Methods, compositions and systems for assessment of visual function

Abstract

Provided herein is a method for treating a subject with eye disease. The method comprises administering a treatment to the subject. The method further comprises determining whether the treatment is therapeutically effective for treating the subject based on the composite biomarker. The composite biomarker is calculated based on at least two variables. At least one of the at least two variables is related to one or more selected from the group including vision, visual function, ocular anatomy, ocular physiology, ocular pathology, and changes thereof.

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims the benefit of U.S. Patent Application No. 63 / 331,189, filed April 14, 2022, which is incorporated herein by reference in its entirety. [Background technology]

[0002] There is a need for effective clinical assessment of disease progression and treatment response in ocular diseases and disorders, such as Stargardt disease (STGD) and Age-Related Macular Degeneration (AMD). Summary of the Invention

[0003] Disclosed herein is a method and system for treating a subject with an ocular disease. Disclosed herein is a method for treating a subject with an ocular disease, the method comprising: (a) administering a treatment to the subject; and (b) determining whether the treatment is therapeutically effective for treating the subject based on a composite biomarker, wherein the composite biomarker is calculated based on at least two variables, and at least one of the at least two variables is related to one or more selected from the group consisting of vision, visual function, ocular anatomy, ocular physiology, ocular pathology, and changes thereof.

[0004] Disclosed herein is a method for treating a subject having an ocular disease, the method comprising: (a) administering a treatment to the subject; (b) performing an assay on the subject to obtain at least two variables, at least one of which is related to one or more selected from the group consisting of vision, visual function, ocular anatomy, ocular physiology, ocular pathology, and changes thereof; (c) calculating the at least two variables to obtain a composite biomarker; and (d) determining whether the treatment is therapeutically effective for treating the subject based on the composite biomarker.

[0005] Disclosed herein is a method for treating a subject having an ocular disease, the method comprising: (a) administering the treatment to the subject; (b) performing a first assay on the subject at a first time point to obtain a first set of at least two variables, wherein at least one of the at least two variables is related to one or more selected from the group consisting of vision, visual function, ocular anatomy, ocular physiology, ocular pathology, and changes thereof; (c) calculating the first set of at least two variables to obtain a first composite biomarker; (d) performing a second assay on the subject at a second time point to obtain a second set of at least two variables; (e) calculating the second set of at least two variables to obtain a second composite biomarker; and (f) determining whether the treatment is therapeutically effective to treat the subject based on the first composite biomarker and the second composite biomarker.

[0006] Disclosed herein is a method for treating a subject having an ocular disease, the method comprising: (a) administering a treatment to the subject; (b) performing an assay on the subject to obtain at least two variables, at least one of which is related to one or more selected from the group consisting of vision, visual function, ocular anatomy, ocular physiology, ocular pathology, and changes thereof; and (c) calculating the at least two variables to obtain a composite biomarker, wherein if the composite biomarker exceeds a threshold, the treatment is therapeutically effective for treating the subject; and if the composite biomarker does not exceed the threshold, the treatment is not therapeutically effective for treating the subject.

[0007] Disclosed herein is a method for treating a subject having an eye disease, the method comprising: (a) administering a first dose of treatment to the subject; (b) performing an assay on the subject to obtain at least two variables, at least one of which is related to one or more selected from the group consisting of vision, visual function, ocular anatomy, ocular physiology, ocular pathology, and changes thereof; (c) calculating the at least two variables to obtain a composite biomarker; (d) determining, based on the composite biomarker, whether the first dose of treatment is therapeutically effective in treating the subject; and (e) administering a second dose of treatment to the subject, wherein if the first dose is determined to be ineffective in treating the subject, the second dose is different from the first dose, and if the first dose is determined to be therapeutically effective in treating the subject, the second dose is approximately the same as the first dose.

[0008] Disclosed herein is a method for treating a subject having an ocular disease, the method comprising: (a) performing a first assay on the subject to obtain a first set of at least two variables, wherein at least one of the at least two variables is related to one or more selected from the group consisting of vision, visual function, ocular anatomy, ocular physiology, ocular pathology, and changes thereof; (b) calculating the first set of at least two variables to obtain a first composite biomarker; (c) administering a treatment to the subject; (d) performing a second assay on the subject to obtain a second set of at least two variables; (e) calculating the second set of at least two variables to obtain a second composite biomarker; and (f) determining whether the treatment is therapeutically effective to treat the subject based on the first composite biomarker and the second composite biomarker.

[0009] Disclosed herein is a method of treating a subject having an ocular disease, the method comprising: (a) performing an assay on the subject to obtain at least two variables, at least one of which is related to one or more selected from the group consisting of vision, visual function, ocular anatomy, ocular physiology, ocular pathology, and changes thereof; (b) calculating the at least two variables to obtain a composite biomarker; (c) selecting the subject for treatment based on the composite biomarker; and (d) administering the treatment to the subject. Includes.

