibitor (e.g., lanebolizumab) is no more than about 24, 18, or 12 months. In further embodiments, the duration of treatment with a complement inhibitor (e.g., lanebolizumab) is about 6-12, 12-18, or 18-24 months.

With respect to apo mimetics, in certain embodiments, the apo mimetic [ e.g., apo a-I mimetic (e.g., L-4F) and/or apo e mimetic (e.g., AEM-28-14) ] is administered (e.g., by intravitreal injection) at a dose of about 0.1 or 0.3-1.5mg, 0.1-0.5mg, 0.5-1mg, 1-1.5mg, 0.1-0.3mg, 0.3-0.5mg, 0.5-0.75mg, 0.75-1mg, 1-1.25mg, or 1.25-1.5mg (e.g., about 0.1-0.5mg or 0.5-1mg) per administration (e.g., per injection) locally, intraocularly, or periocularly. The apo mimetic can also be administered topically at a dose of greater than 1.5mg per administration, e.g., up to about 2mg or more per administration (e.g., per injection). In further embodiments, the apo mimetic [ e.g., apo A-I mimetic (e.g., L-4F) and/or apo E mimetic (e.g., AEM-28-14) ] is administered topically (e.g., by intravitreal injection or by sustained release composition) at a total dose of about 0.5 or 1-10mg, 0.5 or 1-5mg, 5-10mg, 0.5 or 1-3mg, 3-5mg, 5-7.5mg, or 7.5-10mg (e.g., about 0.5-3mg or 3-5mg) over a period of about 6 months, wherein the duration/length of treatment with the apo mimetic can be, for example, about 6-12, 12-18, or 18-24 months or longer. The apo mimetics may also be administered topically at a total dose of greater than 10mg over a period of about 6 months, for example up to about 15mg or more over a period of about 6 months. In still further embodiments, for a complete/complete treatment regimen using an apo mimetic, the apo mimetic [ e.g., apoA-I mimetic (e.g., L-4F) and/or apoE mimetic (e.g., AEM-28-14) ] is administered topically at a total dose of about 1 or 2-20mg, 5-15mg, 1-5mg, 5-10mg, 10-15mg, 15-20mg, 1-3mg, 3-5mg, 5-7.5mg, 7.5-10mg, 10-12.5mg, 12.5-15mg, 15-17.5mg, or 17.5-20mg (e.g., about 1-5mg or 5-10 mg). The apo mimetics can also be administered topically at a total dose greater than 20mg for a complete treatment regimen, e.g., up to a total dose of about 25mg, 30mg, 40mg, 50mg, or more for a complete treatment regimen.

in embodiments where the apo mimetic [ e.g., apoA-I mimetic (e.g., L-4F) and/or apoE mimetic (e.g., AEM-28-14) ] is administered topically, intraocularly, or periocularly, the dose per administration, the total dose over a period of about 6 months, and the total dose for the entire treatment regimen is in certain embodiments for each eye administered, and in other embodiments for both eyes. The blood system may allow for a localized administration (e.g., injection) of an apo mimetic into one eye or some amount (e.g., a therapeutically effective amount) of the apo mimetic in one eye to be distributed to the other eye, in which case the dose of the apo mimetic may be optionally adjusted (e.g., increased) in view of the other eye (which may be in a less diseased condition), and may allow for simultaneous treatment of both eyes with the apo mimetic without additional administration (e.g., injection) of the apo mimetic within or in the other eye. For example, intravitreally injected apo mimetics can cross the blood-retinal barrier to reach two target regions (i.e., the sub-RPE-BL space and bruch's membrane), from which they can enter the choroidal capillaries and ultimately to the corresponding unadministered eye. Also without being bound by theory, some amount of apo mimetic can enter the corresponding unapplied eye through the aqueous humor pathway, which is drained through the trabecular meshwork and schlemm's canal that flows into the blood system. Accordingly, some embodiments relate to a method of treating AMD, comprising administering to a subject in need of treatment a therapeutically effective amount of an apolipoprotein mimic and a therapeutically effective amount of a complement inhibitor, wherein the apolipoprotein mimic is administered to the ocular local, intraocular, ocular or periocular in one eye and both eyes have a therapeutic effect.

In further embodiments, the apo mimetic [ e.g., apoA-I mimetic (e.g., L-4F) and/or apoE mimetic (e.g., AEM-28-14) ] is administered topically (e.g., by intravitreal injection) once per month (4 weeks) or every 1.5 months (6 weeks). In other embodiments, the apo mimetic [ e.g., apoA-I mimetic (e.g., L-4F) and/or apoE mimetic (e.g., AEM-28-14) ] is administered topically (e.g., by intravitreal injection) once every 2 months (8 weeks), every 2.5 months (10 weeks), or every 3 months (12 weeks). In other embodiments, the apo mimetic [ e.g., apoA-I mimetic (e.g., L-4F) and/or apoE mimetic (e.g., AEM-28-14) ] is administered topically (e.g., by intravitreal injection or by a sustained release composition) once every 4, 5, or 6 months. In further embodiments, the apo mimetic [ e.g., apoA-I mimetic (e.g., L-4F) and/or apoE mimetic (e.g., AEM-28-14) ] is administered topically for a total of about 15 or less, 12 or less, 9 or less, 6 or less, or 3 or less (e.g., 3-6 or 7-10) administrations (e.g., injections). Topical application of the apo mimetic can also be applied (e.g., injected) a total of more than 15 times, such as up to about 20 or more times. In embodiments where the apo mimetic is administered topically, intra-ocularly, in-ocularly, or periocularly, the frequency of administration and the total number of administrations (e.g., injections) is in certain embodiments for each eye administered, and in other embodiments for both eyes, since the apo mimetic may also have a therapeutic effect in the corresponding non-administered eye.

In some embodiments, an apo mimetic [ e.g., an apoA-I mimetic (e.g., L-4F) and/or an apoE mimetic (e.g., AEM-28-14) ] and/or a complement inhibitor (e.g., lanebolizumab) is administered topically, intraocularly, or periocularly. Potential routes, sites and topical administration are described elsewhere herein. In some embodiments, the apo mimetic [ e.g., apoA-I mimetic (e.g., L-4F) and/or apoE mimetic (e.g., AEM-28-14) ] and/or complement inhibitor (e.g., lanreolizumab) are administered by injection (e.g., intravitreal, subconjunctival, subretinal, or sub-tenon's capsule injection), eye drops, or implants (e.g., intravitreal, subretinal, or sub-tenon's capsule implants). In certain embodiments, the apo mimetic [ e.g., apoA-I mimetic (e.g., L-4F) and/or apoE mimetic (e.g., AEM-28-14) ] and complement inhibitor (e.g., Lamborrelizumab) are administered by injection (e.g., intravitreal, subconjunctival, subretinal, or sub-tenon's capsule injection). In further embodiments, an apo mimetic [ e.g., an apoA-I mimetic (e.g., L-4F) and/or an apoE mimetic (e.g., AEM-28-14) ] and/or a complement inhibitor (e.g., Lanbolizumab) is administered by a sustained release composition. Non-limiting examples of sustained release compositions include those described elsewhere herein.

In certain embodiments, the apo mimetic [ e.g., apoA-I mimetic (e.g., L-4F) and/or apoE mimetic (e.g., AEM-28-14) ] is administered locally to the eye, intraocularly, in the eye, or periocularly at an early stage of treatment, and then the apo mimetic is administered systemically. As non-limiting examples, the initial administration (e.g., the first one to five administrations) of the apo mimetic can be by injection locally (e.g., intravitreal, subconjunctival, subretinal, or sub-tenon's capsule injection) and then the apo mimetic can be administered systemically, e.g., orally, parenterally (e.g., subcutaneously, intramuscularly, or intravenously), or topically (e.g., intranasally or pulmonary). In other embodiments, the apo mimetic is administered topically only. In other embodiments, the apo mimetic is administered systemically only.

The apo mimetic [ e.g., apoA-I mimetic (e.g., L-4F or a variant or salt thereof) and/or apoE mimetic (e.g., AEM-28-14 or a variant or salt thereof) ] and complement inhibitor (e.g., lanreolizumab) can be administered either in the same pharmaceutical composition or in separate pharmaceutical compositions, wherein the compositions further comprise one or more pharmaceutically acceptable excipients or carriers. If the apo mimetic (e.g., apoA-I mimetic and/or apoE mimetic) and complement inhibitor are administered by the same composition, such composition can be prepared in advance or can be prepared by combining the apo mimetic and complement inhibitor into the same formulation shortly or immediately prior to administration (e.g., by injection) of the formulation. Administration of an apo mimetic (e.g., an apoA-I mimetic and/or an apoE mimetic) and a complement inhibitor in the same composition reduces the number of potentially invasive procedures (e.g., intravitreal injections) performed on the patient compared to separate administration of the therapeutic agent, which can have significant benefits to the patient and care provider as described elsewhere herein.

In some embodiments, a composition comprising an apo mimetic [ e.g., an apoA-I mimetic (e.g., L-4F) and/or an apoE mimetic (e.g., AEM-28-14) ] and/or a composition comprising a complement inhibitor (e.g., lanreolizumab) ] is formulated as an injectable solution or suspension (e.g., for intravitreal, subconjunctival, subretinal, or sub-tenon's capsule injection), whether in the same composition or in separate compositions. Examples of formulations for injection into the eye include, but are not limited to, those described elsewhere herein. In other embodiments, compositions containing an apo mimetic [ e.g., an apoA-I mimetic (e.g., L-4F) and/or an apoE mimetic (e.g., AEM-28-14) ] and/or compositions containing a complement inhibitor (e.g., Lanbolizumab) ] are formulated as eye drops or implants (e.g., intravitreal, subretinal, or sub-tenon's capsule implants), whether in the same composition or separate compositions. The potential problems associated with repeated injections can be avoided by using eye drops or implanting the implant once or twice. In further embodiments, compositions containing an apo mimetic [ e.g., an apoA-I mimetic (e.g., L-4F) and/or an apoE mimetic (e.g., AEM-28-14) ] and/or compositions containing a complement inhibitor (e.g., Lanbolizumab), whether the same composition or separate compositions, are configured for sustained release of the apo mimetic and/or complement inhibitor. Non-limiting examples of sustained release compositions include those described elsewhere herein. The use of sustained release compositions can reduce the number of potentially invasive procedures (e.g., intravitreal injections) performed to administer the drug and can improve the distribution of the amount of drug delivered to the target site over a period of time.

In certain embodiments, a composition comprising an apo mimetic [ e.g., an apoA-I mimetic (e.g., L-4F) and/or an apoE mimetic (e.g., AEM-28-14) ] comprises about 75-95% (e.g., about 90%) and about 5-25% (e.g., about 10%) of a corresponding apolipoprotein (e.g., apoA-I and/or apoE) or an active portion thereof or domain thereof by weight or molar concentration, relative to their combined amount, whether or not complement inhibitors (e.g., lanreozumab) are present.

In some embodiments, a composition comprising an apo mimetic [ e.g., an apoA-I mimetic (e.g., L-4F) and/or an apoE mimetic (e.g., AEM-28-14) ] and/or a composition comprising a complement inhibitor (e.g., lanreolizumab) ] comprises one or more excipients that inhibit peptide/protein aggregation, increase peptide/protein solubility, decrease solution viscosity, or increase peptide/protein stability, or any combination or all thereof, whether the same composition or separate compositions. Examples of such excipients include, but are not limited to, those described elsewhere herein, and the use of these excipients may have benefits as described elsewhere herein. For example, such excipients may improve the injectability of the composition and thus may allow for injection using needles having smaller gauges. Furthermore, the use of these excipients can reduce the volume required to administer a given amount of peptide or protein, and thus can lower intraocular pressure if the peptide or protein is administered by injection into the eye. Furthermore, the use of such excipients may allow for the administration of a larger dose of peptide or protein for a given volume, which may allow for less frequent administration of peptide or protein for a given total dose administered over a period of time.

In some embodiments, a complement inhibitor (e.g., lanreolizumab) is administered at a dose higher than a conventional or recommended dose (e.g., by intravitreal injection) and at a frequency lower than a conventional or recommended dosing frequency for the complement inhibitor without treatment with an apo mimetic [ e.g., an apoA-I mimetic (e.g., L-4F) and/or an apoE mimetic (e.g., AEM-28-14) ]. In certain embodiments, the conventional or recommended dose is for administration (e.g., by intravitreal injection) of a complement inhibitor (e.g., laparolizumab) at a dose that is at least about 10%, 20%, 30%, 50%, 75%, 100%, 150%, or 200% (e.g., at least about 30%), or about 10-30%, 30-50%, 50-100%, 100-150%, or 150-200% (e.g., about 50-100%) higher than the conventional or recommended dose of the complement inhibitor for treatment without apo mimetic [ e.g., apoA-I mimetic (e.g., L-4F) and/or apoE mimetic (e.g., AEM-28-14) ]. In further embodiments, the conventional or recommended dosing frequency is at least about 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, or 6-fold (e.g., at least about 2-fold) less frequent (e.g., by intravitreal injection) administration of a complement inhibitor (e.g., lanreolizumab) without treatment with an apo mimetic [ e.g., an apoA-I mimetic (e.g., L-4F) and/or an apoE mimetic (e.g., AEM-28-14) ], as compared to the conventional or recommended dosing frequency of the complement inhibitor.

In certain embodiments, the complement inhibitor comprises or is ranibizumab, and is administered once by intravitreal injection at about 10mg per month, as compared to the conventional or recommended dose and frequency of administration of ranibizumab for administration (e.g., by intravitreal injection) at a dose of about 12-14mg, 14-16mg, 16-18mg, or 18-20mg once every 2 months, 3 months, 4 months, 5 months, or 6 months (e.g., by intravitreal injection) without treatment with an apo mimetic [ e.g., apoA-I mimetic (e.g., L-4F) and/or apoE mimetic (e.g., AEM-28-14) ], optionally at about 12-14mg, 14-16mg, 14-14 mg, 4 months, 5 months, or 6 months prior to 1 month, 2 months, or 3 months, The dose of 16-18mg or 18-20mg is administered once a month, or after once every 6 weeks at a dose of about 12-14mg, 14-16mg, 16-18mg or 18-20mg for the first 1.5 or 3 months, the dose of Lanbolizumab is administered (e.g., by intravitreal injection) once every 2 months, 3 months, 4 months, 5 months or 6 months at a dose of about 12-14mg, 14-16mg, 16-18mg or 18-20 mg.

In additional embodiments, the apo mimetic [ e.g., apoA-I mimetic (e.g., L-4F) and/or apoE mimetic (e.g., AEM-28-14) ] and complement inhibitor are administered at least at the advanced stage of AMD to further prevent or delay the onset of neovascular (wet) AMD, and/or to treat or slow the progression of wet AMD, including type 1,2, and 3 neovascularisation. The complement inhibitor used to treat wet AMD can be the same as, different from, or additive to the complement inhibitor used to treat dry AMD, including geographic atrophy. In certain embodiments, the complement inhibitor comprises ARC1905 or LFG316, or is ARC1905 or LFG 316. In some embodiments, the anti-angiogenic agent is used in combination with an apo mimetic [ e.g., an apoA-I mimetic (e.g., L-4F) and/or an apoE mimetic (e.g., AEM-28-14) ] and a complement inhibitor for the treatment of wet AMD. In certain embodiments, the anti-angiogenic agent comprises or is the following: an anti-VEGF agent (e.g., aflibercept bevacizumab or ranibizumab, or any combination or all thereof) and/or an anti-PDGF agent (e.g., E10030).

In some embodiments, the anti-angiogenic agent (e.g., anti-VEGF agent) and/or complement inhibitor (e.g., ARC1905) is administered less frequently than a conventional or recommended dosing frequency or at a dose less than a conventional or recommended dose for the anti-angiogenic agent and/or complement inhibitor without treatment with an apo mimetic [ e.g., apoA-I mimetic (e.g., L-4F) and/or apoE mimetic (e.g., AEM-28-14) ]. In certain embodiments, the conventional or recommended dosing frequency is at least about 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, or 6-fold (e.g., at least about 2-fold) less frequent (e.g., by intravitreal injection) administration of the anti-angiogenic agent (e.g., anti-VEGF agent) and/or complement inhibitor (e.g., ARC1905) without treatment with an apo mimetic [ e.g., apoA-I mimetic (e.g., L-4F) and/or apoE mimetic (e.g., AEM-28-14) ]. In further embodiments, the conventional or recommended dose is for administration (e.g., by intravitreal injection) of the anti-angiogenic agent (e.g., anti-VEGF agent) and/or complement inhibitor (e.g., ARC1905) at a dose that is at least about 10%, 20%, 30%, 40%, 50%, 60%, 70% or 80% (e.g., at least about 20%), or about 10-30%, 30-50% or 50-70% less than it without treatment with an apo mimetic [ e.g., apoA-I mimetic (e.g., L-4F) and/or apoE mimetic (e.g., AEM-28-14) ]. Non-limiting examples of dosing frequency and dose of aflibercept, bevacizumab and ranibizumab are provided elsewhere herein.

One or more of the other therapeutic agents described herein can be used in combination with an apo mimetic [ e.g., an apoA-I mimetic (e.g., L-4F) and/or an apoE mimetic (e.g., AEM-28-14) ] and a complement inhibitor for the treatment of dry or wet AMD. In some embodiments, the additional therapeutic agent comprises or is the following: an antioxidant (e.g., a vitamin, safranine carotenoid and/or zinc), an anti-dyslipidemia agent (e.g., a statin (such as atorvastatin)), an anti-inflammatory agent (e.g., an NSAID (such as bromfenac), and/or a corticosteroid (such as fluocinolone acetonide, or triamcinolone acetonide)), or a neuroprotective agent (e.g., an endogenous neuroprotective agent (such as CNTF)), or any combination or all thereof. The use of an apo mimetic [ e.g., an apoA-I mimetic (e.g., L-4F) and/or an apoE mimetic (e.g., AEM-28-14) ] can enhance the efficacy of one or more other therapeutic agents, e.g., reduce oxidative stress, improve altered homeostasis in liposomes, reduce inflammation, or reduce degeneration of RPE cells and retinal cells (e.g., photoreceptors), or any combination or all thereof.

In some embodiments, the additional therapeutic agent is administered at least during the advanced stages of AMD. In further embodiments, the additional therapeutic agent is administered at least during the intermediate stage of AMD. In still further embodiments, the additional therapeutic agent is administered at least at an early stage of AMD. In certain embodiments, the additional therapeutic agents administered at least during the early stages of AMD include or are the following: an anti-dyslipidemia agent that reduces lipid production (e.g. statins) and optionally an antioxidant (e.g. vitamins, safranine carotenoids and/or zinc) and/or an anti-inflammatory agent (e.g. NSAID), and the additional therapeutic agent is administered systemically (e.g. orally) or topically (e.g. via eye drops).

Treatment of AMD with apolipoprotein mimics and antioxidants

additional embodiments of the present disclosure relate to methods of treating AMD, comprising administering to a subject in need of treatment a therapeutically effective amount of an apolipoprotein (apo) mimetic and a therapeutically effective amount of an antioxidant, whether or not the apo mimetic is administered to the ocular region, intraocular, in, or periocular at a dose of about 0.1 or 0.3mg to about 1.5mg per administration (e.g., per injection), or about 0.5 or 1mg to about 10mg in total over a period of about 6 months. In addition, minerals (e.g., zinc or selenium, each of which may also function as antioxidants) may be used in combination with apo mimetics and antioxidants for the treatment of AMD. All embodiments relating to treatment of AMD with apolipoprotein mimics are also applicable to treatment of AMD with apo mimics and antioxidants (and optionally minerals), which embodiments are described in section IV and elsewhere herein.