[0010] Disclosed herein is a method for treating a subject having an ocular disease, the method comprising: (a) performing a first assay on the subject to obtain a first set of at least two variables, wherein at least one of the at least two variables is related to one or more selected from the group consisting of vision, visual function, ocular anatomy, ocular physiology, ocular pathology, and changes thereof; (b) calculating the first set of at least two variables to obtain a first composite biomarker; (c) selecting the subject for treatment based on the first composite biomarker; (d) administering the treatment to the subject; (d) performing a second assay on the subject to obtain a second set of at least two variables; (f) calculating the second set of at least two variables to obtain a second composite biomarker; and (g) determining whether the treatment is therapeutically effective for treating the subject based on the first composite biomarker and the second composite biomarker.

[0011] Disclosed herein is a method of treating a subject having an ocular disease, the method comprising: (a) performing an assay on a subject to obtain at least two variables, at least one of which is related to one or more selected from the group consisting of vision, visual function, ocular anatomy, ocular physiology, ocular pathology, and changes thereof; (b) calculating the at least two variables to obtain a composite biomarker; (c) selecting the subject for treatment if the composite biomarker exceeds a threshold, or optionally not selecting the subject for treatment if the composite biomarker does not exceed a threshold; and (d) administering the treatment to the subject if the subject is selected for treatment, or optionally not administering the treatment to the subject if the subject is not selected for treatment.

[0012] Disclosed herein is a method of treating a subject having an ocular disease, the method comprising: (a) performing a first assay on the subject to obtain a first set of at least two variables, wherein at least one of the at least two variables is related to one or more selected from the group consisting of vision, visual function, ocular anatomy, ocular physiology, ocular pathology, and changes thereof; (b) calculating the first set of at least two variables to obtain a first composite biomarker; (c) selecting the subject for treatment based on the first composite biomarker; (d) administering a first dose of treatment to the subject; and (e) calculating a second composite biomarker of the at least two variables. (f) calculating a second set of at least two variables to obtain a second composite biomarker; (g) determining whether the first dose of treatment is therapeutically effective to treat the subject based on the first composite biomarker and the second composite biomarker; and (h) administering a second dose of treatment to the subject, wherein the second dose is different from the first dose if the first dose is determined to be not therapeutically effective to treat the subject, and the second dose is about the same as the first dose if the first dose is determined to be therapeutically effective to treat the subject.

[0013] Disclosed herein is a method of treating a subject having an ocular disease, the method comprising: (a) performing a first assay on the subject to obtain a first set of at least two variables, wherein at least one of the at least two variables is related to one or more selected from the group consisting of vision, visual function, ocular anatomy, ocular physiology, ocular pathology, and changes thereof; (b) calculating the first set of at least two variables to obtain a first composite biomarker; (d) administering a first dose of treatment to the subject; (e) performing a second assay on the subject to obtain a second set of at least two variables; and (f) calculating the first set of at least two variables to obtain a second composite biomarker. (g) determining that a first dose of treatment is therapeutically effective for treating the subject if the difference between the first composite biomarker and the second composite biomarker exceeds a threshold, or optionally determining that the first dose of treatment is not therapeutically effective for treating the subject if the difference between the first composite biomarker and the second composite biomarker does not exceed a threshold; and (h) administering a second dose of treatment to the subject, wherein the second dose is different from the first dose if the first dose is determined to be not therapeutically effective for treating the subject, and the second dose is about the same as the first dose if the first dose is determined to be therapeutically effective for treating the subject.

[0014] Disclosed herein is a method for monitoring the outcome of a treatment for an ocular disease in a subject, the method comprising determining whether a certain dose of treatment administered to the subject is therapeutically effective in treating the subject by calculating at least two variables of the subject to obtain a composite biomarker, wherein at least one of the at least two variables is related to one or more selected from the group including vision, visual function, ocular anatomy, ocular physiology, ocular pathology, and changes thereof.

[0015] Disclosed herein is a method of treating a subject having an ocular disease, the method comprising administering to the subject a therapeutically effective dose of a treatment, wherein the subject is selected for treatment based on a composite biomarker, the composite biomarker being calculated based on at least two variables of the subject, at least one of the at least two variables being related to one or more selected from the group comprising vision, visual function, ocular anatomy, ocular physiology, ocular pathology, and changes thereof.

[0016] Disclosed herein is a method comprising selecting a subject having an ocular disease for treatment based on a composite biomarker, wherein the composite biomarker is calculated based on at least two variables of the subject, at least one of the at least two variables being related to one or more selected from the group including vision, visual function, ocular anatomy, ocular structure, ocular physiology, ocular pathology, and changes thereof.

[0017] Provided herein is a method for selecting a subject having an eye disease for treatment, the method comprising: (a) calculating at least two variables of the subject to obtain a composite biomarker, wherein at least one of the at least two variables is related to one or more selected from the group consisting of vision, visual function, ocular anatomy, ocular physiology, ocular pathology, and changes thereof; and (b) selecting the subject for treatment if the composite biomarker exceeds a threshold, or optionally not selecting the subject for treatment if the composite biomarker does not exceed the threshold.

[0018] Disclosed herein is a method for selecting a subject having an eye disease for treatment, the method comprising: (a) performing an assay on the subject to obtain at least two variables, at least one of which is related to one or more selected from the group consisting of vision, visual function, ocular anatomy, ocular physiology, ocular pathology, and changes thereof; (b) calculating the at least two variables to obtain a composite biomarker; and (c) selecting the subject for treatment if the composite biomarker exceeds a threshold, or optionally not selecting the subject for treatment if the composite biomarker does not exceed the threshold.

[0019] Disclosed herein is a method for predicting a subject's therapeutic response to a treatment for an ocular disease, the method comprising: (a) calculating at least two variables of the subject to obtain a composite biomarker, wherein at least one of the at least two variables is related to one or more selected from the group consisting of vision, visual function, ocular anatomy, ocular physiology, ocular pathology, and changes thereof; and (b) predicting the subject's therapeutic response to the treatment based on the composite biomarker.

[0020] Disclosed herein is a method for predicting a subject's therapeutic response to a treatment for an ocular disease, the method comprising: (a) performing an assay on the subject to obtain at least two variables, at least one of which is related to one or more selected from the group consisting of vision, visual function, ocular anatomy, ocular physiology, ocular pathology, and changes thereof; (b) calculating the at least two variables to obtain a composite biomarker; and (c) determining that the subject is likely to have a therapeutic response to the treatment if the composite biomarker exceeds a threshold, or optionally, determining that the subject is likely to not have a therapeutic response to the treatment if the composite biomarker does not exceed the threshold.

[0021] Disclosed herein is a method comprising selecting a dosage of treatment for a subject having an ocular disease based on a composite biomarker, wherein the composite biomarker is calculated based on at least two variables of the subject, at least one of the at least two variables being related to one or more selected from the group including vision, visual function, ocular anatomy, ocular physiology, ocular pathology, and changes thereof.

[0022] Disclosed herein is a method for determining the dosage of a treatment for a subject having an eye disease, the method comprising: (a) performing an assay on the subject to obtain at least two variables, at least one of which is related to one or more selected from the group consisting of vision, visual function, ocular anatomy, ocular physiology, ocular pathology, and changes thereof; (b) calculating the at least two variables to obtain a composite biomarker; and (c) determining the dosage of a treatment for the subject based on the composite biomarker.

[0023] Disclosed herein is a method for determining the dosage of a treatment for an eye disease in a subject, the method comprising: (a) performing a first assay on the subject to obtain a first set of at least two variables, wherein at least one of the at least two variables is related to one or more selected from the group consisting of vision, visual function, ocular anatomy, ocular physiology, ocular pathology, and changes thereof; (b) calculating the first set of at least two variables to obtain a first composite biomarker; (b) administering a treatment to the subject; (b) performing a second assay on the subject to obtain a second set of at least two variables; (c) calculating the second set of at least two variables to obtain a second composite biomarker; and (d) determining the dosage of a treatment for the subject based on the first composite biomarker and the second composite biomarker.

[0024] Disclosed herein is a method comprising administering a second dose of treatment to a subject having an ocular disease, wherein a first dose of treatment previously administered to the subject has been determined to lack therapeutic efficacy for treating the ocular disease in the subject based on a composite biomarker calculated from at least two variables of the subject, at least one of which relates to one or more selected from the group comprising vision, visual acuity, visual function, ocular anatomy, ocular physiology, ocular pathology, and changes thereof, and wherein the second dose is different from the first dose.

[0025] Disclosed herein is a method for determining a dosage of a treatment for an ocular disease in a subject, the method comprising: (a) administering a certain dosage of the treatment to the subject; (b) performing an assay on the subject to obtain at least two variables, at least one of which is related to one or more selected from the group consisting of vision, visual function, ocular anatomy, ocular physiology, ocular pathology, and changes thereof; (c) calculating the at least two variables to obtain a composite biomarker; and (d) determining, based on the composite biomarker, whether the dosage of the treatment is therapeutically effective for treating a subject with an ocular disease.

[0026] Disclosed herein is a method for determining a dosage of a treatment for a subject having an ocular disease, the method comprising: (a) performing a first assay on the subject to obtain a first set of at least two variables, at least one of the at least two variables being related to one or more selected from the group consisting of vision, visual function, ocular anatomy, ocular physiology, ocular pathology, and changes thereof; (b) calculating the first set of at least two variables to obtain a first composite biomarker; (c) administering a dosage of the treatment to the subject; and (d) determining a first composite biomarker based on the at least two variables. (c) performing a second assay on the subject to obtain a second set of at least two variables; (c) calculating the second set of at least two variables to obtain a second composite biomarker; and (f) determining that the first dose of treatment is therapeutically effective for treating the subject if the difference between the first composite biomarker and the second composite biomarker exceeds a threshold, or optionally determining that the first dose of treatment is not therapeutically effective for treating the subject if the difference between the first composite biomarker and the second composite biomarker does not exceed a threshold.