Examples of apolipoprotein mimics (including apoA-I mimics and apoE mimics) include, but are not limited to, those described elsewhere herein. In some embodiments, the apo mimetic comprises an apoA-I mimetic or is an apoA-I mimetic. In certain embodiments, the apoA-I mimetic includes 4F or a variant or salt thereof (e.g., acetate), or is 4F or a variant or salt thereof (e.g., acetate). In some embodiments, all of the amino acid residues of 4F have the L-form (L-4F). In other embodiments, one or more or all of the amino acid residues of 4F have the D form (e.g., D-4F with all amino acid residues in the D form). 4F may have a protecting group at the N-terminus (e.g., an acyl group such as acetyl) and/or a protecting group at the C-terminus (e.g., an amide group such as-C (O) NH 2). In certain embodiments, the apoA-I mimetic comprises L-4F having the structure Ac-DWFKAFYDKVAEKFKEAF-NH2(SEQ. ID. NO.13), or L-4F having the structure Ac-DWFKAFYDKVAEKFKEAF-NH2(SEQ. ID. NO. 13). In further embodiments, the apo mimetic comprises an apoE mimetic, or is an apoE mimetic. In certain embodiments, the apoE mimetic includes AEM-28-14 or a variant or salt thereof, or is AEM-28-14 or a variant or salt thereof.

Examples of antioxidants include, but are not limited to, those described elsewhere herein. In certain embodiments, the antioxidants comprise one or more vitamins (e.g., vitamin B6, vitamin C, and vitamin E), one or more carotenoids (e.g., xanthophylls [ e.g., lutein, zeaxanthin, and meso-zeaxanthin ] and carotenoids in Saffron [ e.g., crocin and crocetin ]), or zinc, or any combination or all thereof, e.g., AREDS or AREDS2 formulations, or Saffron 2020TM described elsewhere herein. In addition to the ability to reduce oxidative stress, antioxidants have other beneficial properties. For example, crocin carotenoids have anti-inflammatory and cytoprotective effects, as well as antioxidant effects.

In some embodiments, the antioxidant (e.g., vitamin and/or carotenoid) is administered at a dose that is lower than conventional or recommended doses, and/or is administered at a frequency that is lower than conventional or recommended dosing frequency or for antioxidants in the absence of treatment with an apo mimetic [ e.g., an apo a-I mimetic (e.g., L-4F) and/or an apo e mimetic (e.g., AEM-28-14) ], whether the apo mimetic is administered topically at a dose of about 0.1 or 0.3mg to about 1.5mg per administration (e.g., per injection), or is administered topically at a total dose of about 0.5 or 1mg to about 10mg over a period of about 6 months. Administration of lower doses of antioxidants may be beneficial to the subject, e.g., with fewer side effects. For example, ingestion of more beta-carotene increases the risk of lung cancer in smokers. As another example, ingesting more vitamin E increases the risk of heart failure in high risk populations. In some embodiments, the conventional or recommended dose is for administration of an antioxidant (e.g., a vitamin and/or a carotenoid) at a dose that is at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, or 80% (e.g., at least about 20%), or about 10-30%, 30-50%, or 50-70% less than it without treatment with an apo mimetic [ e.g., an apoA-I mimetic (e.g., L-4F) and/or an apoE mimetic (e.g., AEM-28-14) ], as compared to a conventional or recommended dose of the antioxidant. In further embodiments, the conventional or recommended dosing frequency is at least about 2, 3, 5, 7, or 10 times (e.g., at least about 2 times) less frequent (e.g., by intravitreal injection) than administration of the antioxidant (e.g., vitamin and/or carotenoid) in the absence of treatment with an apo mimetic [ e.g., an apoA-I mimetic (e.g., L-4F) and/or an apoE mimetic (e.g., AEM-28-14) ], as compared to the conventional or recommended dosing frequency of the antioxidant. In certain embodiments, the administration of an antioxidant (e.g., a vitamin and/or carotenoid) is at least once daily, whether systemically (e.g., oral) or locally in a non-invasive manner (e.g., via eye drops), as compared to the conventional or recommended dosing frequency of the antioxidant for once every two or three days without treatment with an apo mimetic [ e.g., an apoA-I mimetic (e.g., L-4F) and/or an apoE mimetic (e.g., AEM-28-14) ].

Treatment of AMD with an apo mimetic [ e.g., an apoA-I mimetic (e.g., L-4F) and/or an apoE mimetic (e.g., AEM-28-14) ] and an antioxidant (e.g., a vitamin and/or a carotenoid) may have a synergistic effect. For example, treatment with an apo mimetic (e.g., an apoA-I mimetic and/or an apoE mimetic) can enhance the efficacy of an antioxidant, and/or vice versa. For example, L-4F can significantly reduce lipid deposition in bruch's membrane and sub-RPE-BL space, thereby reducing the amount of easily oxidized lipids. As another example, the ability of L-4F to reduce lipid oxidation and clear pro-inflammatory oxidized lipids may reduce the required dose and/or frequency of administration of antioxidants. Synergy between the apo mimetic (e.g., apo a-I mimetic and/or apo e mimetic) and the antioxidant may allow, but does not require, for example, administration of the antioxidant at a dose and/or frequency that is lower than conventional or recommended dosing frequency for the antioxidant in the absence of treatment with the apo mimetic.

With respect to apo mimetics, in certain embodiments, the apo mimetic [ e.g., apo a-I mimetic (e.g., L-4F) and/or apo e mimetic (e.g., AEM-28-14) ] is administered (e.g., by intravitreal injection) at a dose of about 0.1 or 0.3-1.5mg, 0.1-0.5mg, 0.5-1mg, 1-1.5mg, 0.1-0.3mg, 0.3-0.5mg, 0.5-0.75mg, 0.75-1mg, 1-1.25mg, or 1.25-1.5mg (e.g., about 0.1-0.5mg or 0.5-1mg) per administration (e.g., per injection), locally, intraocularly, or periocularly. The apo mimetic can also be administered topically at a dose of greater than 1.5mg per administration, e.g., up to about 2mg or more per administration (e.g., per injection). In further embodiments, the apo mimetic [ e.g., apo A-I mimetic (e.g., L-4F) and/or apo E mimetic (e.g., AEM-28-14) ] is administered topically (e.g., by intravitreal injection or by sustained release composition) at a total dose of about 0.5 or 1-10mg, 0.5 or 1-5mg, 5-10mg, 0.5 or 1-3mg, 3-5mg, 5-7.5mg, or 7.5-10mg (e.g., about 0.5-3mg or 3-5mg) over a period of about 6 months, wherein the duration/length of treatment with the apo mimetic can be, for example, about 6-12, 12-18, or 18-24 months or longer. The apo mimetics may also be administered topically at a total dose of greater than 10mg over a period of about 6 months, for example up to about 15mg or more over a period of about 6 months. In still further embodiments, for a complete/complete treatment regimen using an apo mimetic, the apo mimetic [ e.g., apoA-I mimetic (e.g., L-4F) and/or apoE mimetic (e.g., AEM-28-14) ] is administered topically at a total dose of about 1 or 2-20mg, 5-15mg, 1-5mg, 5-10mg, 10-15mg, 15-20mg, 1-3mg, 3-5mg, 5-7.5mg, 7.5-10mg, 10-12.5mg, 12.5-15mg, 15-17.5mg, or 17.5-20mg (e.g., about 1-5mg or 5-10 mg). The apo mimetics can also be administered topically at a total dose greater than 20mg for a complete treatment regimen, e.g., up to a total dose of about 25mg, 30mg, 40mg, 50mg, or more for a complete treatment regimen.

In embodiments where the apo mimetic [ e.g., apoA-I mimetic (e.g., L-4F) and/or apoE mimetic (e.g., AEM-28-14) ] is administered topically, intraocularly, or periocularly, the dose per administration, the total dose over a period of about 6 months, and the total dose for the entire treatment regimen is in certain embodiments for each eye administered, and in other embodiments for both eyes. The blood system may allow for a localized administration (e.g., injection) of an apo mimetic into one eye or some amount (e.g., a therapeutically effective amount) of the apo mimetic in one eye to be distributed to the other eye, in which case the dose of the apo mimetic may be optionally adjusted (e.g., increased) in view of the other eye (which may be in a less diseased condition), and may allow for simultaneous treatment of both eyes with the apo mimetic without additional administration (e.g., injection) of the apo mimetic within or in the other eye. For example, intravitreally injected apo mimetics can cross the blood-retinal barrier to reach two target regions (i.e., the sub-RPE-BL space and bruch's membrane), from which they can enter the choroidal capillaries and ultimately to the corresponding unadministered eye. Without being bound by theory, some amount of apo mimetic can enter the corresponding unapplied eye by the aqueous humor pathway, which is drained through the trabecular meshwork and schlemm's canal into the blood system. Thus, some embodiments relate to a method of treating AMD, comprising administering to a subject in need of treatment a therapeutically effective amount of an apolipoprotein mimic and a therapeutically effective amount of an antioxidant, wherein the apolipoprotein mimic is administered to the ocular region, in or around the eye in one eye and both eyes are therapeutically effective.

In further embodiments, the apo mimetic [ e.g., apoA-I mimetic (e.g., L-4F) and/or apoE mimetic (e.g., AEM-28-14) ] is administered topically (e.g., by intravitreal injection) once a month (4 weeks) or 1.5 months (6 weeks). In other embodiments, the apo mimetic [ e.g., apoA-I mimetic (e.g., L-4F) and/or apoE mimetic (e.g., AEM-28-14) ] is administered topically (e.g., by intravitreal injection) once every 2 months (8 weeks), 2.5 months (10 weeks), or 3 months (12 weeks). In other embodiments, the apo mimetic [ e.g., apoA-I mimetic (e.g., L-4F) and/or apoE mimetic (e.g., AEM-28-14) ] is administered topically (e.g., by intravitreal injection or by a sustained release composition) once every 4, 5, or 6 months. In further embodiments, the apo mimetic [ e.g., apoA-I mimetic (e.g., L-4F) and/or apoE mimetic (e.g., AEM-28-14) ] is administered (e.g., injected) topically for a total of about 15 times or less, 12 times or less, 9 times or less, 6 times or less, or 3 times or less (e.g., 3-6 times or 7-10 times). A total of more administrations (e.g., injections) of the apo mimetic, e.g., up to about 20 or more administrations (e.g., injections), can also be topically administered. In embodiments where the apo mimetic is administered topically, intra-ocularly, in-ocularly, or periocularly, the frequency of administration and the total number of administrations (e.g., injections) is in certain embodiments for each eye administered, and in other embodiments for both eyes, since the apo mimetic may also have a therapeutic effect in the corresponding non-administered eye.

In some embodiments, an apo mimetic [ e.g., an apoA-I mimetic (e.g., L-4F) and/or an apoE mimetic (e.g., AEM-28-14) ] and an antioxidant (e.g., a vitamin and/or a carotenoid) are administered at least at an advanced stage of AMD to treat central pattern atrophy (GA) and/or neovascular AMD (including NV types 1,2, and 3) or slow progression of central pattern atrophy (GA) and/or neovascular AMD (including NV types 1,2, and 3), and/or prevent neovascular AMD or delay the onset neovascular AMD. The use of antioxidants can inhibit the formation of oxidized lipids, which can be strongly pro-inflammatory and thus pro-angiogenic. In further embodiments, the apo mimetic [ e.g., apoA-I mimetic (e.g., L-4F) and/or apoE mimetic (e.g., AEM-28-14) ] and antioxidant (e.g., vitamin and/or carotenoid) are administered at least during the intermediate stage of AMD to treat or slow the progression of non-central GA, and/or to prevent or delay the onset of central GA and/or neovascular AMD. In still further embodiments, an apo mimetic [ e.g., an apoA-I mimetic (e.g., L-4F) and/or an apoE mimetic (e.g., AEM-28-14) ] and an antioxidant (e.g., a vitamin and/or a carotenoid) ] are administered at least at the early stage of AMD or the initial stage of intermediate stage AMD to prevent or delay the onset of non-central GA. In a further embodiment, the antioxidant (e.g., a vitamin and/or a carotenoid) and optionally the apo mimetic [ e.g., an apoA-I mimetic (e.g., L-4F) and/or an apoE mimetic (e.g., AEM-28-14) ] are administered at least at an early stage of AMD.

In certain embodiments, treatment with an apo mimetic [ e.g., an apoA-I mimetic (e.g., L-4F) and/or an apoE mimetic (e.g., AEM-28-14) ] and an antioxidant (e.g., a vitamin) treatment and/or a carotenoid) slows the progression of central GA and/or non-central GA (e.g., reduces the rate of GA progression, or reduces GA lesion area or size) by at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, or 80% (e.g., at least about 20%), or about 20-40%, 40-60%, or 60-80%. In further embodiments, treatment with an apo mimetic [ e.g., an apoA-I mimetic (e.g., L-4F) and/or an apoE mimetic (e.g., AEM-28-14) ] and an antioxidant (e.g., a vitamin and/or a carotenoid) slows the progression of central GA and/or non-central GA (e.g., reduces the rate of GA progression, or reduces GA lesion area or size) by at least about 10%, 20%, 30%, 50%, 100%, 150%, 200%, or 300% (e.g., at least about 20% or 30%), or about 10-30%, 30-50%, 50-100%, 100-200%, or 200-300% (e.g., about 50-100%) more than treatment with an antioxidant without treatment with the apo mimetic.

The apo mimetic [ e.g., apoA-I mimetic (e.g., L-4F) and/or apoE mimetic (e.g., AEM-28-14) ] and antioxidant (e.g., vitamin and/or carotenoid) can be administered by any suitable method. In some embodiments, the apo mimetic (e.g., apoA-I mimetic and/or apoE mimetic) and/or antioxidant is administered topically, intraocularly, or periocularly, such as by injection (e.g., intravitreal, subconjunctival, subretinal, or sub-tenon's capsule injection), eye drops, or implants (e.g., intravitreal, subretinal, or sub-tenon's capsule implants). In certain embodiments, the apo mimetic (e.g., apoA-I mimetic and/or apoE mimetic) is administered topically (e.g., by intravitreal, subconjunctival, subretinal, or sub-tenon's capsule injection). In other embodiments, the apo mimetic (e.g., apoA-I mimetic and/or apoE mimetic) and/or antioxidant are administered systemically (e.g., intravenously or orally). In certain embodiments, the antioxidant is administered systemically (e.g., orally). In some embodiments, the apo mimetic (e.g., apoA-I mimetic and/or apoE mimetic) and/or the antioxidant are administered by a sustained release composition.

In certain embodiments, the apo mimetic [ e.g., apoA-I mimetic (e.g., L-4F) and/or apoE mimetic (e.g., AEM-28-14) ] is administered locally to the eye, intraocularly, in the eye, or periocularly at an early stage of treatment, and then the apo mimetic is administered systemically. As non-limiting examples, the initial administration (e.g., the first one to five administrations) of the apo mimetic can be by injection locally (e.g., intravitreal, subconjunctival, subretinal, or sub-tenon's capsule injection) and then the apo mimetic can be administered systemically, e.g., orally, parenterally (e.g., subcutaneously, intramuscularly, or intravenously), or topically (e.g., intranasally or pulmonary). In other embodiments, the apo mimetic is administered topically only. In other embodiments, the apo mimetic is administered systemically only.

The apo mimetic [ e.g., apoA-I mimetic (e.g., L-4F or a variant or salt thereof) and/or apoE mimetic (e.g., AEM-28-14 or a variant or salt thereof) ] and antioxidant (e.g., vitamin and/or carotenoid) can be administered either in the same pharmaceutical composition or in separate pharmaceutical compositions. If the apo mimetic (e.g., apoA-I mimetic and/or apoE mimetic) and antioxidant are administered in the same composition, such a composition can be prepared in advance or can be prepared by combining the apo mimetic and antioxidant into the same formulation shortly or just prior to administration (e.g., by injection) of the formulation. In some embodiments, the apo mimetic (e.g., apoA-I mimetic and/or apoE mimetic) and the antioxidant are topically administered to the eye, in the eye, or around the eye in the same composition by: such as by injection (e.g., intravitreal, subconjunctival, subretinal, or sub-tenon's capsule injection), eye drops, or implants (e.g., intravitreal, subretinal, or sub-tenon's capsule implants).

in certain embodiments, a composition comprising an apo mimetic [ e.g., an apoA-I mimetic (e.g., L-4F) and/or an apoE mimetic (e.g., AEM-28-14) ] comprises about 75-95% (e.g., about 90%) by weight or molar concentration of the apo mimetic and about 5-25% (e.g., about 10%) by weight or molar concentration of the corresponding apolipoprotein (e.g., apoA-I and/or apoE) or an active portion thereof or domain thereof, relative to their combined amount, whether or not an antioxidant (e.g., a vitamin and/or a carotenoid is present.

One or more of the other therapeutic agents described herein may be used in combination with an apo mimetic [ e.g., an apoA-I mimetic (e.g., L-4F) and/or an apoE mimetic (e.g., AEM-28-14) ] and an antioxidant (e.g., a vitamin and/or a carotenoid) for the treatment of atrophic (dry) or neovascular (wet) AMD. In some embodiments, the additional therapeutic agent comprises or is the following: an anti-angiogenic agent (e.g., an anti-VEGF agent (e.g., aflibercept, bevacizumab, or ranibizumab), and/or an anti-PDGF agent (e.g., E10030)), a complement inhibitor (e.g., a C15 inhibitor (e.g., ARC1905 or LFG316) and/or a complement factor D inhibitor (e.g., lanreozumab)), an anti-inflammatory agent (e.g., an NSAID (e.g., bromfenac), and/or a corticosteroid (e.g., fluocinolone or triamcinolone acetonide)), a neuroprotective agent (e.g., glatiramer acetate and/or CNTF), or an anti-dyslipidemia agent (e.g., a statin (e.g., atorvastatin)), or any combination or all thereof. The use of an apo mimetic [ e.g., an apoA-I mimetic (e.g., L-4F) and/or an apoE mimetic (e.g., AEM-28-14) ] can enhance the efficacy of one or more other therapeutic agents, e.g., reduce the growth and leakage of new blood vessels, reduce inflammation, reduce oxidative stress, reduce the degradation of RPE cells and retinal cells (e.g., photoreceptors), or improve altered intraliposomal homeostasis, or any combination or all thereof.

In some embodiments, the additional therapeutic agent is administered at least during the advanced stages of AMD. In certain embodiments, the additional therapeutic agents include or are the following: anti-angiogenic agents (e.g., anti-VEGF agents) and optionally neuroprotective agents (e.g., endogenous neuroprotective agents (e.g., CNTF)), and are administered at least during the advanced stages of AMD for treating or slowing the progression of wet AMD, including neovascularization types 1,2, and 3. In other embodiments, the additional therapeutic agents include or are the following: complement inhibitors (e.g., lanreolizumab) and/or neuroprotective agents (e.g., endogenous neuroprotective agents (e.g., CNTF)) and are administered at least during the advanced stages of AMD to treat or slow the progression of central pattern atrophy (GA).

In further embodiments, the additional therapeutic agent is administered at least during the intermediate stage of AMD. In certain embodiments, the additional therapeutic agents include or are the following: complement inhibitors (e.g., lanreolizumab) and/or neuroprotective agents (e.g., glatiramer acetate and/or CNTF) and is administered at least during the intermediate stage of AMD to treat or slow the progression of non-central GA, and/or to prevent or delay the onset of central GA, or is administered at least during the early stage of AMD or the initial stage of intermediate AMD to prevent or delay the onset of non-central GA. In still further embodiments, the additional therapeutic agent is administered at least at an early stage of AMD. In certain embodiments, the additional therapeutic agents administered at least during the early stages of AMD include or are the following: an anti-dyslipidemia agent (e.g., statin) and optionally an anti-inflammatory agent (e.g., NSAID) that reduces lipid production, and the additional therapeutic agent is administered systemically (e.g., orally) or topically (e.g., via eye drops).