[0027] In some embodiments, the ocular disease comprises maculopathy, retinopathy, retina atrophy, macular atrophy, macular degeneration, age-related macular degeneration (AMD), Stargardt disease (STGD), RP (Retinitis pigmentosa), ABCA4 gene mutations, or a combination thereof. In some embodiments, the sample from the subject with the ocular disease has an expression level of retinol binding protein 4 (RBP4) at least at a threshold level. In some embodiments, the threshold level is about 25 μg / ml. In some embodiments, the threshold level is about 35 μg / ml. In some embodiments, the threshold level is between about 25 μg / ml and about 100 μg / ml. In some embodiments, the expression level of RBP4 is measured by an assay including an antibody assay, an electrophoresis assay, an immunoassay, a radioimmunoassay, a chromatography assay, a mass spectrometry assay, a microarray-based detection assay, a polymerase chain reaction assay, a sequencing assay, an immunohistochemistry assay, or any combination thereof. In some embodiments, the antibody assay includes an ELISA. In some embodiments, the sample from the subject with the eye disease has an expression level of vitamin A at least at a threshold level. In some embodiments, the presence or absence of one or more genomic variants indicates that the subject has the eye disease. In some embodiments, the presence or absence of one or more genomic variants indicates that the subject has Stargardt disease. In some embodiments, the threshold level is about 150 μg / mL. In some embodiments, the threshold level is about 225 ng / mL or about 390 μg / mL. In some embodiments, the threshold level is about 150 ng / mL to about 500 μg / mL.In some embodiments, the expression level of vitamin A is measured by an assay comprising an antibody assay, an electrophoresis assay, an immunoassay, a radioimmunoassay, a chromatography assay, a mass spectrometry assay, a microarray-based detection assay, a polymerase chain reaction assay, a sequencing assay, an immunohistochemistry assay, or any combination thereof. In some embodiments, the sample comprises a blood sample. In some embodiments, the expression level of RBP4 or vitamin A is measured from plasma or serum derived from a blood sample. In some embodiments, the presence or absence of one or more genomic variants selected from the group consisting of rs4147863, rs2275029, rs1800739, rs4147857, rs4147856, rs1801555, and rs1801574 indicates that the subject has an eye disease. In some embodiments, the one or more genomic variants include at least four of rs4147863, rs2275029, rs1800739, rs4147857, rs4147856, rs1801555, or rs1801574. In some embodiments, the one or more genomic variants include at least four of rs3747961, rs6666652, rs1800717, rs763108716, rs185601596, rs17110761, rs61748519, rs1801359, rs145766145, rs76258939, rs200551567, rs7547651 rs1762114, rs55860151, rs1800549, rs3112831, rs4147830, rs2297634, or rs4847281.

[0028] In some embodiments, the treatment comprises a pharmaceutical composition comprising an RBP4 inhibitor or a compound configured to reduce blood RBP4 levels in a subject. In some embodiments, the pharmaceutical composition comprises a compound of formula (I):

[0029] [ka] or a pharmaceutically acceptable salt thereof, In the formula, R A 1 , R A 2 , R A 3 , R A 4 , and R A 5 are each independently H, halogen, CF, or C-C alkyl; R A 1 , R A 2 , R A 3 , R A 4 , and R A 5 At least two of the groups are other than H, and R A 6 is H, OH, or a halogen, and AA is a group of the structure

[0030] [ka] and wherein α, β, χ, and δ are each independently absent or present, and when present, each represents a bond; X is C or N, Z1 is N, and Z2 is N or NR A 9 and R A 9 is H, C1-C4 alkyl, or oxetane, and B A is a substituted or unsubstituted 5-, 6-, or 7-membered ring structure.

[0031] In some embodiments, the compound has the structure

[0032] [ka] or a pharmaceutically acceptable salt thereof. In some embodiments, the compound has the structure

[0033] [ka] or a pharmaceutically acceptable salt thereof.

[0034] In some embodiments, the pharmaceutical composition comprises a compound of formula (II):

[0035] [ka] or a pharmaceutically acceptable salt thereof, In the formula, ring A B is an optionally further substituted benzene, and R B 1 is an optionally substituted branched C3-C6 alkyl group, and X B 1 is O, S, SO, SO2, or NH, and X B 2 is a bond or a C1-C3 alkylene group, and ring B B is azetidine or piperidine, and X B 3 is CO or SO2, and R B 2 is an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an optionally substituted hydroxy group, an optionally substituted mercapto group, a cyano group, a nitro group, an acyl group, or a halogen atom.