IX. for treating other eye diseases

In addition to age-related macular degeneration (AMD), the therapeutic agents described herein may also be useful in the treatment of other ocular diseases and disorders. Non-limiting examples of other ocular diseases and conditions that can be treated with one or more therapeutic agents described herein include juvenile macular degeneration (e.g., Stargardt disease), maculopathy (e.g., age-related maculopathy [ ARM ] and diabetic maculopathy [ DMP ] [ including partially ischemic DMP ]), macular edema (e.g., diabetic macular edema [ DME ] [ including clinically significant DME, focal DME and diffuse DME ], Irvine-gas syndrome [ post-operative macular edema ] and RVO [ including macular edema after central o and branched RVO ]), retinopathy (e.g., diabetic retinopathy [ including in DME patients ], urtscher retinopathy and radiation retinopathy), Retinal Arterial Obstruction (RAO) (e.g., central and branched RAO), Retinal Vein Obstruction (RVO) (e.g., central o [ central o including CME branch } and RVO including branched cmrve ]) Glaucoma (including low-tension, normal-tension and high-tension glaucoma), ocular hypertension, retinitis (e.g., Coats disease [ exudative retinitis ] and retinitis pigmentosa), chorioretinitis, choroiditis (e.g., creeping choroiditis), uveitis (including anterior uveitis with or without CME, intermediate uveitis with or without CME, posterior uveitis with or without CME, and pan uveitis), Retinal Pigment Epithelium (RPE) detachment, and diseases associated with increased intracellular or extracellular lipid storage or accumulation other than AMD.

in some embodiments, apolipoprotein mimics (e.g., apoA-I mimics [ e.g., L-4F ] and/or apoE mimics [ e.g., AEM-28-14]) are used alone or in combination with one or more other therapeutic agents for the treatment of ocular diseases or conditions other than AMD. In certain embodiments, apo mimetics having anti-inflammatory properties (e.g., apoA-I mimetics [ e.g., L-4F ] and/or apoE mimetics [ e.g., AEM-28-14]) are administered alone or in combination with another therapeutic agent for the treatment of an inflammatory ocular disease or disorder (e.g., uveitis). In this case, apo mimetics (e.g., L-4F) act as anti-inflammatory agents and can be used in place of steroidal or non-steroidal anti-inflammatory drugs. Apo mimetics (e.g., apoA-I mimetics [ e.g., L-4F ] and/or apoE mimetics [ e.g., AEM-28-14]) are used in combination with anti-angiogenic agents (e.g., anti-VEGF agents) to treat ocular diseases and conditions other than AMD as described elsewhere herein. In further embodiments, an apo mimetic (e.g., an apoA-I mimetic [ e.g., L-4F ] and/or an apoE mimetic [ e.g., AEM-28-14]) is administered in combination with an anti-VEGF agent, a neuroprotective agent, a kinase inhibitor, or a c-peptide (linker peptide), or any combination or all thereof, to treat diabetic retinopathy. Embodiments that involve the use of apo mimetics [ e.g., apo a-I mimetics (e.g., L-4F) and/or apo e mimetics (e.g., AEM-28-14) ] alone or in combination with another therapeutic agent (e.g., an anti-angiogenic agent [ e.g., an anti-VEGF agent ], a complement inhibitor or an antioxidant) as well as those described elsewhere herein for the treatment of AMD are also applicable to the use of apo mimetics alone or in combination with a given type of therapeutic agent for the treatment of other ocular diseases and conditions.

Administration of therapeutic agents

The therapeutic agents described herein can be administered to a subject by any suitable method, including any suitable means for local or systemic administration. In certain embodiments, the therapeutic agent is administered by: intravitreal injection or implantation, subconjunctival injection or implantation, subretinal injection or implantation, sub tenon's capsule injection or implantation, periocular injection, eye drops, oral ingestion, or intravenous injection or infusion.

In some embodiments, one or more or all of the therapeutic agents are administered topically. Topical administration of a therapeutic agent may more effectively deliver the agent to the target site, avoid first-pass metabolism and require lower doses for administration, and may thereby reduce any side effects caused by the agent. Because the pathological events of AMD occur in the eye, therapeutic agents for treating AMD can be topically applied to the eye for more effective treatment. For example, lipid-containing substances (e.g., lipids, lipoproteins, and apolipoproteins) that accumulate in bruch's membrane (BrM), sub-RPE-BL space, and subretinal space appear to be of intraocular origin (e.g., secreted by retinal pigment epithelium [ RPE ] cells). Thus, to more effectively reduce the accumulation of such substances may involve the topical application of one or more anti-dyslipidemia agents to a target site in the eye.

potential routes/modes of topical administration include, but are not limited to, intracameral (aqueous humor), peribulbar, retrobulbar, suprachoroidal space, subconjunctival, intraocular, periocular, subretinal, intrascleral, posterior juxtascleral (posteror juxtascleral), transscleral, tenon's capsule, intravitreal, and transvitreal. Subretinal administration is the administration of a therapeutic agent below the retina, such as the subretinal space, the RPE, the sub-RPE-BL space, or the choroid, or any combination or all thereof. Potential sites of local administration include, but are not limited to, the anterior (aqueous) and posterior chambers of the eye, the vitreous humor (vitreous), the retina (including the macula and/or photoreceptor layer), the subretinal space, the RPE, the sub-RPE-BL space, the choroid (including BrM and the choroidal capillary endothelium), the sclera, and the sub-tenon's capsule/space.

In some embodiments, the therapeutic agent is delivered through the sclera and choroid to the vitreous humor from which it can diffuse to target tissues such as the retina (e.g., photoreceptors), sub-retinal space, RPE, sub-RPE-BL space, or BrM, or any combination or all thereof. In other embodiments, the therapeutic agent is delivered through the sclera and choroid to a target tissue, such as the retina (e.g., photoreceptors), the subretinal space, the RPE and/or the sub-RPE-BL space, and if BrM is the target tissue, the therapeutic agent can diffuse from, for example, the retina (e.g., photoreceptors), the subretinal space, the RPE and/or the sub-RPE-BL space to BrM. In further embodiments, the therapeutic agent is administered intraocularly, for example, into the anterior or posterior chamber of the eye, the vitreous humor, the retina, or the subretinal space.

Potential means of topical administration include, but are not limited to, injection, implantation, and means for topical administration to the eye (e.g., eye drops and contact lenses). In some embodiments, one or more or all of the therapeutic agents are administered by intravitreal (e.g., within the micro-vitreous), subconjunctival, subretinal, or sub-tenon's capsule injection or implantation. As an example, in certain embodiments, one or more apolipoprotein mimics [ e.g., apoA-I mimic (e.g., L-4F) and/or apoE mimic (e.g., AEM-28-14) ] is injected into the vitreous humor, subconjunctival, subretinal, or sub-tenon's capsule of the eye at least once every 4 weeks (1 month), 6 weeks, 8 weeks (2 months), 10 weeks, 12 weeks (3 months), 4 months, 5 months, or 6 months (e.g., about 6 months, 12 months, 18 months, or 24 months or more) according to the determination by the treating physician for treatment of, for example, atrophic AMD (including non-central and/or central pattern atrophy) and/or neovascular AMD.

A method by which a therapeutic agent may be administered less frequently than intravitreal injections is posterior juxtascleral cavity administration. For example, a blunt, colored, posterior juxtascleral cavity cannula that delivers an amount (e.g., about 15mg) of anecortave acetate to the sclera directly behind the macula while leaving the globe intact. Anecortave acetate may be administered every 6 months using this method of delivery, as opposed to monthly or bimonthly by intravitreal injection of ranibizumab or aflibercept. In addition, posterior juxtascleral cavity administration methods greatly reduce the risk of intraocular infections, endophthalmitis, and retinal detachment.

although topical administration of a therapeutic agent to the eye to treat AMD or another ocular condition may have advantages such as higher efficacy and reduced side effects, systemic administration of the therapeutic agent may be desirable in certain circumstances. For example, if, for example, an external preparation for topical delivery (e.g., eye drops or contact lenses) cannot be made for a therapeutic agent, oral administration of the therapeutic agent can increase patient compliance due to ease of use and non-invasiveness. As another example, pathological events of AMD may have a non-local component. For example, the amount of lipid-containing substances secreted by RPE cells into BrM, the sub-RPE-BL space, and the subretinal space may be influenced in part by the uptake of plasma lipids (e.g., cholesterol and fatty acids) and lipoproteins (e.g., LDL) by RPE cells. In such cases, it may be desirable to administer one or more anti-dyslipidemia agents systemically, which reduces the production of such lipids and lipoproteins by the liver.

in some embodiments, the one or more therapeutic agents are administered systemically. Potential routes of systemic administration include, but are not limited to, oral, parenteral (e.g., intradermal, subcutaneous, intramuscular, intravascular, intravenous, intraarterial, intramedullary, and intrathecal), intracavitary, intraperitoneal, and topical (e.g., transdermal, transmucosal, intranasal [ e.g., by nasal spray or drops ], pulmonary [ e.g., by inhalation ], buccal, sublingual, rectal, and vaginal).

In certain embodiments, the one or more anti-dyslipidemia agents are administered systemically. For example, in certain embodiments, the fibrate and/or statin is administered orally, and/or the GLP-1 receptor agonist is administered subcutaneously. In further embodiments, the one or more antioxidants are administered systemically. For example, in certain embodiments, the vitamins, saffron carotenoids, and/or zinc are administered orally. In still further embodiments, the one or more anti-inflammatory agents are administered systemically. For example, in certain embodiments, the NSAID (e.g., coxibs) is administered orally, and/or the complement inhibitor (e.g., an anti-C5 antibody (e.g., LFG316)) is administered intravenously.

In some embodiments, one or more polypeptide therapeutic agents (e.g., endogenous angiogenesis inhibitors such as soluble VEGFR [ e.g., VEGFR1] or angiostatin) and/or endostatin) are administered by means of a viral (e.g., adenoviral or lentiviral) vector that expresses the polypeptide therapeutic agent. For example, AVA-101 comprises an adeno-associated virus 2(AAV2) vector, which contains a gene encoding soluble VEGFR1 (FLT-1). Topical administration of AVA-101 into the eye (e.g., RPE or choriocapillaris endothelium) results in host retinal cells expressing soluble VEGFR 1. Soluble VEGFR1 protein binds to VEGF in the extracellular space, which prevents VEGF from binding to membrane-bound VEGFR and thereby inhibits angiogenesis. AVA-101 can be administered, for example, as a single subretinal injection for the treatment of, for example, neovascular AMD (including neovascularisation types 1,2, and/or 3), which obviates the need for multiple or frequent injections.

In additional embodiments, one or more polypeptide therapeutic agents (e.g., a neuroprotective agent [ e.g., ciliary neurotrophic factor ] or an anti-angiogenic agent [ e.g., an anti-VEGF agent (e.g., soluble VEGFR) ]) are administered by way of genetically engineered cells (e.g., NTC-201 cells) that produce the polypeptide therapeutic agent and are encapsulated in a polymer particle or polymer implant. For example, an expression vector containing a gene encoding ciliary neurotrophic factor (CNTF) is transfected into RPE cells to produce genetically engineered NTC-201 cells. NTC-201 cells are encapsulated in, for example, a semipermeable hollow fiber membrane pouch contained in a scaffold of six strands of polyethylene terephthalate yarns. The capsule and scaffold maintain the cells (e.g., growth support and delivery of nutrients). Upon implantation of an encapsulated cell-based drug delivery system (e.g., through the scleral tunnel), NTC-201 cells produce and secrete CNTF through the semipermeable sac. This encapsulated cell technology (e.g., NT-501) provides controlled, continuous and sustained delivery of CNTF and extends the half-life of CNTF from about 1-3 minutes to about 20-50 months. Intraocular delivery of CNTF using this encapsulated cell technique can, for example, reduce photoreceptor loss associated with retinal cell degeneration and thus can be used to treat, for example, geographic atrophy.

One or more polypeptide therapeutic agents can also be delivered by administration of naturally occurring cells that produce and release these agents. For example, cells derived from umbilical cord tissue can reportedly rescue photoreceptors and visual function by producing and releasing neuroprotective agents (e.g., neurotrophic factors).

The therapeutically effective amount and frequency of administration and duration of treatment of a particular therapeutic agent for the treatment of AMD or another ocular disorder may depend on a variety of factors, including the ocular disease, the severity of the disease, the mode of administration, the age, weight, general health, sex and diet of the subject, and the subject's response to treatment, and may be determined by the treating physician. In some embodiments, the dosing regimen of one or more or all of the therapeutic agents comprises one or more loading doses followed by one or more maintenance doses. One or more loading doses are designed to establish a relatively high or therapeutically effective level of the therapeutic agent at the target site relatively quickly, and one or more maintenance doses are designed to establish a therapeutically effective level of the therapeutic agent during treatment. The loading dose can be provided at the beginning of treatment, for example, by administering a dose that is greater (e.g., 2, 3,4, or 5 times greater) than the maintenance dose, or by administering a dose that is substantially similar to the maintenance dose more frequently (e.g., 2, 3,4, or 5 times more frequently). For example, for treatment of neovascular AMD, including neovascularization type 1,2 and/or 3, in certain embodiments, a loading dose of the anti-angiogenic agent aflibercept is administered by intravitreal injection (about 2mg per month for 3 months) three times, followed by a maintenance dose (about 2mg) every 2 months for a period of time determined by the treating physician.

Xi pharmaceutical compositions, delivery systems and kits

the therapeutic agent may be administered as a pharmaceutical composition comprising one or more pharmaceutically acceptable carriers or excipients. If two or more therapeutic agents are used to treat AMD or another ocular disease, they may be administered in the same pharmaceutical composition or separate pharmaceutical compositions.

Pharmaceutically acceptable carriers and excipients include pharmaceutically acceptable materials, carriers and substances. Non-limiting examples of excipients include liquid and solid fillers, diluents, binders, lubricants, glidants, surfactants, dispersants, disintegrants, emulsifiers, wetting agents, suspending agents, thickeners, solvents, isotonic/isotonic agents, buffers, pH adjusting agents, absorption delaying agents, sweeteners, flavoring agents, colorants, stabilizers, preservatives, antioxidants, antimicrobial agents, antibacterial agents, antifungal agents, adjuvants, encapsulating materials, and coating materials. The use of such excipients in pharmaceutical formulations is known in the art. Unless any conventional carriers or excipients are incompatible with the therapeutic agent, the present disclosure includes the use of conventional carriers and excipients in formulations containing the therapeutic agents described herein. See, e.g., Remington, The Science and Practice of Pharmacy,21st Ed., Lippincott Williams & Wilkins (Philadelphia, Pennsylvania [2005 ]); handbook of Pharmaceutical Excipients,5th Ed., Rowe et al, eds., The Pharmaceutical Press and The American Pharmaceutical Association (2005); handbook of Pharmaceutical Additives,3rd Ed., Ash and Ash, eds., Gower Publishing Co. (2007); and Pharmaceutical pressure modulation and Formulation, Gibson, Ed., CRC Press LLC (Boca Raton, Florida [2004 ]).

compositions and formulations (e.g., injectable formulations) for use in the present disclosure can be prepared in sterile form. Mixing or manufacturing sterile pharmaceutical formulations, such as United States pharmaceutical Chapters 797,1072 and 1211, according to pharmaceutical grade sterilization standards known to those of skill in the art; california Business & Promissions Code 4127.7; 16 California Code of Regulations 1751; and those disclosed or claimed in 21 Code of Federal Regulations 211.

As illustrative examples, one or more therapeutic agents may be formulated for delivery into the eye (e.g., intravitreal, subconjunctival, subretinal, or sub-tenon's capsule injections or eye drops). Excipients and carriers that may be used in the preparation of such formulations include, but are not limited to, solvents (e.g., aqueous solvents such as water, saline, and phosphate buffered saline), isotonic/isotonic agents (e.g., NaCl and sugars [ e.g., sucrose ]), pH adjusting agents (e.g., sodium dihydrogen phosphate and disodium hydrogen phosphate), and emulsifying agents (e.g., nonionic surfactants such as polysorbates [ e.g., polysorbate 20 ]). If the one or more therapeutic agents include peptides or proteins, such formulations (and any other kind of formulation) may contain one or more of the following: inhibiting peptide/protein aggregation, increasing peptide/protein solubility, decreasing solution viscosity, or increasing peptide/protein stability, or any combination or all thereof, such as non-hydrophobic amino acids (e.g., arginine and histidine), polyols (e.g., inositol and sorbitol), sugars (e.g., glucose, lactose, sucrose, and trehalose), osmotic agents (e.g., trehalose, amino acids [ e.g., glycine, proline, and sarcosine ] and betaines [ e.g., trimethylglycine ]), nonionic surfactants (e.g., alkylpolyglycosides), and alkyl sugars (e.g., disaccharides [ e.g., maltose or sucrose ] coupled with long chain fatty acids or corresponding long chain alcohols). Because these substances increase the solubility of the peptide/protein, they can be used to increase the peptide/protein concentration and thereby reduce the volume required to administer a given amount of peptide or protein, which can have beneficial effects such as lowering intraocular pressure (e.g., in intravitreal injections). In addition, these materials can be used to stabilize lipophilic peptides and proteins during their preparation, storage and reconstitution.

In some embodiments, one or more or all of the therapeutic agents are delivered independently from the sustained release composition. As used herein, the term "sustained release composition" includes sustained release, extended release, delayed release, slow release and controlled release compositions, systems and devices. The use of sustained release compositions can have benefits such as improved distribution of the amount of drug delivered to the target site over a period of time, as well as improved patient compliance and health due to less invasive procedures for drug administration (e.g., injection into the eye). In some embodiments, the sustained release composition is a drug encapsulation system, such as a nanoparticle, microparticle, round plug, or capsule made from, for example, a biodegradable polymer and/or hydrogel. In certain embodiments, the sustained release composition comprises a hydrogel. Non-limiting examples of polymers from which the hydrogel may be composed include polyvinyl alcohol, acrylate polymers (e.g., sodium polyacrylate), and other homopolymers and copolymers having a plurality of hydrophilic groups (e.g., hydroxyl and/or carboxylic acid groups). In other embodiments, the sustained release drug encapsulation system comprises a membrane enclosed reservoir, wherein the reservoir contains the drug and the membrane is permeable to the drug.

In certain embodiments, the sustained release composition consists of a hydrogel formed by combining a cellulose polymer (e.g., hydroxypropyl methylcellulose or derivatives thereof) and polystyrene nanoparticles. Such hydrogels can be administered topically to the eye by, for example, eye dropping, injection, or implantation. The polymer chains of the cellulose polymer and the polystyrene nanoparticles can form relaxed bonds under pressure, which allows the hydrogel to flow easily when pushed by the needle, but can form cured bonds within a few seconds of pressure release, which allows the hydrogel to be converted into drug-carrying capsules in the eye. In certain embodiments, the hydrogel is loaded with a peptide or protein, such as an apolipoprotein mimetic or an anti-VEGF/VEGFR agent. As the edges of the hydrogel are gradually eroded by exposure to the water in the eye, the peptides or proteins may be released from the hydrogel, which allows the peptides or proteins to be released from the hydrogel over the course of months or even years.

In some embodiments, the sustained release composition is a polymeric implant (e.g., a round plug, a capsule, or any other suitable form) or a polymeric nanoparticle or microparticle, wherein the polymeric particle can be delivered, for example, by eye drops or injection or implant. In some embodiments, the polymeric implant or polymeric nanoparticle or microparticle is composed of biodegradable polymers (one or more biodegradable homopolymers, one or more biodegradable copolymers, or mixtures thereof). In certain embodiments, the biodegradable polymer comprises lactic acid and/or glycolic acid [ e.g., an L-lactic acid-based copolymer, such as poly (L-lactide-co-glycolide) or poly (L-lactic acid-co-D, L-2-hydroxyoctanoic acid ]). The biodegradable polymer of the polymer implant or polymer nanoparticles or microparticles may be selected such that the polymer is substantially completely degraded at about the end of the intended treatment period, and such that the by-products of the degradation of the polymer (e.g., the polymer) are biocompatible.

Non-limiting examples of biodegradable polymers include polyesters, poly (alpha-hydroxy acids), polylactides, polyglycolides, poly (epsilon-caprolactone), polydioxanones, poly (hydroxyalkanoates), poly (hydroxypropionates), poly (3-hydroxypropionates), poly (hydroxybutyrate), poly (3-hydroxybutyrate), poly (4-hydroxybutyrate), poly (hydroxyvalerate), poly (3-hydroxyvalerate), poly (4-hydroxyvalerate), poly (hydroxyoctanoate), poly (2-hydroxyoctanoate), poly (3-hydroxyoctanoate), polysalicylates/polysalicylates, polycarbonates, poly (trimethylene carbonate), poly (ethylene carbonate), poly (propylene carbonate), Tyrosine derived polycarbonates, L-tyrosine derived polycarbonates, polyiminocarbonates, poly (DTH iminocarbonate), poly (bisphenol A iminocarbonate), poly (amino acids), poly (ethylglutamate), poly (propylfumarate), polyanhydrides, polyorthoesters, poly (DETOSU-1,6HD), poly (DETOSU-t-CDM), polyurethanes, polyphosphazenes, polyimides, polyamides, nylons, nylon 12, polyoxyethylated castor oil, poly (ethylene glycol), polyvinylpyrrolidone, poly (L-lactide-co-D-lactide), poly (L-lactide-co-D, L-lactide), poly (D-lactide-co-D, L-lactide), poly (lactide-co-glycolide), Poly (lactide-co-epsilon-caprolactone), poly (glycolide-co-epsilon-caprolactone), poly (lactide-co-dioxanone), poly (glycolide-co-dioxanone), poly (lactide-co-trimethylene carbonate), poly (glycolide-co-trimethylene carbonate), poly (lactide-co-ethylene carbonate), poly (glycolide-co-ethylene carbonate), poly (lactide-co-propylene carbonate), poly (glycolide-co-propylene carbonate), poly (lactide-co-2-methyl-2-carboxy-propylene carbonate), poly (glycolide-co-2-caprolactone), poly (glycolide-co-2-carboxy-propylene carbonate), poly (glycolide-co-2-caprolactone), poly (glycolide-co-, Poly (lactide-co-hydroxybutyrate), poly (lactide-co-3-hydroxybutyrate), poly (lactide-co-4-hydroxybutyrate), poly (glycolide-co-3-hydroxybutyrate), poly (glycolide-co-4-hydroxybutyrate), poly (lactide-co-hydroxyvalerate), poly (lactide-co-3-hydroxyvalerate), poly (lactide-co-4-hydroxyvalerate), poly (glycolide-co-3-hydroxyvalerate), poly (glycolide-co-4-hydroxyvalerate), poly (lactide-co-3-hydroxyvalerate), poly (glycolide-co-4-hydroxyvalerate), poly (lactide-co-hydroxy-3-hydroxy, Poly (3-hydroxybutyrate-co-4-hydroxybutyrate), poly (hydroxybutyrate-co-hydroxyvalerate), poly (3-hydroxybutyrate-co-3-hydroxyvalerate), poly (3-hydroxybutyrate-co-4-hydroxyvalerate), poly (4-hydroxybutyrate-co-3-hydroxyvalerate), (4-hydroxybutyrate-co-4-hydroxyvalerate), poly (epsilon-caprolactone-co-fumarate), poly (epsilon-caprolactone-co-propylene fumarate), poly (ester-co-ether), poly (lactide-co-ethylene glycol), poly (glycolide-co-ethylene glycol), poly (epsilon-caprolactone), poly (methyl methacrylate), poly (ethyl methacrylate), poly (methyl methacrylate), poly, Poly (ester-co-amide), poly (DETOSU-1,6 HD-co-DETOSU-t-CDM), poly (lactide-co-cellulose ester), poly (lactide-co-cellulose acetate), poly (lactide-co-cellulose butyrate), poly (lactide-co-cellulose acetate butyrate), poly (lactide-co-cellulose propionate), poly (glycolide-co-cellulose ester), poly (glycolide-co-cellulose acetate), poly (glycolide-co-cellulose butyrate), poly (glycolide-co-cellulose acetate butyrate), poly (glycolide-co-cellulose propionate), poly (lactide-co-glycolide-co-epsilon-caprolactone), Poly (lactide-co-glycolide-co-trimethylene carbonate), poly (lactide-co-epsilon-caprolactone-co-trimethylene carbonate), poly (glycolide-co-epsilon-caprolactone-co-trimethylene carbonate), poly (3-hydroxybutyrate-co-3-hydroxyvalerate-co-4-hydroxybutyrate), poly (3-hydroxybutyrate-co-4-hydroxyvalerate-co-4-hydroxybutyrate), collagen, casein, polysaccharides, cellulose esters, cellulose acetate, cellulose butyrate, cellulose acetate butyrate, cellulose propionate, chitin, chitosan, dextran, starch, modified starch, and copolymers and blends thereof, wherein the lactide comprises L-lactide, D-lactide and D, L-lactide.

as illustrative examples, a sustained release composition comprising one or more peptides or proteins (e.g., an apolipoprotein mimetic [ e.g., apoA-I or apoE mimetic ] and/or an antibody or fragment thereof [ e.g., an anti-VEGF antibody or fragment thereof ]) for injection (e.g., intravitreal, subconjunctival, subretinal, or tenon's capsule injection) may be composed of one or more biodegradable polymers, such as hexyl-substituted poly (lactic acid) (hexPLA). HexPLA is a hydrophobic polyester with a semi-solid state of aggregation that facilitates formulation. The peptide/protein can be micronized and incorporated into a liquid hexPLA polymer matrix by cryogenic grinding to form a homogeneous and injectable suspension. The peptide/protein may have good compatibility with the hexPLA polymer, good storage stability (e.g., for a long time at about 4 ℃ (e.g., about 3 months or longer)), and better stability inside the polymer when isolated from the surrounding aqueous medium. Peptide/protein formulations with hexPLA may have drug loading of, for example, about 1-5% or 5-10%, and the hexPLA may have a Molecular Weight (MW) of, for example, about 1000-2000g/mol, 2000-3000g/mol, or 3000-4000 g/mol. The formulation may form a spherical depot in an aqueous medium (e.g., buffer) and release the peptide/protein for an extended period of time (e.g., about 1,2, 3,4, 5, or 6 months). The release rate of the peptide/protein can be influenced by the viscosity of the polymer based on the MW of the polymer and to a lesser extent by the drug loading, which allows fine tuning of the drug release profile. The peptides/proteins may retain their structure when incorporated into the polymer matrix and may retain their biological activity (e.g., high affinity for their biological target) after being released from the polymer matrix.

As an alternative to release from the polymeric microparticles, the solid therapeutic agent may be administered in the form of microparticles that comprise or consist essentially of the therapeutic agent. Such agents in particulate form will substantially completely dissolve over time after administration and thus have a longer duration of action and require less administration (e.g., injection) than agents that are substantially completely dissolved in an aqueous medium after administration. In addition, such microparticles may form a reservoir for prolonged therapeutic agent delivery. Such microparticles may optionally contain a relatively small amount of one or more excipients. Microparticles comprising or consisting essentially of a therapeutic agent can be administered locally by, for example, injection (e.g., intravitreal, subconjunctival, subretinal, or sub-tenon's capsule injection), eye drops, or implants (e.g., intravitreal, subretinal, or sub-tenon's capsule implants).

In some embodiments, the sustained release composition releases a low or relatively low but therapeutically effective dose of the one or more therapeutic agents over a period of about 1 week, 2 weeks, 4 weeks (1 month), 6 weeks, 8 weeks (2 months), 10 weeks, 3 months, 6 months, 1 year, 1.5 years, 2 years, 2.5 years, 3 years, or more.

An example of a slow release polymer implant is an intravitreal implant in the form of a microtube made of polyimide and sealed with a silicone adhesive on one end and polyvinyl alcohol on the other end and which releases very little of the corticosteroid fluocinolone acetonide for 3 years. Another example of a sustained release polymer implant is a biodegradable intravitreal implant that uses a solid polymer delivery system to deliver the extended release corticosteroid dexamethasone. Other therapeutic agents that may be delivered by a sustained release biodegradable intravitreal implant include, but are not limited to, the neuroprotective agent brimonidine.

Another example of a sustained release ophthalmic drug delivery system is that described in U.S. Pat. No.6,375,972 to Guo et al. The system of Guo includes an inner drug core containing a drug and an inner tube impermeable to the passage of the drug, wherein the inner tube has first and second ends and covers at least a portion of the inner drug core, and the inner tube is sized and formed of a material such that the inner tube is dimensionally stable to accept the inner drug core without changing shape. An impermeable membrane is positioned at the first end of the inner tube and prevents passage of the drug through the first end of the inner tube and out of the inner drug core. A permeable membrane is positioned at the second end of the inner tube and allows the drug to diffuse out of the inner drug core through the second end of the inner tube. For example, the sustained release system of Guo can be applied by injection or implantation into the vitreous humor, subretinal or episcleral.

another example of a controlled release ophthalmic drug delivery system is that described in Yaacobi, U.S. patent No.6,413,540. The Yaacobi system includes a body having a scleral surface for placement adjacent the sclera, and a bore having an opening to the scleral surface and an inner core containing a drug. The system delivers drugs at a controlled rate to the choroid and retina through the sclera or to the retina through the choroid.

Another exemplary ocular drug delivery device is an osmotic pump, such as that described by Ambati et al. The osmotic pump of Ambati delivers IgG and anti-ICAM-1 monoclonal antibodies, respectively, to the choroid and retina through the sclera with negligible systemic absorption. Ambati et al, invest, opthalmol, vis, sci, 41:1186-91 (2000).

Drug eluting contact lenses may also be used as sustained release drug delivery systems. Such contact lenses can be considered implantable devices or used as compositions for topical administration. The duration of release of the drug eluting contact lens may be increased by: such as molecular imprinting, dispersion of barriers or nanoparticles/microparticles, increasing drug binding to the polymer, or sandwiching a layer of polymer [ e.g., poly (lactide-co-glycolide) ] in the lens, or any combination or all thereof. Contact lenses can provide extended drug release, for example, hours to days, as needed, and can increase patient compliance due to their ease of use and minimal invasiveness.

In some embodiments, one or more therapeutic agents (e.g., a polynucleotide [ e.g., an antisense polynucleotide ] and/or a polypeptide [ e.g., an apolipoprotein mimetic ]) are independently contained in a nanoparticle, microparticle, or liposome having a lipid bilayer. In some embodiments, the lipid bilayer is comprised of one or more phospholipids. Non-limiting examples of phospholipids include phosphatidic acids (e.g., DMPA, DPPA and DSPA), phosphatidylcholines (e.g., DDPC, DEPC, DLPC, DMPC, DOPC, DPPC, DSPC and POPC), phosphatidylethanolamines (e.g., DMPE, DOPE, DPPE and DSPE), phosphatidylglycerols (e.g., DMPG, DPPG, DSPG and POPG), and phosphatidylserines (e.g., DOPS). Nanoparticles, microparticles, or liposomes having a lipid bilayer composed of fusogenic lipids (e.g., DPPG) can be fused to the plasma membrane of cells and thereby deliver therapeutic agents into those cells. Nanoparticles, microparticles or liposomes having a lipid bilayer can be administered locally or systemically.

in some embodiments, the anti-angiogenic agent (e.g., an anti-VEGF/VEGFR agent) and the anti-inflammatory agent (e.g., an apolipoprotein mimetic [ e.g., apoA-I mimetic ], CRP inhibitor, complement inhibitor, inflammatory body inhibitor, corticosteroid, or NSAID, or any combination or all thereof) are contained in the same or different liposomes, nanoparticles, or microparticles consisting of biodegradable polymers or lipid bilayers and administered for the treatment of, for example, neovascular AMD, including type 1,2, and/or 3 neovascularization. In certain embodiments, the liposome, nanoparticle or microparticle is topically administered by: for example, by eye drops or injection (e.g., intravitreal, subconjunctival, subretinal, or sub-tenon's capsule injection).

Compositions comprising one or more therapeutic agents may be presented as a single dose in a single dosage form in which all active and inactive ingredients are combined in a suitable system and no mixing of the components is required to form the composition to be administered. The unit dosage form may contain an effective dose of each of the one or more therapeutic agents or an appropriate fraction thereof. Examples of unit dosage forms are tablets, capsules or pills for oral administration. Another example of a unit dosage form is a disposable vial, ampoule or pre-filled syringe containing a composition of one or more therapeutic agents and excipients dissolved or suspended in a suitable carrier (e.g., an aqueous solvent). The vial or ampoule may be included in a kit containing a device for administering the composition (e.g., a syringe, filter or filter needle, and an injection needle for injecting the composition). The kit may further comprise instructions for storing and administering the composition.

Alternatively, a composition comprising one or more therapeutic agents may be provided in a kit, wherein the one or more therapeutic agents, excipients, and carriers (e.g., solvents) are provided in two or more separate containers (e.g., ampoules, vials, tubes, bottles, or syringes) and need to be combined to prepare the composition to be administered. In some embodiments, two or more therapeutic agents (e.g., an apoA-I mimetic and/or an apoE mimetic plus an anti-angiogenic agent, a neuroprotective agent, an anti-inflammatory agent, a complement inhibitor, an antioxidant, or a substance that reduces lipid production) are combined into the same formulation shortly before or just before the formulation is administered (e.g., by injection). The one or more therapeutic agents may be provided in any suitable form (e.g., in a stable medium or lyophilized). The kit may contain a device for administering the composition (e.g., a syringe, filter or filter needle, and a needle for injecting a solution or suspension). The kit may also contain instructions for storing the kit contents and for preparing and administering the composition.

XII salt form

Compounds/molecules (e.g., apolipoprotein mimics, such as L-4F and AEM-28-14) may exist in non-salt form (e.g., free base or free acid, or without basic or acidic atoms or functional groups) or as salts if they can form salts. The compounds that can form salts can be used in non-salt form or in the form of pharmaceutically acceptable salts. If a compound has, for example, a basic nitrogen atom, the compound may form an addition salt with an acid (e.g., an inorganic acid [ such as HCl, HBr, HI, nitric acid, phosphoric acid, or sulfuric acid ] or an organic acid [ such as a carboxylic acid or sulfonic acid ]). Suitable acids for preparing pharmaceutically acceptable salts include, but are not limited to, acetic acid, 2-dichloroacetic acid, acylated amino acids, adipic acid, alginic acid, ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, boric acid, (+) -camphoric acid, camphorsulfonic acid, (+) - (1S) -camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1, 2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, D-gluconic acid, D-glucuronic acid, L-glutamic acid, alpha-oxoglutaric acid, glucoheptonic acid, D-glucuronic acid, L-glutamic acid, alpha-oxoglutaric acid, adipic acid, alginic, Glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, (±) -DL-lactic acid, (+) -L-lactic acid, lactobionic acid, lauric acid, maleic acid, (-) -L-malic acid, malonic acid, (±) -DL-mandelic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1, 5-disulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, perchloric acid, phosphoric acid, propionic acid, L-pyroglutamic acid, pyruvic acid, sugar acids, salicylic acid, 4-amino-salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, (+) -DL-tartaric acid, (+) -L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid, (+) -L-tartaric acid, and mixtures thereof, Undecylenic acid and valeric acid.

if a compound has an acidic group (e.g., carboxyl), the compound can form an addition salt with a base. Pharmaceutically acceptable base addition salts can be formed, for example, with metals (e.g., alkali metals or alkaline earth metals) or amines (e.g., organic amines). Non-limiting examples of metals that can be used as cations include alkali metals (e.g., lithium, sodium, potassium, and cesium), alkaline earth metals (e.g., magnesium and calcium), aluminum, and zinc. The metal cations can be provided, for example, by inorganic bases such as hydroxides, carbonates, and bicarbonates. Non-limiting examples of organic amines useful for forming base addition salts include chloroprocaine, choline, cyclohexylamine, dibenzylamine, N' -dibenzylethylenediamine, dicyclohexylamine, diethanolamine, ethylenediamine, N-ethylpiperidine, histidine, isopropylamine, N-methylglucamine, procaine, pyrazine, triethylamine, and trimethylamine. Pharmaceutically acceptable Salts are discussed in detail in Handbook of Pharmaceutical Salts, Properties, Selection and Use, P.Stahl and C.Wermuth, eds., Wiley-VCH (2011).

representative embodiments of xiii

The following embodiments of the present disclosure are provided by way of example only:

1. A method of treating age-related macular degeneration (AMD), comprising administering to a subject in need of treatment a therapeutically effective amount of an apolipoprotein (apo) mimetic, wherein the apo mimetic is administered to the eye topically, intraocularly, in the eye, or periocularly at a dose of about 0.1 or 0.3mg to about 1.5mg per administration, or at a total dose of about 0.5 or 1mg to about 10mg over a period of about 6 months.

2. The method of embodiment 1, wherein said apo mimetic comprises, or is, an apoA-I mimetic.

3. The method of embodiment 2, wherein said apoA-I mimetic comprises 4F or a variant or salt thereof (e.g., acetate), or is 4F or a variant or salt thereof (e.g., acetate).

4. The method of embodiment 3, wherein the apoA-I mimetic comprises L-4F or D-4F, or is L-4F or D-4F, each optionally having a protecting group [ e.g., Ac-DWFKAFYDKVAEKFKEAF-NH2(SEQ. ID. NO.13) ] at the N-terminus and/or C-terminus.

5. The method of any one of the preceding embodiments, wherein the apo mimetic comprises an apoE mimetic, or is an apoE mimetic.

6. The method of embodiment 5, wherein the apoE mimetic comprises AEM-28-14 or a variant or salt thereof, or is AEM-28-14 or a variant or salt thereof.

7. The method of any one of the preceding embodiments, wherein the apo mimetic (e.g., L-4F) is administered topically at a dose of about 0.1-0.5mg, 0.5-1mg, 1-1.5mg, 0.1-0.3mg, 0.3-0.5mg, 0.5-0.75mg, 0.75-1mg, 1-1.25mg, or 1.25-1.5mg (e.g., about 0.1-0.5mg or 0.5-1mg) per administration (e.g., per injection).

8. the method of any one of the preceding embodiments, wherein the apo mimetic (e.g., L-4F) is administered topically at a total dose of about 0.5 or 1-5mg, 5-10mg, 0.5 or 1-3mg, 3-5mg, 5-7.5mg, or 7.5-10mg (e.g., about 0.5-3mg or 3-5mg) over a period of about 6 months.

9. The method of any one of the preceding embodiments, wherein the apo mimetic (e.g., L-4F) is administered topically at a total dose of about 1 or 2-20mg or 5-15mg for the entire treatment regimen.

10. The method of embodiment 9, wherein the apo mimetic (e.g., L-4F) is administered topically at a total dose of about 1-5mg, 5-10mg, 10-15mg, 15-20mg, 1-3mg, 3-5mg, 5-7.5mg, 7.5-10mg, 10-12.5mg, 12.5-15mg, 15-17.5mg, or 17.5-20mg (e.g., about 1-5mg or 5-10mg) for an entire treatment regimen.

11. the method of any one of the preceding embodiments, wherein the dose per administration, the total dose over a period of about 6 months, and the total dose of the entire treatment regimen are for each eye treated.

12. The method of any one of the preceding embodiments, wherein the apo mimetic (e.g., L-4F) is administered topically by injection (e.g., intravitreal, subconjunctival, subretinal, or sub-tenon's capsule injection), eye drops, or implants (e.g., intravitreal, intracameral, sub-retinal, or sub-tenon's capsule implants).

13. The method of embodiment 12, wherein said apo mimetic (e.g., L-4F) is administered topically by injection (e.g., intravitreal, subconjunctival, subretinal, or sub-tenon's capsule injection).

14. The method of embodiment 13, wherein the apo mimetic (e.g., L-4F) is administered topically by injection (e.g., intravitreal injection) at a dosage concentration of about 1,2, 3,4, or 5mg/mL to about 12 or 15 mg/mL.

15. The method of embodiment 14, wherein the apo mimetic (e.g., L-4F) is administered topically by injection (e.g., intravitreal injection) at a dosage concentration of about 1-4mg/mL, 4-8mg/mL, 8-12mg/mL, 1-5mg/mL, 5-10mg/mL, 10-15mg/mL, 1-3mg/mL, 3-5mg/mL, 5-7.5mg/mL, 6-8mg/mL, 7.5-10mg/mL, 10-12.5mg/mL, or 12.5-15mg/mL (e.g., about 1-5mg/mL, 5-10mg/mL, or 6-8 mg/mL).

16. The method of any one of embodiments 13 to 15, wherein the apo mimetic (e.g., L-4F) is administered topically by injection (e.g., intravitreal injection) in a dosage volume of about 50-150 μ L or 50-100 μ L.

17. The method of embodiment 16, wherein the apo mimetic (e.g., L-4F) is administered locally by injection (e.g., intravitreal injection) at a dose volume of about 50-75 μ L, 75-100 μ L, 100-.

18. The method of any one of embodiments 13 to 17, wherein the apo mimetic (e.g., L-4F) is administered topically by injection (e.g., intravitreal injection) once a month (4 weeks) or 1.5 months (6 weeks).

19. The method of any one of embodiments 13 to 17, wherein the apo mimetic (e.g., L-4F) is administered topically by injection (e.g., intravitreal injection) once every 2 months (8 weeks), 2.5 months (10 weeks), or 3 months (12 weeks).