[0036] In some embodiments, the compound is 4-(3-(2-tert-butylphenoxy)azetidin-1-yl)-4-oxobutanoic acid, 3-{3-[(2-tert-butyl-4-fluorophenoxy)methyl]azetidin-1-yl}-3-oxopropanoic acid, 2-{[3-(2-tert-butyl-4-chlorophenoxy)azetidin-1-yl]carbonyl}pyridine, 4-[3-(2-tert-butyl-4-chlorophenoxy)azetidin-1-yl]-4-oxobutanoic acid, {3-[(2-tert-butyl-4-chlorophenoxy)methyl]azetidin-1-yl}(oxo)acetic acid, {3-[(2-tert-butylphenoxy)methyl]azetidin-1-yl}(oxo)acetic acid, 3-{3-[(2-tert-butylphenoxy)methyl]azetidin-1-yl}-3-oxopropanoic acid, {4-[(2-tert-butyl-4-chlorophenoxy)methyl]piperidin-1-yl}(oxo)acetic acid, [4-(2-tert-butylphenoxy)piperidin-1-yl](oxo)acetic acid, or {4-[(2-tert-butylphenoxy)methyl]piperidin-1-yl}(oxo)acetic acid, or a pharmaceutically acceptable salt thereof.

[0037] In some embodiments, the pharmaceutical composition comprises a compound of formula (III):

[0038] [ka] A compound having the structure In the formula, ring A C is a benzene ring optionally substituted with 1 to 3 substituents selected from the group consisting of (a) halogen atoms, and (b) C1-C6 alkyl groups, and ring B C is a piperazine ring optionally substituted with 1 to 3 substituents selected from the group consisting of (a) a halogen atom, (b) a C1-C6 alkyl group optionally substituted with 1 to 3 halogen atoms, and (c) a C1-C6 alkoxy group optionally substituted with 1 to 3 halogen atoms, and R C (1) optionally substituted C1-C 10alkyl group, (2) optionally substituted C-C 14 (1) an optionally substituted aryl group, (2) an optionally substituted 5- or 6-membered aromatic heterocyclic group, (3) an optionally substituted amino group, (4) an optionally substituted carboxy group, or (5) an optionally substituted carbamoyl group, or a pharmaceutically acceptable salt thereof.

[0039] In some embodiments, the compound is N-{[4-(2-tert-butylphenyl)piperazin-1-yl]carbonyl}glycine, 3-[4-(2-tert-butylphenyl)piperazin-1-yl]-3-oxopropanoic acid, [4-(2-tert-butyl-4-chlorophenyl)piperazin-1-yl](oxo)acetic acid, 5-{2-[4-(2-tert-butylphenyl)piperazin-1-yl]-2-oxoethyl}imidazolidine-2,4-dione, [(5-{[4-(2-tert-butylphenyl)piperazin-1-yl]carbonyl}isoxazol-3-yl)oxy]acetic acid, or a pharmaceutically acceptable salt thereof.

[0040] In some embodiments, the pharmaceutical composition comprises a compound of formula (IV):

[0041] [ka] or a pharmaceutically acceptable salt thereof, In the formula, ring A D is a 5-membered non-aromatic heterocycle optionally further substituted with one oxo group, and ring B D is a benzene ring optionally further substituted with 1 to 4 substituents, and XD is O, CHO, OCH, CH, (CH), S, CHS, SCH, S(O), CHS(O), S(O)CH, S(O), CHS(O), or S(O)CH.

[0042] In some embodiments, the compound is ({(3S)-1-[3,5-bis(trifluoromethyl)phenyl]pyrrolidin-3-yl}oxy)acetic acid, ({1-[4-chloro-3-(trifluoromethyl)phenyl]pyrrolidin-3-yl}sulfanyl)acetic acid, 3-{(2R,5S)-5-[3,5-bis(trifluoromethyl)phenyl]tetrahydrofuran-2-yl}propanoic acid, or a pharmaceutically acceptable salt thereof.

[0043] In some embodiments, the pharmaceutical composition comprises a compound of formula (V):

[0044] [ka] A compound having the structure In the formula, ring A E is a pyrazole ring, a pyridine ring, an oxazole ring, an imidazole ring, or a pyrimidine ring, and X E is S, optionally substituted alkylene, or O, and R E is a hydrogen atom or a C1-C6 alkyl group, or a pharmaceutically acceptable salt thereof.

[0045] In some embodiments, the compound is ((4-(3,5-bis(trifluoromethyl)phenyl)-1,3-oxazol-2-yl)sulfanyl)acetic acid, ethyl ((6-(3,5-bis(trifluoromethyl)phenyl)-pyridin-3-yl)sulfanyl)acetic acid, ((6-(3,5-bis(trifluoromethyl)-phenyl)pyridin-3-yl)sulfanyl)acetic acid, or 3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-pyrazol-1-yl)butanoic acid, or 3-{3-[3,5-bis(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}propanoic acid (also known as STG-001).