20. The method of any one of embodiments 13 to 17, wherein the apo mimetic (e.g., L-4F) is administered topically by injection (e.g., intravitreal injection) once every 4, 5, or 6 months.

21. the method of any one of embodiments 13 to 20, wherein the apo mimetic (e.g., L-4F) is administered topically for a total of about 15 injections (e.g., intravitreal injections) or less, 12 injections or less, 9 injections or less, 6 injections or less, or 3 injections or less.

22. The method of embodiment 21, wherein the apo mimetic (e.g., L-4F) is administered topically in a total of about 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, or 3 (e.g., about 3-6 or 7-10) injections (e.g., intravitreal injections).

23. The method of any one of the preceding embodiments, wherein the apo mimetic (e.g., L-4F) is administered locally (e.g., by intravitreal injection) at a higher dose and/or more frequently during the early stages of treatment.

24. The method of any one of the preceding embodiments, wherein the treatment regimen with the apo mimetic (e.g., L-4F) lasts for about 36 months or less, 30 months or less, 24 months or less, 18 months or less, 12 months or less, or 6 months or less.

25. The method of embodiment 24, wherein said treatment regimen with said apo mimetic (e.g., L-4F) lasts for about 6-12, 12-18, 18-24, 24-30, or 30-36 months (e.g., about 6-12 or 12-24 months).

26. The method of any one of the preceding embodiments, wherein the apo mimetic (e.g., L-4F) is administered at least at an advanced (late) stage of AMD (e.g., to treat central pattern atrophy [ GA ] and/or prevent neovascular AMD, and/or treat neovascular AMD).

27. The method of embodiment 26, wherein said apo mimetic (e.g., L-4F) is administered topically by injection (e.g., intravitreal, subconjunctival, subretinal, or sub-tenon's capsule injection) once every about 4-8 weeks or 4-6 weeks at the end of AMD, with about 8-12 or more injections in total, a dose of up to about 1-1.5mg per injection, or a total dose of up to about 15-20mg throughout the treatment regimen, or any combination or all thereof.

28. The method of any one of the preceding embodiments, wherein the apo mimetic (e.g., L-4F) is administered at least during the intermediate stage of AMD (e.g., to treat non-central GA and/or prevent central GA and/or neovascular AMD, or is administered during the initial stage of intermediate AMD to prevent or prevent non-central GA).

29. The method of embodiment 28, wherein the apo mimetic (e.g., L-4F) is administered topically by injection (e.g., intravitreal, subconjunctival, subretinal, or sub-tenon's capsule injection) once every about 4-8 weeks or 4-6 weeks, about 8-12 or more total injections, up to about 1-1.5mg per injection, or up to about 15-20mg total dose of the entire treatment regimen, or any combination or all thereof, during the middle stage of AMD.

30. The method of any one of the preceding embodiments, wherein the apo mimetic (e.g., L-4F) is administered at least at the early stage of AMD (e.g., to prevent or prevent non-central GA).

31. The method of embodiment 30, wherein the apo mimetic (e.g., L-4F) is administered locally by injection (e.g., intravitreal, subconjunctival, subretinal, or sub-tenon's capsule injection) early in AMD at a lower frequency (e.g., once every about 3,4, or 6 months), a lesser total number of injections (e.g., about 1,2, or 3 injections), or a higher dose per injection (e.g., about 0.5-1mg or 1-1.5mg per injection), or any combination or all thereof.

32. The method of any one of the preceding embodiments, wherein the later the stage of AMD or the more severe the AMD condition, the more frequently (which may result in more total number of administrations) and/or locally (e.g., by intravitreal injection) the apo mimetic (e.g., L-4F) is administered (which may result in a higher total number of administrations) and/or at higher doses (higher doses per administration and/or higher total doses for the complete treatment regimen).

33. The method of any one of the preceding embodiments, wherein the apo mimetic (e.g., L-4F) is administered topically (e.g., by intravitreal injection) in a fixed routine regimen, an on-demand regimen, or a therapeutic and protracted regimen.

34. The method of any one of the preceding embodiments, wherein the apo mimetic (e.g., L-4F) is administered topically by a composition comprising about 75-95% (e.g., about 90%) by weight or molar concentration of the apo mimetic and about 5-25% (e.g., about 10%) of the corresponding apolipoprotein (e.g., apoA-I) or an active portion or domain thereof, relative to their combined amount.

35. The method of any one of the preceding embodiments, wherein the apo mimetic (e.g., L-4F) is administered topically in a composition comprising one or more excipients that inhibit peptide/protein aggregation, increase peptide/protein solubility, decrease solution viscosity, or increase peptide/protein stability, or any combination or all thereof.

36. The method of any one of the preceding embodiments, wherein the apo mimetic (e.g., L-4F) is administered topically via a sustained release composition.

37. The method of any one of the preceding embodiments, further comprising administering one or more additional therapeutic agents.

38. The method of embodiment 37, wherein said one or more additional therapeutic agents are selected from the group consisting of: anti-dyslipidemic agents, PPAR-alpha agonists, PPAR-delta agonists, PPAR-gamma agonists, anti-amyloid agents, inhibitors of lipofuscin or components thereof, antioxidants, neuroprotective agents (neuroprotective agents), apoptosis inhibitors, necrosis inhibitors, C-reactive protein (CRP) inhibitors, inhibitors of the complement system or components thereof (e.g., proteins), inflammatory body inhibitors, anti-inflammatory agents, immunosuppressive agents, modulators of Matrix Metalloproteinases (MMPs), anti-angiogenic agents and RPE cell replacement therapy.

39. a method of preventing age-related macular degeneration (AMD), delaying the onset of AMD, slowing the progression of AMD, or reducing the extent of vision impairment or loss associated with AMD, comprising administering to a subject in need thereof a therapeutically effective amount of an apolipoprotein (apo) mimetic of any one of embodiments 1-38.

40. The method of embodiment 39, wherein said AMD is atrophic AMD (including non-central and/or central pattern atrophy) or neovascular AMD (including neovascularisation type 1,2 and/or 3).

41. A method of treating age-related macular degeneration (AMD) comprising administering to a subject in need thereof a therapeutically effective amount of an apolipoprotein (apo) mimetic according to any one of embodiments 1 to 38 and a therapeutically effective amount of an anti-angiogenic agent.

42. The method of embodiment 41, wherein said apo mimetic comprises an apoA-I mimetic (e.g., L-4F or D-4F) and/or an apoE mimetic (e.g., AEM-28-14), or is an apoA-I mimetic (e.g., L-4F or D-4F) and/or an apoE mimetic (e.g., AEM-28-14).

43. The method of embodiment 41 or 42, wherein the anti-angiogenic agent comprises or is the following: a substance that inhibits the action of vascular endothelial growth factor (anti-VEGF agent) and/or a substance that inhibits the action of platelet-derived growth factor (anti-PDGF agent).

44. The method of embodiment 43, wherein said anti-VEGF agent is selected from the group consisting of: squalamine, PAN-90806, anti-VEGF antibodies and fragments thereof (e.g., bevacizumab ranibizumab ESBA1008 and ESBA903), anti-VEGF aptamers (e.g., pegaptanib), anti-VEGF designed ankyrin repeat proteins (DARPins) (e.g., perazappa (abicipipergol)), soluble receptors for VEGF (e.g., VEGFR1), soluble fusion proteins containing one or more extracellular domains of VEGFR (e.g., aflibercept and conicept), and combinations thereof.

45. The method of embodiment 44, wherein said anti-VEGF agent comprises or is the following: aflibercept, bevacizumab, or ranibizumab, or any combination or all thereof.

46. The method of any one of embodiments 41 to 45, wherein the anti-angiogenic agent (e.g., anti-VEGF agent) is administered at a frequency and/or dose that is less than a conventional or recommended dosing frequency for the anti-angiogenic agent in the absence of treatment with the apo mimetic (e.g., L-4F).

47. the method of embodiment 46, wherein the conventional or recommended dosing frequency is at least about 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, or 6-fold (e.g., at least about 2-fold) less frequent (e.g., by intravitreal injection) administration of the anti-angiogenic agent (e.g., anti-VEGF agent) in the absence of treatment with the apo mimetic (e.g., L-4F) as compared to the conventional or recommended dosing frequency of the anti-angiogenic agent.

48. the method of embodiment 46 or 47, wherein the conventional or recommended dose is for administration (e.g., by intravitreal injection) of the anti-angiogenic agent (e.g., anti-VEGF agent) at a dose that is at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, or 80% (e.g., at least about 20%), or about 10-30%, 30-50%, or 50-70% less than the conventional or recommended dose of the anti-angiogenic agent without treatment with the apo mimetic (e.g., L-4F).

49. The method of any one of embodiments 46 to 48, wherein treatment with the apo mimetic (e.g., L-4F) reduces the total number of administrations (e.g., total number of injections) of the anti-angiogenic agent (e.g., anti-VEGF agent).

50. The method of embodiment 49, wherein the anti-angiogenic agent (e.g., anti-VEGF agent) is administered (e.g., by intravitreal injection) no more than about 20, 18, 15, 12, or 10 times.

51. the method of any one of embodiments 46 to 50, wherein treatment with said apo mimetic (e.g., L-4F) and said anti-angiogenic agent (e.g., anti-VEGF agent) has a synergistic effect.

52. The method of any one of embodiments 46 to 51, wherein:

The anti-angiogenic agent comprises or is aflibercept and

Administering by intravitreal injection 2mg every 2 months after once monthly administration of 2mg for 3 months prior to treatment, compared to the conventional or recommended dose and frequency of administration of aflibercept for administration (e.g., by intravitreal injection) once every 3 months, 4 months, 5 months, or 6 months without treatment with the apo mimetic (e.g., L-4F), optionally after once monthly administration at a dose of about 1-1.5mg or 1.5-2mg for the first 1 month, 2 months, or 3 months, or after once every 6 weeks at a dose of about 1-1.5mg or 1.5-2mg for the first 1.5 or 3 months, once every 3 months, Administered (e.g., by intravitreal injection) once for 4 months, 5 months, or 6 months.

53. The method of any one of embodiments 46 to 51, wherein:

the anti-angiogenic agent comprises or is aflibercept; and

(ii) aflibercept is administered (e.g., by intravitreal injection) at a dose of about 1-1.25mg, 1.25-1.5mg, or 1.5-1.75mg, at a frequency substantially similar to or the same as the conventional or recommended dosing frequency of aflibercept for treatment without the apo mimetic (e.g., L-4F).

54. The method of any one of embodiments 46 to 51, wherein:

The anti-angiogenic agent comprises or is ranibizumab and

(ii) ranibizumab administered once per month by intravitreal injection at a dose of about 0.2-0.3mg, 0.3-0.4mg, or 0.4-0.5mg (e.g., by intravitreal injection) once per 2 months, 3 months, 4 months, 5 months, or 6 months, optionally after once per month administration at a dose of about 0.2-0.3mg, 0.3-0.4mg, or 0.4-0.5mg for the first 1,2, or 3 months, or once per 6 weeks at a dose of about 0.2-0.3mg, 0.3-0.4mg, or 0.4-0.5mg for the first 1.5 or 3 months, or after once per 6 weeks at a dose of about 0.2-0.3mg, 0.3-0.4mg, or 0.4-0.5mg for the first 1.5 or 3 months, compared to once per month administration of 0.5mg by intravitreal injection of ranibizumab, Administered (e.g., by intravitreal injection) once for 3 months, 4 months, 5 months, or 6 months.

55. The method of any one of embodiments 46 to 51, wherein:

The anti-angiogenic agent comprises or is ranibizumab; and

Ranibizumab is administered monthly (e.g., by intravitreal injection) at a dose of about 0.2-0.3mg or 0.3-0.4 mg.

56. The method of any one of embodiments 46 to 51, wherein:

The anti-angiogenic agent comprises or is bevacizumab

Bevacizumab is administered once per month by intravitreal injection at about 1.25mg, once per month compared to a conventional or recommended dose and dosing frequency for bevacizumab for the treatment of AMD that is not treated with the apo mimetic (e.g., L-4F) of about 0.5-0.75mg, 0.75-1mg, or 1-1.25mg once per 2 months, 3 months, 4 months, 5 months, or 6 months (e.g., by intravitreal injection), optionally after once per month administration at a dose of about 0.5-0.75mg, 0.75-1mg, or 1-1.25mg for the first 1,2, or 3 months or after once per 6 weeks at a dose of about 0.5-0.75mg, 0.75-1mg, or 1-1.25mg for the first 1.5 or 3 months, bevacizumab is administered at about 0.5-0.75mg, A dose of 0.75-1mg or 1-1.25mg is administered (e.g., by intravitreal injection) once every 2 months, 3 months, 4 months, 5 months, or 6 months.

57. The method of any one of embodiments 46 to 51, wherein:

The anti-angiogenic agent comprises or is bevacizumab; and

Bevacizumab is administered (e.g., by intravitreal injection) once a month at a dose of about 0.5-0.75mg or 0.75-1 mg.

58. The method of any one of embodiments 46 to 51, wherein the anti-angiogenic agent (e.g., anti-VEGF agent) is administered (e.g., by intravitreal injection) once every 2, 3,4,5, or 6 months.

59. The method of any one of embodiments 41 to 58, wherein the anti-angiogenic agent (e.g., anti-VEGF agent) is administered topically to the eye, intraocularly, in the eye, or periocularly, such as by injection (e.g., intravitreal injection, subconjunctival, subretinal, or sub-tenon's capsule injection), eye drops, or implants (e.g., intravitreal, intracameral, sub-retinal, or sub-tenon's capsule implants).

60. The method of any one of embodiments 41 to 59, wherein the anti-angiogenic agent (e.g., anti-VEGF agent) is administered to treat or slow the progression of neovascular (wet) AMD, including neovascularisation types 1,2, and 3.

61. The method of any one of embodiments 41 to 60, wherein the anti-angiogenic agent (e.g., anti-VEGF agent) is administered at least at an advanced (late) stage of AMD to prevent, delay the onset of, or slow the progression of neovascular AMD.

62. the method of any one of embodiments 41 to 61, wherein the apo mimetic (e.g., L-4F) is administered at least at the advanced stage of AMD.

63. The method of embodiment 62, wherein the apo mimetic (e.g., L-4F) is administered to treat central geographic atrophy, and/or to prevent, delay the onset of, or slow the progression of neovascular AMD, including neovascular AMD types 1,2, and 3.

64. The method of any one of embodiments 41 to 63, wherein the anti-angiogenic agent (e.g., anti-VEGF agent) is administered in a fixed routine regimen, an on-demand regimen or a therapeutic and protracting regimen.

65. The method of any one of embodiments 41 to 64, wherein said apo mimetic (e.g., L-4F) and said anti-angiogenic agent (e.g., anti-VEGF agent) are administered in separate compositions.

66. The method of any one of embodiments 41 to 64, wherein said apo mimetic (e.g., L-4F) and said anti-angiogenic agent (e.g., anti-VEGF agent) are administered in the same composition.

67. A method of treating age-related macular degeneration (AMD) comprising administering to a subject in need thereof a therapeutically effective amount of an apolipoprotein (apo) mimetic according to any one of embodiments 1 to 38 and a therapeutically effective amount of a complement inhibitor.

68. the method of embodiment 67, wherein said apo mimetic comprises an apoA-I mimetic (e.g., L-4F or D-4F) and/or an apoE mimetic (e.g., AEM-28-14), or is an apoA-I mimetic (e.g., L-4F or D-4F) and/or an apoE mimetic (e.g., AEM-28-14).

69. The method of embodiment 67 or 68, wherein the apo mimetic (e.g., L-4F) and the complement inhibitor are administered to treat Geographic Atrophy (GA).

70. The method of embodiment 69, wherein the apo mimetic (e.g., L-4F) and the complement inhibitor are administered to prevent central GA and/or non-central GA, delay the onset of central GA and/or non-central GA, or slow the progression of central GA and/or non-central GA.

71. The method of embodiment 69 or 70, wherein the apo mimetic (e.g., L-4F) and the complement inhibitor are administered at least at the advanced (late) stage of atrophic (dry) AMD to treat or slow progression of central GA, and/or to prevent or delay the onset of neovascular AMD.

72. The method of any one of embodiments 69 to 71, wherein the apo mimetic (e.g., L-4F) and the complement inhibitor are administered at least at the metaphase stage of AMD to treat or slow the progression of non-central GA, and/or to prevent or delay the onset of central GA and/or neovascular AMD.

73. The method of any one of embodiments 69 to 72, wherein the apo mimetic (e.g., L-4F) and the complement inhibitor are administered to prevent or delay the onset of non-central GA at least at the early stage of AMD or the initial stage of intermediate AMD.

74. The method of any one of embodiments 67 to 73, wherein said complement inhibitor is selected from the group consisting of: anti-complement factor b (cfb) antibodies and fragments thereof (e.g., TA106), anti-CFD antibodies and fragments thereof (e.g., lanbolilizumab), C3 inhibitors (e.g., C3 complement inhibin and derivatives thereof [ e.g., POT-4], soluble forms of mycophenolic acid-glucosamine conjugates and proteins or fragments thereof [ e.g., CR1, decay accelerating factor and membrane cofactor protein ]), anti-C3 b/iC3b antibodies and fragments thereof (e.g., 3E7), anti-C5 antibodies and fragments thereof (e.g., eculizumab and LFG316), anti-C5 aptamers (e.g., ARC1905), other C5 inhibitors (e.g., Coversin), C5a receptor antagonists (e.g., JPE-1375, m-7717, PMX-025, PMX-53, and anti-C5 aR antibodies and fragments thereof [ e.g., nootkin ]) mabs, inhibitors of the alternative complement pathway (e.g., sCR1, 30, and zinc), Inhibitors of the classical complement pathway (e.g., sCR1), inhibitors of the lectin complement pathway (e.g., inhibitors of mannose-related serine proteases [ MASP ], such as anti-MASP antibodies and fragments thereof [ e.g., OMS721]), inhibitors of Membrane Attack Complex (MAC) formation (e.g., zinc, CD59, and modified CD59 with glycolipid anchors), and analogs, derivatives, fragments, salts, and combinations thereof.

75. The method of embodiment 74, wherein said complement inhibitor comprises or is the following: lanreolizumab, LFG316, or ARC1905, or any combination or all thereof.

76. The method of embodiment 75, wherein said complement inhibitor comprises or is landolizumab.

77. The method of embodiment 76, wherein said subject has a mutation in a gene encoding complement factor i (cfi).

78. The method of any one of embodiments 67 to 77, wherein treatment with the apo mimetic (e.g., L-4F) and the complement inhibitor (e.g., lanreolizumab) slows progression of central GA and/or non-central GA (e.g., reduces the rate of GA progression, or reduces GA lesion area or size) by at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, or 80% (e.g., at least about 20% or 40%), or about 20-40%, 40-60%, or 60-80%.

79. The method of any one of embodiments 67 to 78, wherein treatment with the apo mimetic (e.g., L-4F) and the complement inhibitor (e.g., Landolizumab) slows the progression of central GA and/or non-central GA (e.g., reduces the rate of GA progression, or reduces GA lesion area or size) by at least about 10%, 20%, 30%, 50%, 100%, 150%, 200%, or 300% (e.g., at least about 20% or 30%), or about 10-30%, 30-50%, 50-100%, 100-200%, or 200-300% (e.g., about 50-100%) compared to treatment with the complement inhibitor without treatment with the apo mimetic.

80. The method of any one of embodiments 67 to 79, wherein the complement inhibitor (e.g., lanreolizumab) is administered at a frequency and/or dose that is lower than a conventional or recommended dosing frequency or dose for a complement inhibitor in the absence of treatment with the apo mimetic (e.g., L-4F).

81. The method of embodiment 80, wherein the conventional or recommended dosing frequency is at least about 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, or 6-fold (e.g., at least about 2-fold) less frequent (e.g., by intravitreal injection) administration of the complement inhibitor (e.g., lanreolizumab) in the absence of treatment with the apo mimetic (e.g., L-4F) as compared to the conventional or recommended dosing frequency of the complement inhibitor.

82. The method of embodiment 80 or 81, wherein the conventional or recommended dose is for administration (e.g., by intravitreal injection) of the complement inhibitor (e.g., lanreolizumab) at a dose that is at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, or 80% (e.g., at least about 20%), or about 10-30%, 30-50%, or 50-70% less than it without treatment with the apo mimetic (e.g., L-4F) compared to the conventional or recommended dose of the complement inhibitor.

83. The method of any one of embodiments 80 to 82, wherein treatment with the apo mimetic (e.g., L-4F) reduces the total number of administrations (e.g., total number of injections) of the complement inhibitor (e.g., lanbrizumab).

84. The method of embodiment 83, wherein the complement inhibitor (e.g., lanebolizumab) is administered (e.g., by intravitreal injection) no more than about 20, 18, 15, 12, or 10 times.

85. The method of any one of embodiments 80 to 84, wherein treatment with the apo mimetic (e.g., L-4F) and the complement inhibitor (e.g., lanreolizumab) has a synergistic effect.

86. the method of any one of embodiments 80 to 85, wherein:

The complement inhibitor comprises or is Lanbolizumab; and

once by intravitreal injection, at a dose of about 4-6mg, 6-8mg, or 8-10mg once every 2 months, 3 months, 4 months, 5 months, or 6 months, optionally after once monthly administration at a dose of about 4-6mg, 6-8mg, or 8-10mg for the first 1 month, 2 months, or 3 months, or after once every 6 weeks administration at a dose of about 4-6mg, 6-8mg, or 8-10mg for the first 1.5 or 3 months, compared to once monthly administration by intravitreal injection of about 10mg for the conventional or recommended dose and dosing frequency of lan bollizumab for the absence of the apo mimetic (e.g., L-4F, 6-8mg, or 8-10 mg), A dose of 6-8mg or 8-10mg is administered (e.g., by intravitreal injection) once every 2 months, 3 months, 4 months, 5 months, or 6 months.

87. the method of any one of embodiments 80 to 85, wherein:

The complement inhibitor comprises or is laplizumab; and

Lanbolizumab is administered (e.g., by intravitreal injection) once monthly (4 weeks) or 1.5 months (6 weeks) at a dose of about 3-5mg, 5-7mg, or 7-9 mg.

88. The method of any one of embodiments 80 to 86, wherein the complement inhibitor (e.g., lanreolizumab) is administered (e.g., by intravitreal injection) once every 2, 3,4, 5, or 6 months (e.g., every 2 months).

89. The method of any one of embodiments 67-88, wherein the complement inhibitor (e.g., lanreolizumab) is administered topically, intraocularly, in the eye, or periocularly, such as by injection (e.g., intravitreal, subconjunctival, subretinal, or sub-tenon's capsule injection), eye drops, or implants (e.g., intravitreal, subconjunctival, sub-retinal, or sub-tenon's capsule implants).

90. The method of any one of embodiments 67-89, wherein said apo mimetic (e.g., L-4F) and said complement inhibitor (e.g., Lanboluzumab) are administered in separate compositions.

91. The method of any one of embodiments 67-89, wherein the apo mimetic (e.g., L-4F) and the complement inhibitor (e.g., Lanboluzumab) are administered in the same composition.

92. The method of any one of embodiments 67 to 91, wherein the apo mimetic (e.g., L-4F) and the complement inhibitor are administered at least at an advanced stage of AMD to prevent, delay the onset, or slow the progression of neovascular AMD, including neovascular AMD types 1,2, and 3.

93. The method of embodiment 92, further comprising administering a therapeutically effective amount of an anti-angiogenic agent.

94. The method of embodiment 93, wherein said anti-angiogenic agent comprises or is the following: an anti-VEGF agent (e.g., abiceptable bevacizumab or ranibizumab, or any combination or all thereof) and/or an anti-PDGF agent (e.g., E10030).

95. The method of any one of embodiments 92 to 94, wherein the complement inhibitor comprises ARC1905 or LFG316, or is ARC1905 or LFG 316.

96. The method of any one of embodiments 67 to 95, wherein the complement inhibitor (e.g., lebelezumab, ARC1905, or LFG316, or any combination or all thereof) is administered in a fixed routine regimen, an on-demand regimen, or a therapeutic and extension regimen.

97. A method of treating age-related macular degeneration (AMD) comprising administering to a subject in need thereof a therapeutically effective amount of an apolipoprotein (apo) mimetic according to any one of embodiments 1 to 38 and a therapeutically effective amount of an antioxidant.

98. The method of embodiment 97, wherein said apo mimetic comprises an apoA-I mimetic (e.g., L-4F or D-4F) and/or an apoE mimetic (e.g., AEM-28-14), or is an apoA-I mimetic (e.g., L-4F or D-4F) and/or an apoE mimetic (e.g., AEM-28-14).

99. The method of embodiment 97 or 98, wherein the antioxidant is selected from the group consisting of anthocyanins, benzenediol abietane diterpenes (e.g., carnosic acid), carnosine, carotenoids (e.g., carotenes [ e.g., beta-carotene ], xanthophylls [ e.g., lutein, zeaxanthin, and meso-zeaxanthin ], and carotenoids in saffron [ e.g., crocin and crocetin ]), curcuminoids (e.g., curcumin), cyclopentenone prostaglandins (e.g., 15d-PGJ2), flavonoids (e.g., flavonoids in ginkgo biloba [ e.g., myricetin and quercetin ]), prenylflavonoids (e.g., isoxanthohumol), retinoids, stilbenoids (e.g., resveratrol), uric acid, vitamin a, vitamin B1 (thiamine), vitamin B2 (riboflavin), vitamin B3 (niacin), vitamin B6 (e.g., pyridoxal, pyridoxamine, 4-pyridoxic acid, and pyridoxine), vitamin B9 (folic acid), vitamin B12 (cobalamin), vitamin C, vitamin E (e.g., tocopherol and tocotrienol), selenium, zinc (e.g., zinc monocysteine), inhibitors and scavengers of lipid peroxidation and its byproducts (e.g., vitamin E [ e.g., alpha-tocopherol ], tirapazate, NXY-059, and XJB-5-131), activators (e.g., OT-551) of nuclear factor (erythrocyte-derived 2) like 2(NFE2L2 or NRF2), superoxide dismutase (SOD) mimics (e.g., OT-551), and analogs, derivatives, salts, and combinations thereof.

100. The method of embodiment 99, wherein the antioxidants comprise one or more vitamins (e.g., vitamin B6, vitamin C, and vitamin E), one or more carotenoids (e.g., xanthophylls [ e.g., lutein, zeaxanthin, and meso-zeaxanthin ] and carotenoids in Saffron [ e.g., crocin and crocetin ]), or zinc, or any combination or all thereof, such as AREDS or AREDS2 formulations, preparations, or Saffron 2020 TM.

101. The method of any one of embodiments 97 to 100, wherein the antioxidant (e.g., vitamin and/or carotenoid) is administered at a dose that is lower than, and/or at a frequency that is lower than, a conventional or recommended dosing frequency for the antioxidant in the absence of treatment with the apo mimetic (e.g., L-4F).

102. the method of embodiment 101, wherein the conventional or recommended dose of the antioxidant is for an antioxidant (e.g., a vitamin and/or a carotenoid) administered at a dose that is at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, or 80% (e.g., at least about 20%), or about 10-30%, 30-50%, or 50-70% less than it without treatment with the apo mimetic (e.g., L-4F) as compared to a conventional or recommended dose of the antioxidant.

103. The method of embodiment 101 or 102, wherein the conventional or recommended dosing frequency is at least about 2, 3,5, 7, or 10 times (e.g., at least about 2 times) less frequent (e.g., by intravitreal injection) than administration of the antioxidant (e.g., vitamin and/or carotenoid) in the absence of treatment with the apo mimetic (e.g., L-4F) as compared to the conventional or recommended dosing frequency of the antioxidant.

104. The method of embodiment 103, wherein said conventional or recommended dosing frequency for said antioxidant (e.g., vitamin and/or carotenoid) is administered once every two or three days in the absence of treatment with said apo mimetic (e.g., L-4F) is at least once per day as compared to said conventional or recommended dosing frequency for said antioxidant.

105. The method of any one of embodiments 97 to 104, wherein the apo mimetic (e.g., L-4F) and the antioxidant (e.g., vitamin and/or carotenoid) are administered at least at the advanced (late) stage of AMD to treat or slow the progression of central pattern atrophy (GA) and/or neovascular AMD (including NV types 1,2 and 3), and/or to prevent or delay the onset of neovascular AMD.

106. The method of any one of embodiments 97 to 105, wherein the apo mimetic (e.g., L-4F) and the antioxidant (e.g., vitamin and/or carotenoid) are administered at least during the mid-stage of AMD to treat or slow the progression of non-central GA, and/or to prevent or delay the onset of central GA and/or neovascular AMD.

107. the method of any one of embodiments 97 to 106, wherein the apo mimetic (e.g., L-4F) and the antioxidant (e.g., vitamin and/or carotenoid) are administered at least at the early stage of AMD or the initial stage of intermediate AMD to prevent or delay the onset of non-central GA.

108. The method of any one of embodiments 97 to 107, wherein the antioxidant (e.g., vitamin and/or carotenoid) and optionally the apo mimetic (e.g., L-4F) are administered at least at the early stage of AMD.

109. The method of any one of embodiments 105 to 108, wherein treatment with the apo mimetic (e.g., L-4F) and the antioxidant (e.g., vitamin and/or carotenoid) slows the progression of central GA and/or non-central GA (e.g., reduces the rate of GA progression, or reduces GA lesion area or size) by at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, or 80% (e.g., at least about 20%, or about 20-40%, 40-60%, or 60-80%).

110. The method of any one of embodiments 105 to 109, wherein treatment with the apo mimetic (e.g., L-4F) and the antioxidant (e.g., a vitamin and/or a carotenoid) slows the progression of central GA and/or non-central GA (e.g., reduces the rate of GA progression, or reduces GA lesion area or size) by at least about 10%, 20%, 30%, 50%, 100%, 150%, 200%, or 300% (e.g., at least about 20% or 30%), or about 10-30%, 30-50%, 50-100%, 100-200%, or 200-300% (e.g., about 50-100%) more than it does not with the apo mimetic and antioxidant treatment.

111. The method of any one of embodiments 101-110, wherein treatment with the apo mimetic (e.g., L-4F) and the antioxidant (e.g., vitamin and/or carotenoid) has a synergistic effect.

112. the method of any one of embodiments 97-111, wherein the antioxidant (e.g., vitamin and/or carotenoid) is administered systemically (e.g., orally) or topically, intraocularly, or periocularly (e.g., by injection [ e.g., intravitreal, subconjunctival, subretinal, or sub-tenon's capsule injection ], eye drops or implants [ e.g., intravitreal, subretinal, or sub-tenon's capsule implants ]).

113. The method of any one of embodiments 97-112, wherein the apo mimetic (e.g., L-4F) and the antioxidant (e.g., vitamin and/or carotenoid) are administered in separate compositions.

114. The method of any one of embodiments 97-112, wherein said apo mimetic (e.g., L-4F) and said antioxidant (e.g., vitamin and/or carotenoid) are administered in the same composition.

XIV example

the following examples are intended only to illustrate the present disclosure. Other assays, procedures, methods, techniques, conditions, and materials may optionally be used as appropriate, and other studies may be performed.

Example 1 reduction of lipid deposition of bruch's Membrane in aged monkeys by L-4F

Macaque studies were performed according to accepted guidelines. 9 female cynomolgus monkeys (Macaca fascicularis, both over 20 years old) with naturally occurring age-related macular degeneration (exhibiting age-related drusen macular changes/maculopathy resembling early AMD in humans) were injected intravitreally with sterile Balanced Salt Solution (BSS) (n-7) of apoA-I mimetic L-4F (Ac-DWFKAFYDKVAEKFKEAF-NH2 acetate (seq. id. No.13)) or placebo (sterile BSS of L-4F [ sL-4F ] with identical amino acids but in a disordered non-functional order) (n-2). One eye of each animal received 6 monthly injections of 50 μ L volumes of the same escalating dose of L-4F or scrambled L-4F (625 μ g total). The second eye of each animal was not injected and was observed only. The injected eyes initially exhibited worse drusen changes than the non-injected eyes of each animal. Table 1 shows the dosing regimen used in the macaque study.

TABLE 1

Clinical laboratory tests (including serology, hemogram, and liver enzymes) were performed, and also ophthalmic tests (including fundus photography, Optical Coherence Tomography (OCT), intraocular pressure testing, and blood sampling) were performed. After 7 months, all animals were sacrificed and the eyes were immediately prepared for histological examination. Histochemistry was performed using oil red O for neutral lipids and felodipine for esterified cholesterol. Immunohistochemistry was performed for complement factor d (cfd) and membrane attack complex (MAC, C5b-9), both markers of alternative complement pathway activation.

For staining with oil red O (oro), the samples were treated with 0.3% oil red O (Sigma-Aldrich Biochemie GmbH, Hamburg, germany) solution (in 99% isopropanol) at Room Temperature (RT) for 30 minutes and then immersed in 60% isopropanol solution for 12 minutes. After washing the samples with deionized water for 3 minutes, counterstaining was performed with hematoxylin (Carl Roth GmbH, Karlsruhe, Germany). The samples were then mounted with mounting solution (Aquatex from Merck Millipore, Darmstadt, Germany), covered with glass coverslips (Menzel-Graeser GmbH), and examined using a fully automated inverted light microscope for life sciences (DMI 6000 from Leica Microsystems Wetzlar, Germany). Image analysis was performed by grading the intensity of ORO staining (red) of bruch's membrane (BrM) according to qualitative assessments assessed in four different regions in two separate slices per eye, with a score ranging from 0 to 4 (a total of 8 different regions per eye). BrM and qualitative ORO staining score of choroid: 0-no staining; 1 ═ +; 2 ═ + +; 3 ═ + + +; 4 ═ + + + +.

For staining with felipine, the samples were washed once with deionized water for 5 minutes and then treated with 70% ethanol for 45 minutes. After washing with deionized water for 5 minutes, the sample was treated with cholesterol esterase (8.12 units/mL) diluted in 0.1M potassium phosphate buffer (PPB, pH 7.4) at 37 ℃ for 3.5 hours. The samples were then washed twice with PPB and Phosphate Buffered Saline (PBS) for 3 minutes, followed by cold (4 ℃) PBS overnight. Then, the cells were stained with 250pg/mL of nonlevel (Sigma-Aldrich Biochemie GmbH, Hamburg, Germany), diluted in N, N-dimethylformamide (Merck Millipore, Darmstadt, Germany) and light-shielded at room temperature for 60 minutes. The samples were then washed sequentially with PBS and deionized water, mounted with mounting solution (Carl Roth GmbH, Karlsruhe, Germany), covered with glass coverslips, and examined using an inverted fluorescence microscope (DMI 6000 from Leica Microsystems, Wetzlar, Germany). The nonlevel fluorescence was observed using a UV filter set (. lamda.ex/. lamda.em. ═ 350nm/455 nm). As a negative control, the cholesterol esterase was replaced with PBS, which prevented the release of cholesterol from cholesterol esters and subsequent binding by felodipine. Semi-quantitative analysis of the intensity of non-uniformly flat fluorescence at three separate regions of BrM was performed on three different slides from the same eye (a total of 9 different regions from each eye).

the same assay was performed for immunohistochemistry for membrane attack complex (MAC, C5b-9) and complement factor d (cfd) except using monoclonal antibodies specific for each complement component. The specimens were treated with 10. mu.g/mL proteinase K in PBS (Sigma-Aldrich Biochemie GmbH, Hamburg, Germany) for 30 min of antigen retrieval at room temperature. Sections were then blocked with goat serum (5% goat serum, 0.3% Triton X-100 in PBS) for 60 min at room temperature. The samples were then reacted with primary antibodies against C5b-9 (1: 30 dilution in PBS, mouse monoclonal antibody, Dako Deutschland GmbH, Hamburg, Germany) or complement factor D (1: 200 dilution in PBS, mouse monoclonal antibody, Santa Cruz Biotechnology, Dallas, Tex, USA) overnight at 4 ℃. After washing with PBS, the samples were reacted with a secondary antibody (1: 200 dilution in PBS, anti-mouse Alexa Fluor 488, Life Technologies Deutschland GmbH, Darmstadt, Germany) for 1 hour at 37 ℃. After washing the samples three times with PBS, cell nuclei were stained with DAPI (1. mu.g/mL, Life Technologies GmbH, Darmstadt, Germany) for 10 minutes. The samples were then washed three times with PBS, mounted with a fade-resistant solution (Carl Roth GmbH, Karlsruhe, germany) and covered with glass coverslips for microscopic examination. Fluorescence microscopy imaging was performed using an inverted fluorescence microscope (DMI 6000 from Leica Microsystems, Wetzlar, germany) and a filter set of λ ex/λ em ═ 470nm/525 nm. For semi-quantitative analysis of fluorescence intensity of C5b-9, 3-5 different regions in one slide from 3 different slides per eye (a total of 9-15 different regions per eye) were analyzed. For semi-quantitative analysis of the fluorescence intensity of complement factor D, 3 different regions of each eye were evaluated.

Both control animals injected with placebo (scrambled L-4F) showed strong and specific staining of bruch's membrane (BrM) and choroidal capillaries in both eyes, with oil red O for neutral lipids and not uniformly for esterified cholesterol. For example, staining with oil red O showed the presence of significant amounts of lipids in BrM and BrM in two control animals. In contrast, eyes injected with L-4F showed about a 56% reduction in lipid deposits from BrM after 6 months when stained with oil red O compared to eyes injected with placebo. Figure 2 shows the scores for neutral lipids staining with oil red o (oro) in and on bruch's membrane in macaque injected eyes, which received 6 injections of L-4F or placebo (scrambled L-4F) intravitreally per month, and corresponding non-injected eyes. Semi-quantitative evaluation of felodipine fluorescence showed an approximately 68% reduction in esterified cholesterol in BrM in the L-4F injected eye compared to the placebo injected eye. Figure 3 shows the intensity of esterified cholesterol staining with nonlevel in bruch's membrane in cynomolgus injected eyes, which received 6 injections of L-4F or placebo (scrambled L-4F) each month intravitreally, and the corresponding non-injected eyes.

By semi-quantitative analysis of the fluorescence intensity of each specific antibody, the L-4F injected eye showed about a 58% reduction in BrM and MAC (C5b-9) levels and a 41% reduction in complement factor D levels compared to the scrambled peptide injected eye. Fig. 4 shows the staining intensity of the membrane challenge complex (MAC, C5b-9) in the choroidal capillaries of bruch's membrane in cynomolgus monkey-injected eyes, which received 6 intravitreal injections of L-4F or placebo (scrambled L-4F) per month, and in the corresponding non-injected eyes. Figure 5 shows the staining intensity of complement factor D in cynomolgus injected eyes and corresponding non-injected eyes that received 6 injections of L-4F or placebo (scrambled L-4F) intravitreally every month.

Lipid deposition in bruch's membrane thickened BrM. Bruch's membrane thickness was measured after autopsy by electron microscopy at the extratemporal macula of the enucleated eye. The L-4F injected eye showed about a 24% reduction in BrM thickness (1.31 μm SE 0.11) compared to the placebo injected eye (1.73 μm SE 0.02). Figure 6 shows the thickness of bruch's membrane measured at the extratemporal macula in cynomolgus injected eyes and corresponding non-injected eyes that received 6 injections of L-4F or placebo (scrambled L-4F) intravitreally every month.

After 6 monthly intravitreal injections, L-4F had similar effects on the corresponding non-injected and injected eyes (see fig. 2-6). Without being bound by theory, L-4F intravitreally injected into one eye reaches BrM, and from there may have entered the choroidal capillaries and thus the systemic circulation and eventually the corresponding non-injected eye. Also not to be bound by theory, the magnitude of the therapeutic effect of L-4F in the non-injected eyes may be due in part to the relative small body weight of the macaque relative to the eye size and the macaque's diet being predominantly vegetarian such that the macaque does not exhibit atherosclerosis (a potential target for L-4F in the systemic circulation).

L-4F is well tolerated in all macaques because the macaques injected intravitreally with L-4F do not experience any significant adverse events or side effects. For example, 6 monthly injections of L-4F into the vitreous did not increase the blood level of highly sensitive C-reactive protein (hscRP) compared to the blood level of hscRP one day before the first injection of L-4F. Circulating hsCRP (produced primarily in the liver) is a non-specific marker of systemic inflammation.