[0046] In some embodiments, at least one of the at least two variables relates to one or more selected from the group including visual acuity, the mean score on a functional visual questionnaire, and a measurement obtained from an imaging technique. In some embodiments, at least one of the at least two variables relates to one or more selected from the group including a change in visual acuity, a change in the mean score on a functional visual questionnaire, and a change in a measurement obtained from an imaging technique for detecting or quantifying changes in ocular structure or visual function. In some embodiments, at least one of the at least two variables relates to a change in visual acuity, a change in the mean score on a functional visual questionnaire, and a change in a measurement obtained from an imaging technique for detecting or quantifying changes in optic atrophy or visual function. In some embodiments, at least two variables relate to a change in visual acuity, a change in the mean score on a functional visual questionnaire, and a change in a measurement obtained from an imaging technique for detecting or quantifying changes in optic atrophy or visual function. In some embodiments, at least two variables relate to a change in visual acuity and a change in the mean score on a functional visual questionnaire. In some embodiments, at least two variables relate to a change in visual acuity and a change in a measurement obtained from an imaging technique for detecting or quantifying changes in optic atrophy or visual function. In some embodiments, the at least two variables relate to a change in the mean score of a functional vision questionnaire and a change in a measurement obtained from an imaging technique for detecting or quantifying changes in optic atrophy or visual function. In some embodiments, the at least two variables are all related to a change in visual acuity. In some embodiments, the at least two variables are all related to a change in the mean score of a functional vision questionnaire. In some embodiments, the at least two variables are all related to a change in a measurement obtained from an imaging technique for detecting or quantifying changes in optic atrophy or visual function. In some embodiments, at least one of the at least two variables is related to a change in ocular structure, a change in ocular pathology, a change in retinal atrophy, a change in macular atrophy, a change in macular degeneration, or a combination thereof.In some embodiments, two of the at least two variables are correlated with each other. In some embodiments, one of the at least two variables is correlated with visual acuity. In some embodiments, one of the at least two variables is correlated with a change in visual acuity. In some embodiments, all of the at least two variables are correlated with a change in visual acuity. In some embodiments, one of the at least two variables is correlated with an ocular disease state. In some embodiments, one of the at least two variables is correlated with the progression of an ocular disease. In some embodiments, the at least two variables comprise values ​​obtained from a logarithm of the minimum angle of resolution (logMAR) chart, a Snellen chart, a best corrected visual acuity (BCVA) test, an Early Treatment Diabetic Retinopathy Study (ETDRS) letter test, or a combination thereof. In some embodiments, the at least two variables comprise values ​​obtained from a functional visual questionnaire vest that includes one or more questions related to the following: (a) the subject's confidence in navigating different locations during the day or night; (b) the subject's ability to recognize people, participate in sports, or obtain information; and (c) the subject's ability for social interaction or task performance, wherein each of the one or more questions is scored for the subject. In some embodiments, each of the one or more questions is scored for the subject on a severity scale of 0 to 4 according to the following: (a) a response of "NEVER" is scored 0; (b) a response of "ALMOST NEVER" is scored 1; (c) a response of "SOMETIMES" is scored 2; (d) a response of "ALMOST ALWAYS" is scored 3; and (e) a response of "ALWAYS" is scored 4. In some embodiments, the at least two variables comprise values ​​obtained from microperimetry (MP), perimetry, or both.In some embodiments, the MP comprises measuring a spatial map of the subject's retinal sensitivity. In some embodiments, the MP comprises measuring the subject's mean retinal sensitivity or a change therein. In some embodiments, the at least two variables comprise values ​​obtained from one or more selected from the group including fundus photography, fundus angiography (FA), fundus autofluorescence (FAF), spectral domain-optical coherence tomography (SD-OCT), quantitative autofluorescence (qAF), infrared (IR) imaging, optical coherence tomography-angiography (OCT-A), and widefield imaging. In some embodiments, the at least two variables comprise one or more selected from the group comprising an area of ​​questionable decreased autofluorescence (QDAF), an area of ​​definite decreased autofluorescence (DDAF), an area of ​​decreased autofluorescence (DAF), retina thickness, ellipsoid zone (EZ) defect width, central subfield retina thickness (CST), outer subfield retina thickness (OST), middle subfield retina thickness (MST), and changes therein.In some embodiments, the regions of decreased autofluorescence (DAF) include regions of questionable decreased autofluorescence (QDAF) and regions of definite decreased autofluorescence (DDAF). In some embodiments, the at least two variables include two or more selected from the group including visual acuity, QDAF, DAF, EZ defect width, or a change thereof. In some embodiments, the at least two variables include visual acuity, QDAF, DAF, EZ defect width, or a change thereof. In some embodiments, EZ defect width is correlated with visual acuity. In some embodiments, EZ defect width is correlated with QDAF. In some embodiments, EZ defect width is correlated with DAF. In some embodiments, visual acuity is correlated with QDAF. In some embodiments, EZ defect width is correlated with visual acuity, QDAF, and DAF. In some embodiments, visual acuity is correlated with EZ defect width and QDAF. In some embodiments, EZ defect width is correlated with visual acuity, QDAF, and DAF, with a correlation coefficient greater than about 0.8 and a p-value less than about 0.05. In some embodiments, visual acuity is correlated with EZ defect width and QDAF, with a p-value of less than about 0.05. In some embodiments, the at least two variables of the subject are obtained from both the right and left eyes of the subject. In some embodiments, the method further comprises predicting whether the prognostic potentials of the treatment will improve based on one or more composite biomarkers. In some embodiments, if the composite biomarkers exceed a threshold, the treatment is therapeutically effective for treating the subject. In some embodiments, if the composite biomarkers do not exceed a threshold, the treatment is not therapeutically effective for treating the subject.