In conclusion, apoA-I mimic L-4F acts as a potent lipid scavenger in a monkey model of age-related macular degeneration and removes lipid deposits from BrM. Removal of the lipid deposits from BrM restored BrM integrity by electron microscopy. In addition, a reduction in downstream effects of lipid deposition (e.g., local inflammation) is evidenced by a significant reduction in complement activation in the eye injected with L-4F.

Example 2 phase I/II safety/efficacy Studies of L-4F alone

a randomized, open-label, dose escalation phase I/I study was performed to assess the safety, tolerability, pharmacokinetics, and effective dose of L-4F or a variant thereof (e.g., D-4F) or salt (e.g., acetate) administered (e.g., by intravitreal injection) to patients with AMD (e.g., intermediate AMD). Molluscum is a high risk factor for the progression of AMD, and is clinically recognized as a lipid-rich sub-RPE-BL deposit (a hallmark of AMD). The cumulative dose of L-4F up to the reduction of drusen and the maximum tolerated dose provide important information on the optimal L-4F dose in other studies including those in which L-4F (or variants or salts thereof) is administered in combination with one or more other therapeutic agents (e.g., anti-angiogenic or complement inhibitors) for the treatment of neovascular (wet) AMD or atrophic (dry) AMD.

In the phase I/I study, L-4F or a variant thereof (e.g., D-4F) or a salt thereof (e.g., acetate salt) is administered to one eye by intravitreal injection at certain doses (e.g., escalating doses from about 0.1mg to about 1.5mg) at a specific frequency (e.g., monthly or every two months) for a sustained period of time (e.g., about 6, 9, or 12 months). The other eye was not injected and was used as a control eye in individuals. Post-treatment evaluation is conducted, for example, to about 12 months. Primary outcome measurement criteria included quantifying the reduction in soft drusen (e.g., a reduction in total drusen volume of about 30%) (e.g., a time frame of about 15 months) by, for example, Spectral Domain Optical Coherence Tomography (SDOCT) and quantifying the stabilization or increase in fundus autofluorescence (qAF) intensity). Secondary outcome measures include, for example, stability or improvement in vision (e.g., visual object deformation, dark adaptation, and Best Corrected Vision (BCVA)) for, for example, about 9 and 15 months from onset.

Example 3 phase II efficacy Studies of L-4F in combination with an anti-angiogenic agent

A phase II study was conducted to evaluate the primary and confirmed efficacy of L-4F or variants (e.g., D-4F) or salts (e.g., acetate) thereof in combination with an anti-angiogenic agent (e.g., an anti-VEGF agent such as aflibercept bevacizumab or ranibizumab) in neovascular (wet) AMD patients. The drug is administered (e.g., by intravitreal injection) at a certain frequency (e.g., monthly or every two months) until extravasation of neovascularisation (e.g., type 1, type 2 or type 3 neovascularisation) ceases. Post-treatment evaluations were performed. The drug was injected into the poor eye and the other eye was not injected and served as the in vivo control eye. The goals include reducing the dose and number of injections of the anti-VEGF agent required to reduce neovascularization.

Example 4 phase II efficacy Studies of L-4F in combination with complement inhibitors

A phase II study was conducted to evaluate the preliminary and confirmed efficacy of L-4F or its variants (e.g., D-4F) or salts (e.g., acetate) in combination with complement inhibitors (e.g., lanebolizumab, ARC1905, or LFG316) in patients with intermediate or advanced atrophic (dry) AMD and exhibiting non-central or central pattern atrophy (GA). The drug is administered (e.g., by intravitreal injection) at a specific frequency (e.g., monthly or every two months) to assess its efficacy (e.g., reduce the rate of GA progression, or reduce GA lesion area or size) in slowing the progression of non-central or central GA. Post-treatment evaluations were performed. The drug was injected into the poor eye and the other eye was not injected and served as the in vivo control eye. Goals include a reduction in the dose and number of injections of complement inhibitors required to slow the progression of non-central or central GA.

It should be understood that while particular embodiments have been illustrated and described, various modifications may be made thereto and are contemplated herein. It should also be understood that the disclosure is not limited to the particular embodiments provided herein. The descriptions and illustrations of the embodiments and examples of the disclosure herein are not intended to be construed in a limiting sense. It is also to be understood that all aspects of the present disclosure are not limited to the specific depictions, configurations or relative proportions set forth herein which may depend upon a variety of conditions and variables. Various modifications and changes in form and detail of the embodiments and examples of the disclosure will be apparent to those skilled in the art. It is therefore contemplated that the present disclosure also covers any and all such modifications, variations and equivalents.

Claims (114)

1. A method of treating age-related macular degeneration (AMD), comprising administering to a subject in need of treatment a therapeutically effective amount of an apolipoprotein (apo) mimetic, wherein the apo mimetic is administered to the eye topically, intraocularly, in the eye, or periocularly at a dose of about 0.1 or 0.3mg to about 1.5mg per administration, or at a total dose of about 0.5 or 1mg to about 10mg over a period of about 6 months.

2. The method of claim 1, wherein the apo mimetic comprises an apoA-I mimetic, or is an apoA-I mimetic.

3. the method of claim 2, wherein the apoA-I mimetic comprises 4F, or a variant or salt thereof (e.g., acetate), or is 4F, or a variant or salt thereof (e.g., acetate).

4. The method of claim 3, wherein the apoA-I mimetic comprises L-4F or D-4F, or is L-4F or D-4F, each optionally having a protecting group [ e.g., Ac-DWFKAFYDKVAEKFKEAF-NH2(SEQ. ID. NO.13) ] at the N-terminus and/or C-terminus.

5. The method of any one of the preceding claims, wherein the apo mimetic comprises an apoE mimetic, or is an apoE mimetic.

6. the method of claim 5, wherein the apoE mimetic comprises AEM-28-14 or a variant or salt thereof, or is AEM-28-14 or a variant or salt thereof.

7. The method of any one of the preceding claims, wherein the apo mimetic (e.g., L-4F) is administered topically at a dose of about 0.1-0.5mg, 0.5-1mg, 1-1.5mg, 0.1-0.3mg, 0.3-0.5mg, 0.5-0.75mg, 0.75-1mg, 1-1.25mg, or 1.25-1.5mg (e.g., about 0.1-0.5mg or 0.5-1mg) per administration (e.g., per injection).

8. the method of any one of the preceding claims, wherein the apo mimetic (e.g., L-4F) is administered topically at a total dose of about 0.5 or 1-5mg, 5-10mg, 0.5 or 1-3mg, 3-5mg, 5-7.5mg, or 7.5-10mg (e.g., about 0.5-3mg or 3-5mg) over a period of about 6 months.

9. The method of any of the preceding claims, wherein the apo mimetic (e.g., L-4F) is administered topically at a total dose of about 1 or 2-20mg or 5-15mg for the entire treatment regimen.

10. The method of claim 9, wherein the apo mimetic (e.g., L-4F) is administered topically at a total dose of about 1-5mg, 5-10mg, 10-15mg, 15-20mg, 1-3mg, 3-5mg, 5-7.5mg, 7.5-10mg, 10-12.5mg, 12.5-15mg, 15-17.5mg, or 17.5-20mg (e.g., about 1-5mg or 5-10mg) for an entire treatment regimen.

11. the method of any one of the preceding claims, wherein the dose per administration, the total dose over a period of about 6 months, and the total dose of the entire treatment regimen are for each eye treated.

12. The method of any one of the preceding claims, wherein the apo mimetic (e.g., L-4F) is administered topically by injection (e.g., intravitreal, subconjunctival, subretinal, or sub-tenon's capsule injection), eye drops, or implants (e.g., intravitreal, intracameral, sub-retinal, or sub-tenon's capsule implants).

13. the method of claim 12, wherein the apo mimetic (e.g., L-4F) is administered topically by injection (e.g., intravitreal, subconjunctival, subretinal, or sub-tenon's capsule injection).

14. The method of claim 13, wherein the apo mimetic (e.g., L-4F) is administered topically by injection (e.g., intravitreal injection) at a dosage concentration of about 1,2, 3,4, or 5mg/mL to about 12 or 15 mg/mL.

15. The method of claim 14, wherein the apo mimetic (e.g., L-4F) is administered topically by injection (e.g., intravitreal injection) at a dosage concentration of about 1-4mg/mL, 4-8mg/mL, 8-12mg/mL, 1-5mg/mL, 5-10mg/mL, 10-15mg/mL, 1-3mg/mL, 3-5mg/mL, 5-7.5mg/mL, 6-8mg/mL, 7.5-10mg/mL, 10-12.5mg/mL, or 12.5-15mg/mL (e.g., about 1-5mg/mL, 5-10mg/mL, or 6-8 mg/mL).

16. The method of any one of claims 13 to 15, wherein the apo mimetic (e.g., L-4F) is administered topically by injection (e.g., intravitreal injection) in a dosage volume of about 50-150 μ L or 50-100 μ L.

17. The method of claim 16, wherein the apo mimetic (e.g., L-4F) is administered locally by injection (e.g., intravitreal injection) at a dose volume of about 50-75 μ L, 75-100 μ L, 100-125 μ L, or 125-150 μ L, or about 50 μ L, 75 μ L, 100 μ L, 125 μ L, or 150 μ L (e.g., about 100 μ L).

18. The method of any one of claims 13 to 17, wherein the apo mimetic (e.g., L-4F) is administered topically by injection (e.g., intravitreal injection) once a month (4 weeks) or 1.5 months (6 weeks).

19. the method of any one of claims 13 to 17, wherein the apo mimetic (e.g., L-4F) is administered topically by injection (e.g., intravitreal injection) every 2 months (8 weeks), 2.5 months (10 weeks), or 3 months (12 weeks).

20. The method of any one of claims 13 to 17, wherein the apo mimetic (e.g., L-4F) is administered topically by injection (e.g., intravitreal injection) once every 4,5, or 6 months.

21. The method of any one of claims 13 to 20, wherein the apo mimetic (e.g., L-4F) is administered topically in a total of about 15 injections (e.g., intravitreal injections) or less, 12 injections or less, 9 injections or less, 6 injections or less, or 3 injections or less.

22. The method of claim 21, wherein the apo mimetic (e.g., L-4F) is administered topically in a total of about 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, or 3 (e.g., about 3-6 or 7-10) injections (e.g., intravitreal injections).

23. the method of any one of the preceding claims, wherein the apo mimetic (e.g., L-4F) is administered locally (e.g., by intravitreal injection) at a higher dose and/or more frequently during the early stages of treatment.

24. The method of any one of the preceding claims, wherein the treatment regimen with the apo mimetic (e.g., L-4F) lasts about 36 months or less, 30 months or less, 24 months or less, 18 months or less, 12 months or less, or 6 months or less.

25. The method of claim 24, wherein the treatment regimen with the apo mimetic (e.g., L-4F) lasts for about 6-12, 12-18, 18-24, 24-30, or 30-36 months (e.g., about 6-12 or 12-24 months).

26. The method of any one of the preceding claims, wherein the apo mimetic (e.g., L-4F) is administered at least at an advanced (late) stage of AMD (e.g., for treating central geographic atrophy [ GA ] and/or preventing neovascular AMD, and/or treating neovascular AMD).

27. The method of claim 26, wherein the apo mimetic (e.g., L-4F) is administered topically by injection (e.g., intravitreal, subconjunctival, subretinal, or sub-tenon's capsule injection) once every about 4-8 weeks or 4-6 weeks at a total of about 8-12 or more injections, at a dose of up to about 1-1.5mg per injection, or at a total dose of up to about 15-20mg throughout the treatment regimen, or any combination or all thereof, at a later stage of AMD.

28. The method of any one of the preceding claims, wherein the apo mimetic (e.g., L-4F) is administered at least during the intermediate stage of AMD (e.g., to treat non-central GA and/or prevent central GA and/or neovascular AMD, or is administered during the initial stage of intermediate AMD to prevent or prevent non-central GA).

29. The method of claim 28, wherein the apo mimetic (e.g., L-4F) is administered topically by injection (e.g., intravitreal, subconjunctival, subretinal, or sub-tenon's capsule injection) once every about 4-8 weeks or 4-6 weeks during the middle stage of AMD, in a total of about 8-12 or more injections, in a dose of up to about 1-1.5mg per injection, or in a total dose of up to about 15-20mg throughout the treatment regimen, or any combination or all thereof.

30. The method of any one of the preceding claims, wherein the apo mimetic (e.g., L-4F) is administered at least at the early stage of AMD (e.g., to prevent or prevent non-central GA).

31. The method of claim 30, wherein the apo mimetic (e.g., L-4F) is administered topically by injection (e.g., intravitreal, subconjunctival, subretinal, or sub-tenon's capsule injection) early in AMD at a lower frequency (e.g., once every about 3,4, or 6 months), a lesser total number of injections (e.g., about 1,2, or 3 injections), or a higher dose per injection (e.g., about 0.5-1mg or 1-1.5mg per injection), or any combination or all thereof.

32. The method of any of the preceding claims, wherein the later the stage of AMD or the more severe the AMD condition, the more frequently (which may result in more total number of administrations) and/or locally (e.g., by intravitreal injection) the apo mimetic (e.g., L-4F) is administered (which may result in higher total number of administrations) and/or at higher doses (higher doses per administration and/or higher total doses for a complete treatment regimen).

33. The method of any one of the preceding claims, wherein the apo mimetic (e.g., L-4F) is administered topically (e.g., by intravitreal injection) in a fixed routine regimen, an on-demand regimen, or a therapeutic and protracted regimen.

34. The method of any one of the preceding claims, wherein the apo mimetic (e.g., L-4F) is administered topically by a composition comprising about 75-95% (e.g., about 90%) by weight or molar concentration of apo mimetic and about 5-25% (e.g., about 10%) of the corresponding apolipoprotein (e.g., apoA-I) or an active portion or domain thereof, relative to their combined amount.

35. the method of any one of the preceding claims, wherein the apo mimetic (e.g., L-4F) is administered topically in a composition comprising one or more excipients that inhibit peptide/protein aggregation, increase peptide/protein solubility, decrease solution viscosity, or increase peptide/protein stability, or any combination or all thereof.

36. The method of any one of the preceding claims, wherein the apo mimetic (e.g., L-4F) is administered topically via a sustained release composition.

37. the method of any one of the preceding claims, further comprising administering one or more additional therapeutic agents.

38. the method of claim 37, wherein the one or more additional therapeutic agents are selected from the group consisting of: anti-dyslipidemic agents, PPAR-alpha agonists, PPAR-delta agonists, PPAR-gamma agonists, anti-amyloid agents, inhibitors of lipofuscin or components thereof, antioxidants, neuroprotective agents (neuroprotective agents), apoptosis inhibitors, necrosis inhibitors, C-reactive protein (CRP) inhibitors, inhibitors of the complement system or components thereof (e.g., proteins), inflammatory body inhibitors, anti-inflammatory agents, immunosuppressive agents, modulators of Matrix Metalloproteinases (MMPs), anti-angiogenic agents and RPE cell replacement therapy.

39. a method of preventing age-related macular degeneration (AMD), delaying the onset of AMD, slowing the progression of AMD, or reducing the extent of vision impairment or loss associated with AMD, comprising administering to a subject in need thereof a therapeutically effective amount of an apolipoprotein (apo) mimetic of any one of claims 1-38.

40. The method of claim 39, wherein the AMD is atrophic AMD (including non-central and/or central pattern atrophy) or neovascular AMD (including neovascularisation type 1,2 and/or 3).

41. A method of treating age-related macular degeneration (AMD) comprising administering to a subject in need thereof a therapeutically effective amount of an apolipoprotein (apo) mimetic according to any one of claims 1 to 38 and a therapeutically effective amount of an anti-angiogenic agent.

42. The method of claim 41, wherein the apo mimetic comprises an apoA-I mimetic (e.g., L-4F or D-4F) and/or an apoE mimetic (e.g., AEM-28-14), or the apo mimetic is an apoA-I mimetic (e.g., L-4F or D-4F) and/or an apoE mimetic (e.g., AEM-28-14).

43. The method of claim 41 or 42, wherein the anti-angiogenic agent comprises or is the following: a substance that inhibits the action of vascular endothelial growth factor (anti-VEGF agent) and/or a substance that inhibits the action of platelet-derived growth factor (anti-PDGF agent).

44. The method of claim 43, wherein said anti-VEGF agent is selected from the group consisting of: squalamine, PAN-90806, anti-VEGF antibodies and fragments thereof (e.g., bevacizumab ranibizumab ESBA1008 and ESBA903), anti-VEGF aptamers (e.g., pegaptanib) anti-VEGF designed ankyrin repeat proteins (DARPins) (e.g., perazappa (abicipipergol)), soluble receptors for VEGF (e.g., VEGFR1), soluble fusion proteins containing one or more extracellular domains of VEGFR (e.g., aflibercept and conicept), and combinations thereof.

45. The method of claim 44, wherein the anti-VEGF agent comprises or is the following: aflibercept, bevacizumab, or ranibizumab, or any combination or all thereof.

46. The method of any one of claims 41 to 45, wherein the anti-angiogenic agent (e.g., anti-VEGF agent) is administered at a frequency that is lower than a conventional or recommended dosing frequency and/or dose that is lower than a conventional or recommended dose for the anti-angiogenic agent in the absence of treatment with the apo mimetic (e.g., L-4F).

47. The method of claim 46, wherein the anti-angiogenic agent (e.g., anti-VEGF agent) is administered (e.g., by intravitreal injection) at a frequency that is at least about 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, or 6-fold (e.g., at least about 2-fold) lower than the conventional or recommended dosing frequency of the anti-angiogenic agent for dosing in the absence of treatment with the apo mimetic (e.g., L-4F).

48. the method of claim 46 or 47, wherein the anti-angiogenic agent (e.g., anti-VEGF agent) is administered (e.g., by intravitreal injection) at a dose that is at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, or 80% (e.g., at least about 20%), or about 10-30%, 30-50%, or 50-70% less than the conventional or recommended dose of the anti-angiogenic agent, which is for a dose in the absence of treatment with the apo mimetic (e.g., L-4F).

49. The method of any one of claims 46 to 48, wherein treatment with the apo mimetic (e.g., L-4F) reduces the total number of administrations (e.g., total number of injections) of the anti-angiogenic agent (e.g., anti-VEGF agent).

50. The method of claim 49, wherein the anti-angiogenic agent (e.g., anti-VEGF agent) is administered (e.g., by intravitreal injection) no more than about 20, 18, 15, 12, or 10 times.

51. The method of any one of claims 46 to 50, wherein treatment with the apo mimetic (e.g., L-4F) and the anti-angiogenic agent (e.g., anti-VEGF agent) has a synergistic effect.

52. the method of any one of claims 46 to 51, wherein:

the anti-angiogenic agent comprises or is aflibercept and

In contrast to conventional or recommended doses and dosing frequency of aflibercept, aflibercept is administered (e.g., by intravitreal injection) once every 3 months, 4 months, 5 months, or 6 months at a dose of about 1-1.5mg or 1.5-2mg, optionally after monthly administration at a dose of about 1-1.5mg or 1.5-2mg for the first 1 month, 2 months, or 3 months, or once every 6 weeks at a dose of about 1-1.5mg or 1.5-2mg for the first 1.5 or 3 months, aflibercept is administered (e.g., by intravitreal injection) once every 3 months, 4 months, 5 months, or 6 months at a dose of about 1-1.5mg or 1.5-2mg,

The conventional or recommended dose and dosing frequency were administered once a month at 2mg for 3 months prior to treatment, followed by intravitreal injection at 2mg every 2 months for the absence of treatment with the apo mimetic (e.g., L-4F).

53. The method of any one of claims 46 to 51, wherein:

The anti-angiogenic agent comprises or is aflibercept; and

Aflibercept is administered (e.g., by intravitreal injection) at a dose of about 1-1.25mg, 1.25-1.5mg, or 1.5-1.75mg at a frequency substantially similar or identical to the conventional or recommended dosing frequency for aflibercept for administration without treatment with the apo mimetic (e.g., L-4F).