[0047] Incorporation by Reference All publications, patents, and patent applications mentioned herein are hereby incorporated by reference for the particular purposes identified herein. [Brief explanation of the drawings]

[0048] The novel features of the invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings. [Figure 1A] Figure 1A shows the reduction in autofluorescence (AF) using qAF in the right eye (Figure 1A) and left eye (Figure 1B) of subject 3 after treatment with an RBP4 inhibitor. The left image in each figure is labeled Phase 2 Baseline, and the right image in each figure is labeled Month 2, Day 6. The qAF values ​​are labeled 335, 275, 351, and 268 for each image (left to right). [Figure 1B] Figure 1A shows the reduction in autofluorescence (AF) using qAF in the right eye (Figure 1A) and left eye (Figure 1B) of subject 3 after treatment with an RBP4 inhibitor. The left image in each figure is labeled Phase 2 Baseline, and the right image in each figure is labeled Phase 2 Day 6. The qAF values ​​are labeled 335, 275, 351, and 268 for each image (left to right). [Figure 1C] Fundus autofluorescence (FAF) of the right eye of subject 3 at Phase 2 baseline (left) and Phase 2 6 months (right) is shown. Lesion areas are labeled 2.7 mm2 (left) and 2.7 mm2 (right). [Figure 1D] EZ defect analysis of the left eye of subject 3 at Phase 2 baseline (left) and Phase 2 month 6 (right). Red lines are labeled 2.91 mm (left) and 2.71 mm (right). [Figure 1E]Figure 1 shows the change in MST and OST (retinal thickening) in the left eye of subject 3 after treatment with an RBP4 inhibitor. The top image is labeled Phase 2 Baseline, and the bottom image is labeled Phase 2 Month 6. The left side of each image shows the eye region and mean thickness. For Phase 2 Baseline, the mean thickness values ​​in the legend are (top to bottom): marker (97 microns), center (97 microns), central minimum (97 microns), and central maximum (202 microns). For Phase 2 Month 6, the mean thickness values ​​in the legend are (top to bottom): marker (112 microns), center (112 microns), central minimum (104 microns), and central maximum (216 microns). The right side of each image shows the eye region and retinal thickness. The retinal thickness scale on the right is labeled 0 to 800 in 100-unit intervals. The size scale inlaid into the image is labeled 200 microns. [Figure 2A] 1 shows the stabilization of QDAF size in the left eye of subject 4 after treatment with an RBP4 inhibitor. The image on the left is labeled Phase 2 Baseline and the image on the right is labeled Month 2 Day 6. [Figure 2B] Figure 1 shows the change in MST and OST (retinal thickness) in the left eye of subject 4 after treatment with an RBP4 inhibitor. The top image is labeled Phase 2 Baseline, and the bottom image is labeled Phase 2 Month 6. The left side of each image shows the eye region and mean thickness. For Phase 2 Baseline, the mean thickness values ​​in the legend are (top to bottom): marker (60 microns), center (63 microns), central minimum (57 microns), and central maximum (218 microns). For Phase 2 Month 6, the mean thickness values ​​in the legend are (top to bottom): marker (56 microns), center (58 microns), central minimum (54 microns), and central maximum (199 microns). The right side of each image shows the eye region and retinal thickness. The retinal thickness scale on the right is labeled 0 to 800 in 100-unit intervals. The size scale inset into the image is labeled 200 microns. [Figure 2C]EZ defect analysis of the right eye of subject 4 at Phase 2 baseline (left) and Phase 2 month 6 (right). Red lines are labeled 1.79 mm (left) and 1.85 mm (right). [Figure 3A] 1 shows SD-OCT changes in the right eye of subject 11 after treatment with an RBP4 inhibitor. The image on the left is labeled Phase 2 Baseline, and the image on the right is labeled 2 / 6. [Figure 3B] 1 shows the change in autofluorescence in the right eye of subject 11 after treatment with an RBP4 inhibitor. The image on the left is labeled Phase 2 Baseline, and the image on the right is labeled 2 / 6. [Figure 3C] EZ defect analysis of the left eye of subject 11 at Phase 2 baseline (left) and Phase 2 month 6 (right). Red lines are labeled 2.20 mm (left) and 2.29 mm (right). Detailed Description of the Invention