54. The method of any one of claims 46 to 51, wherein:

The anti-angiogenic agent comprises or is ranibizumab and

In contrast to conventional or recommended doses and dosing frequency of ranibizumab, ranibizumab is administered (e.g., by intravitreal injection) once every 2 months, 3 months, 4 months, 5 months, or 6 months at a dose of about 0.2-0.3mg, 0.3-0.4mg, or 0.4-0.5mg, optionally after once every month at a dose of about 0.2-0.3mg, 0.3-0.4mg, or 0.4-0.5mg for the first 1,2, or 3 months, or once every 6 weeks at a dose of about 0.2-0.3mg, 0.3-0.4mg, or 0.4-0.5mg for the first 1.5 or 3 months, ranibizumab is administered at a dose of about 0.2-0.3mg, 0.3-0.4mg, or 0.4-0.5mg every 2 months, 3 months, 4 months, 5 months, or 6 months (e.g., by intravitreal injection),

The conventional or recommended dose and dosing frequency were administered by intravitreal injection at 0.5mg once a month for the absence of treatment with the apo mimetic (e.g., L-4F).

55. the method of any one of claims 46 to 51, wherein:

The anti-angiogenic agent comprises or is ranibizumab; and

Ranibizumab is administered (e.g., by intravitreal injection) once a month at a dose of about 0.2-0.3mg or 0.3-0.4 mg.

56. the method of any one of claims 46 to 51, wherein:

The anti-angiogenic agent comprises or is bevacizumab

In contrast to conventional or recommended doses and dosing frequency of bevacizumab for the treatment of AMD, bevacizumab is administered (e.g., by intravitreal injection) once every 2 months, 3 months, 4 months, 5 months, or 6 months at a dose of about 0.5-0.75mg, 0.75-1mg, or 1-1.25mg, optionally after once every month at a dose of about 0.5-0.75mg, 0.75-1mg, or 1-1.25mg for the first 1,2, or 3 months or after once every 6 weeks at a dose of about 0.5-0.75mg, 0.75-1mg, or 1-1.25mg for the first 1.5 or 3 months, bevacizumab is administered (e.g., by intravitreal injection) once every 2 months, 3 months, 4 months, 5 months, or 6 months at a dose of about 0.5-0.75mg, 0.75-1mg, or 1-1.25mg,

The conventional or recommended dose and dosing frequency were administered once a month by intravitreal injection of about 1.25mg without treatment with the apo mimetic (e.g., L-4F).

57. The method of any one of claims 46 to 51, wherein:

the anti-angiogenic agent comprises or is bevacizumab; and

Bevacizumab is administered (e.g., by intravitreal injection) once a month at a dose of about 0.5-0.75mg or 0.75-1 mg.

58. The method of any one of claims 46 to 51, wherein the anti-angiogenic agent (e.g., anti-VEGF agent) is administered (e.g., by intravitreal injection) once every 2, 3,4, 5, or 6 months.

59. The method of any one of claims 41 to 58, wherein the anti-angiogenic agent (e.g., anti-VEGF agent) is administered topically, intraocularly, or periocularly, such as by injection (e.g., intravitreal injection, subconjunctival, subretinal, or sub-tenon's capsule injection), eye drops, or implants (e.g., intravitreal, intracameral, sub-retinal, or sub-tenon's capsule implants).

60. The method of any one of claims 41 to 59, wherein the anti-angiogenic agent (e.g., anti-VEGF agent) is administered to treat or slow the progression of neovascular (wet) AMD, including neovascularisation types 1,2 and 3.

61. the method of any one of claims 41 to 60, wherein the anti-angiogenic agent (e.g., anti-VEGF agent) is administered at least at an advanced (late) stage of AMD to prevent, delay the onset of, or slow the progression of neovascular AMD.

62. The method of any one of claims 41 to 61, wherein the apo mimetic (e.g., L-4F) is administered at least at an advanced stage of AMD.

63. The method of claim 62, wherein the apo mimetic (e.g., L-4F) is administered to treat central geographic atrophy, and/or to prevent, delay the onset, or slow the progression of neovascular AMD, including neovascular AMD types 1,2, and 3.

64. The method of any one of claims 41 to 63, wherein the anti-angiogenic agent (e.g., anti-VEGF agent) is administered in a fixed routine regimen, an on-demand regimen, or a therapeutic and protracting regimen.

65. The method of any one of claims 41 to 64, wherein the apo mimetic (e.g., L-4F) and the anti-angiogenic agent (e.g., anti-VEGF agent) are administered in separate compositions.

66. The method of any one of claims 41 to 64, wherein the apo mimetic (e.g., L-4F) and the anti-angiogenic agent (e.g., anti-VEGF agent) are administered in the same composition.

67. a method of treating age-related macular degeneration (AMD) comprising administering to a subject in need thereof a therapeutically effective amount of an apolipoprotein (apo) mimetic according to any one of claims 1 to 38 and a therapeutically effective amount of a complement inhibitor.

68. The method of claim 67, wherein the apo mimetic comprises an apoA-I mimetic (e.g., L-4F or D-4F) and/or an apoE mimetic (e.g., AEM-28-14), or an apoA-I mimetic (e.g., L-4F or D-4F) and/or an apoE mimetic (e.g., AEM-28-14).

69. The method of claim 67 or 68, wherein the apo mimetic (e.g., L-4F) and the complement inhibitor are administered to treat Geographic Atrophy (GA).

70. The method of claim 69, wherein the apo mimetic (e.g., L-4F) and the complement inhibitor are administered to prevent central GA and/or non-central GA, delay the onset of central GA and/or non-central GA, or slow the progression of central GA and/or non-central GA.

71. The method of claim 69 or 70, wherein the apo mimetic (e.g., L-4F) and the complement inhibitor are administered at least at the advanced (late) stage of atrophic (dry) AMD to treat or slow progression of central GA, and/or to prevent or delay the onset of neovascular AMD.

72. The method of any one of claims 69 to 71, wherein the apo mimetic (e.g., L-4F) and the complement inhibitor are administered at least at the mid-stage of AMD to treat or slow progression of non-central GA, and/or to prevent or delay onset of central GA and/or neovascular AMD.

73. The method of any one of claims 69 to 72, wherein the apo mimetic (e.g., L-4F) and the complement inhibitor are administered to prevent or delay the onset of non-central GA at least at the early stage of AMD or at the initial stage of intermediate AMD.

74. The method of any one of claims 67 to 73, wherein the complement inhibitor is selected from the group consisting of: anti-complement factor b (cfb) antibodies and fragments thereof (e.g., TA106), anti-CFD antibodies and fragments thereof (e.g., lanbolilizumab), C3 inhibitors (e.g., C3 compstatin and derivatives thereof [ e.g., POT-4], soluble forms of mycophenolic acid-glucosamine conjugates and proteins or fragments thereof [ e.g., CR1, decay accelerating factor and membrane cofactor protein ]), anti-C3 b/iC3b antibodies and fragments thereof (e.g., 3E7), anti-C5 antibodies and fragments thereof (e.g., eculizumab and LFG316), anti-C5 aptamers (e.g., ARC1905 other C5 inhibitors (e.g., Coversin), C5a receptor antagonists (e.g., JPE-1375, m-7717, PMX-025, PMX-53, and anti-C5 aR antibodies and fragments thereof [ e.g., nougatan ]), inhibitors of the alternative complement pathway (e.g., sCR1, 30, zinc), Inhibitors of the classical complement pathway (e.g., sCR1), inhibitors of the lectin complement pathway (e.g., inhibitors of mannose-related serine proteases [ MASP ], such as anti-MASP antibodies and fragments thereof [ e.g., OMS721]), inhibitors of Membrane Attack Complex (MAC) formation (e.g., zinc, CD59, and modified CD59 with glycolipid anchors), and analogs, derivatives, fragments, salts, and combinations thereof.

75. The method of claim 74, wherein the complement inhibitor comprises or is the following: lanreolizumab, LFG316, or ARC1905, or any combination or all thereof.

76. The method of claim 75, wherein the complement inhibitor comprises or is Lanoglucizumab.

77. The method of claim 76, wherein the subject has a mutation in a gene encoding Complement Factor I (CFI).

78. The method of any one of claims 67 to 77, wherein treatment with the apo mimetic (e.g., L-4F) and the complement inhibitor (e.g., Lanborlizumab) slows progression of central GA and/or non-central GA (e.g., reduces the rate of GA progression, or reduces GA lesion area or size) by at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, or 80% (e.g., at least about 20% or 40%), or about 20-40%, 40-60%, or 60-80%.

79. The method of any one of claims 67 to 78, wherein treatment with the apo mimetic (e.g., L-4F) and the complement inhibitor (e.g., Lanbeads) slows the progression of central GA and/or non-central GA (e.g., reduces the rate of GA progression, or reduces GA lesion area or size) by at least about 10%, 20%, 30%, 50%, 100%, 150%, 200%, or 300% (e.g., at least about 20% or 30%), or about 10-30%, 30-50%, 50-100%, 100-200%, or 200-300% (e.g., about 50-100%) as compared to treatment with the complement inhibitor without treatment with the apo mimetic.

80. The method of any one of claims 67 to 79, wherein the complement inhibitor (e.g., Lanbolizumab) is administered at a frequency and/or dose that is less than a conventional or recommended dosing frequency or dose for a complement inhibitor in the absence of treatment with the apo mimetic (e.g., L-4F).

81. The method of claim 80, wherein the frequency of administration (e.g., by intravitreal injection) of the complement inhibitor (e.g., lanreolizumab) is at least about 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, or 6-fold (e.g., at least about 2-fold) less than the conventional or recommended frequency of administration of the complement inhibitor for the frequency of administration without treatment with the apo mimetic (e.g., L-4F).

82. The method of claim 80 or 81, wherein the complement inhibitor (e.g., Langolizumab) is administered (e.g., by intravitreal injection) at a dose that is at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, or 80% (e.g., at least about 20%), or about 10-30%, 30-50%, or 50-70% less than the conventional or recommended dose of the complement inhibitor for a dose that would be without treatment with the apo mimetic (e.g., L-4F).

83. The method of any one of claims 80 to 82, wherein treatment with the apo mimetic (e.g., L-4F) reduces the total number of administrations (e.g., total number of injections) of the complement inhibitor (e.g., Lanboluzumab).

84. The method of claim 83, wherein the complement inhibitor (e.g., lanebolizumab) is administered (e.g., by intravitreal injection) no more than about 20, 18, 15, 12, or 10 times.

85. The method of any one of claims 80 to 84, wherein treatment with the apo mimetic (e.g., L-4F) and the complement inhibitor (e.g., Lanboluzumab) have a synergistic effect.

86. The process of any one of claims 80 to 85, wherein:

the complement inhibitor comprises or is Lanbolizumab; and

In contrast to conventional or recommended doses and dosing frequency of Lanborlizumab, Lanborlizumab is administered (e.g., by intravitreal injection) once every 2 months, 3 months, 4 months, 5 months, or 6 months at a dose of about 4-6mg, 6-8mg, or 8-10mg, optionally after once monthly administration at a dose of about 4-6mg, 6-8mg, or 8-10mg in the first 1 month, 2 months, or 3 months, or once every 6 weeks at a dose of about 4-6mg, 6-8mg, or 8-10mg in the first 1.5 or 3 months, Lanborlizumab is administered (e.g., by intravitreal injection) once every 2 months, 3 months, 4 months, 5 months, or 6 months at a dose of about 4-6mg, 6-8mg, or 8-10mg,

The conventional or recommended dose and dosing frequency were administered by intravitreal injection at about 10mg once a month for the absence of treatment with the apo mimetic (e.g., L-4F).

87. The process of any one of claims 80 to 85, wherein:

The complement inhibitor comprises or is laplizumab; and

Lanbolizumab is administered (e.g., by intravitreal injection) once monthly (4 weeks) or 1.5 months (6 weeks) at a dose of about 3-5mg, 5-7mg, or 7-9 mg.

88. the method of any one of claims 80 to 86, wherein the complement inhibitor (e.g., lanreolizumab) is administered (e.g., by intravitreal injection) once every 2, 3,4, 5, or 6 months (e.g., every 2 months).

89. The method of any one of claims 67-88, wherein the complement inhibitor (e.g., lanreolizumab) is administered topically, intraocularly, or periocularly, such as by injection (e.g., intravitreal, subconjunctival, subretinal, or sub-tenon's capsule injection), eye drops, or implants (e.g., intravitreal, subconjunctival, sub-retinal, or sub-tenon's capsule implants).

90. The method of any one of claims 67-89, wherein the apo mimetic (e.g., L-4F) and the complement inhibitor (e.g., Lanboluzumab) are administered in separate compositions.

91. the method of any one of claims 67-89, wherein the apo mimetic (e.g., L-4F) and the complement inhibitor (e.g., lanreolizumab) are administered in the same composition.

92. The method of any one of claims 67 to 91, wherein the apo mimetic (e.g., L-4F) and the complement inhibitor are administered at least at an advanced stage of AMD to prevent, delay the onset of, or slow the progression of neovascular AMD, including neovascular AMD types 1,2, and 3.

93. the method of claim 92, further comprising administering a therapeutically effective amount of an anti-angiogenic agent.

94. The method of claim 93, wherein the anti-angiogenic agent comprises or is the following: anti-VEGF agents (e.g., abexpiprep bevacizumab or ranibizumab, or any combination or all thereof) and/or anti-PDGF agents (e.g., E10030)

95. The method of any one of claims 92 to 94, wherein the complement inhibitor comprises ARC1905 or LFG316, or is ARC1905 or LFG 316.

96. The method of any one of claims 67 to 95, wherein the complement inhibitor (e.g., Lamborrelizumab, ARC1905 or LFG316, or any combination or all thereof) is administered in a fixed routine regimen, an on-demand regimen or a therapeutic and extension regimen.

97. A method of treating age-related macular degeneration (AMD) comprising administering to a subject in need thereof a therapeutically effective amount of an apolipoprotein (apo) mimetic according to any one of claims 1 to 38 and a therapeutically effective amount of an antioxidant.

98. The method of claim 97, wherein the apo mimetic comprises an apoA-I mimetic (e.g., L-4F or D-4F) and/or an apoE mimetic (e.g., AEM-28-14), or an apoA-I mimetic (e.g., L-4F or D-4F) and/or an apoE mimetic (e.g., AEM-28-14).

99. The method of claim 97 or 98, wherein the antioxidant is selected from the group consisting of anthocyanins, benzenediol abietane diterpenes (e.g., carnosic acid), carnosine, carotenoids (e.g., carotene [ e.g., beta-carotene ], xanthophylls [ e.g., lutein, zeaxanthin, and meso-zeaxanthin ], and carotenoids in saffron [ e.g., crocin and crocetin ]), curcuminoids (e.g., curcumin), cyclopentenone prostaglandins (e.g., 15d-PGJ2), flavonoids (e.g., flavonoids in ginkgo biloba [ e.g., myricetin and quercetin ]), prenylflavonoids (e.g., isoxanthohumol), retinoids, stilbenoids (e.g., resveratrol), uric acid, vitamin A, vitamin B1 (thiamine), vitamin B2 (riboflavin), vitamin B3 (niacin), vitamin B6 (e.g., pyridoxal, pyridoxamine, 4-pyridoxic acid, and pyridoxine), vitamin B9 (folic acid), vitamin B12 (cobalamin), vitamin C, vitamin E (e.g., tocopherol and tocotrienol), selenium, zinc (e.g., zinc monocysteine), inhibitors and scavengers of lipid peroxidation and its byproducts (e.g., vitamin E [ e.g., alpha-tocopherol ], tirapazate, NXY-059, and XJB-5-131), activators (e.g., OT-551) of nuclear factor (erythrocyte-derived 2) like 2(NFE2L2 or NRF2), superoxide dismutase (SOD) mimics (e.g., OT-551), and analogs, derivatives, salts, and combinations thereof.

100. The method of claim 99, wherein the antioxidants comprise one or more vitamins (e.g., vitamin B6, vitamin C, and vitamin E), one or more carotenoids (e.g., xanthophylls [ e.g., lutein, zeaxanthin, and meso-zeaxanthin ] and carotenoids in Saffron [ e.g., crocin and crocetin ]), or zinc, or any combination or all thereof, such as AREDS or AREDS2 formulations, preparations, or Saffron 2020 TM.

101. The method of any one of claims 97 to 100, wherein the antioxidant (e.g., vitamin and/or carotenoid) is administered at a dose that is lower than, and/or at a frequency that is lower than, a conventional or recommended dosing frequency for the antioxidant in the absence of treatment with the apo mimetic (e.g., L-4F).

102. The method of claim 101, wherein the antioxidant (e.g., vitamin and/or carotenoid) is administered at a dose that is at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, or 80% (e.g., at least about 20%), or about 10-30%, 30-50%, or 50-70% less than a conventional or recommended dose of the antioxidant, which is for a dose that would be without treatment with the apo mimetic (e.g., L-4F).

103. The method of claim 101 or 102, wherein the frequency of administration (e.g., by intravitreal injection) of the antioxidant (e.g., vitamin and/or carotenoid) is at least about 2, 3, 5, 7, or 10 times (e.g., at least about 2 times) less than the conventional or recommended dosing frequency of the antioxidant for dosing without treatment with the apo mimetic (e.g., L-4F).

104. The method of claim 103, wherein the antioxidant (e.g., vitamin and/or carotenoid) is administered once every two or three days as compared to a conventional or recommended dosing frequency of the antioxidant for at least once a day without treatment with the apo mimetic (e.g., L-4F).

105. the method of any one of claims 97 to 104, wherein the apo mimetic (e.g., L-4F) and the antioxidant (e.g., vitamin and/or carotenoid) are administered at least at the advanced (late) stage of AMD to treat or slow progression of central pattern atrophy (GA) and/or neovascular AMD (including NV types 1,2, and 3), and/or to prevent or delay the onset of neovascular AMD.

106. The method of any one of claims 97 to 105, wherein the apo mimetic (e.g., L-4F) and the antioxidant (e.g., vitamin and/or carotenoid) are administered at least during the mid-stage of AMD to treat or slow progression of non-central GA, and/or prevent or delay the onset of central GA and/or neovascular AMD.

107. the method of any one of claims 97 to 106, wherein the apo mimetic (e.g., L-4F) and the antioxidant (e.g., vitamins and/or carotenoids) are administered at least at the early stage of AMD or the initial stage of intermediate AMD to prevent or delay the onset of non-central GA.

108. The method of any one of claims 97 to 107, wherein the antioxidant (e.g., vitamin and/or carotenoid) and optionally the apo mimetic (e.g., L-4F) are administered at least at the early stage of AMD.

109. The method of any one of claims 105 to 108, wherein treatment with the apo mimetic (e.g., L-4F) and the antioxidant (e.g., vitamin and/or carotenoid) slows the progression of central GA and/or non-central GA (e.g., reduces the rate of GA progression, or reduces GA lesion area or size) by at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, or 80% (e.g., at least about 20%, or about 20-40%, 40-60%, or 60-80%).

110. The method of any one of claims 105 to 109, wherein treatment with the apo mimetic (e.g., L-4F) and the antioxidant (e.g., a vitamin and/or a carotenoid) slows the progression of central GA and/or non-central GA (e.g., reduces the rate of GA progression, or reduces GA lesion area or size) by at least about 10%, 20%, 30%, 50%, 100%, 150%, 200%, or 300% (e.g., at least about 20% or 30%), or about 10-30%, 30-50%, 50-100%, 100-200%, or 200-300% (e.g., about 50-100%) as compared to no treatment with the apo mimetic and antioxidant.

111. The method of any one of claims 101-110 wherein treatment with the apo mimetic (e.g., L-4F) and the antioxidant (e.g., vitamin and/or carotenoid) has a synergistic effect.

112. The method of any one of claims 97-111, wherein the antioxidant (e.g., vitamin and/or carotenoid) is administered systemically (e.g., orally) or is administered topically, intraocularly, or periocularly (e.g., by injection [ e.g., intravitreal, subconjunctival, subretinal, or sub-tenon's capsule injection ], eye drops or implants [ e.g., intravitreal, sub-retinal, or sub-tenon's capsule implants ]).

113. The method of any one of claims 97-112, wherein the apo mimetic (e.g., L-4F) and the antioxidant (e.g., vitamin and/or carotenoid) are administered in separate compositions.

114. The method of any one of claims 97-112, wherein the apo mimetic (e.g., L-4F) and the antioxidant (e.g., vitamin and/or carotenoid) are administered in the same composition.