[0049] As used in this specification and the appended claims, the singular forms "a," "and," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, a reference to "an agent" includes a plurality of such agents; a reference to "the cell" includes a reference to one or more cells (or cells) and equivalents thereof known to those of skill in the art, and so forth. When ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formulas, all combinations and subcombinations of ranges and specific embodiments therein are intended to be included. When referring to a number or numerical range, the term "about" means that the referenced number or numerical range is approximate within experimental variability (or within statistical experimental error); therefore, the number or numerical range will, in some instances, vary by 1% to 15% of the stated number or numerical range. The term "comprising" (and related terms such as "comprise" or "comprises" or "having" or "including") is not intended to exclude certain other embodiments, such as, for example, any composition, composition, method, or process described herein, from "consisting of" or "consist essentially of" the described features.

[0050] Eye Diseases and Treatments Provided herein are methods for assessing disease progression and treating ocular diseases in subjects. Ocular diseases include diseases affecting visual function, ocular structure, ocular anatomy, retinal structure, retinal function, retinal pathology, macular structure, macular function, macular pathology, or a combination thereof. For example, ocular diseases include, but are not limited to, maculopathy, retinopathy, retinal atrophy, macular atrophy, macular degeneration, diabetic retinopathy, inherited retina disease, age-related macular degeneration (AMD), Stargardt disease (STGD), RP (Retinitis pigmentosa), ABCA4 gene mutations, or a combination thereof. Patients with retina degenerative diseases may experience loss or decline in visual acuity (VA), or pathological or structural changes in the retina. Age-related macular degeneration (AMD) is a common eye disease and a leading cause of vision loss among people over the age of 50. This damages the macula, a small spot near the center of the retina that is essential for sharp, central vision. As AMD progresses, a blurred area near the center of vision is a common symptom. Over time, the blurred area may grow larger, and the subject may develop a blank spot in their central vision. Stargardt disease (STGD) is a juvenile maculopathy that shares a pathology similar to AMD. STGD is the more prevalent form of hereditary macular degeneration, with STGD1 being the most common subtype. STGD affects approximately 1 in 10,000 people worldwide. Early-onset Stargardt disease (<20 years of age) is usually associated with worsening disease severity. In retinal degenerative diseases, including STGD and AMD, accumulation of lipofuscin associated with tissue autofluorescence (AF) in the retinal pigmented epithelium (RPE) has been observed, and the bisretinoid N-retinyl-N-retinylidene ethanolamine (A2E) is a component of lipofuscin. Accumulation of A2E is likely to be a cause of retinal atrophy.Excessive lipofuscin accumulation has been recognized as a common pathogenic pathway in various retinal diseases, including AMD, preceding photoreceptor degeneration. The appearance of AF correlates with disease pathology. Quantitative AF can directly assess the relative levels of A2E and related bisretinoids in retinal tissue. Significantly elevated AF levels have been shown in childhood-onset STGD1 compared with adult-onset STGD1. AF in childhood-onset STGD1 is up to eight-fold higher than that in healthy eyes. Childhood-onset STGD1 has been characterized by rapid decline in visual acuity. Adult-onset STGD1 has been shown to have a milder phenotype with foveal sparing, allowing stable vision for several years. Mutations in the ATP-binding cassette, subfamily A, member 4 (ABCA4) gene can result in excessive accumulation of the cytotoxic bisretinoid A2E. A2E is the primary source of abnormal autofluorescence (AF) in the retina. The stable increase in AF in STGD1 and AMD can lead to retinal atrophy and subsequent photoreceptor cell loss, which causes a decrease in AF. These retinal lesions, called distinct areas of decreased AF (DDAF), can be quantified using imaging techniques. Tanna,P.,et al.(2016)British Journal of Ophthalmology,101(1):25-30;Invest Ophthalmol Vis Sci.2011;52:9379-9390;Invest Ophthalmol Vis Sci.2015;56:8179-8186;Invest Ophthalmol Vis Sci.2014;55:2841-2852;Ophthalmology 2015;122:335-344;Br J Ophthalmol 2017;101:25-30;AM J Ophthalmol 2020;211:159-175;JAMA Ophthalmol 2017;135:1232-1241;Invest See Ophthalmol Vis Sci. 2016;57:5186-5191. The blood retinol transporter, retinol-binding protein 4 (RBP4), is secreted by adipocytes and the liver.The reduction of RBP4 level can lead to the reduction of lipofuscin accumulation, which leads to vision loss in diseases such as AMD, dry (atrophic) AMD, and STGD.The reduction of RBP4 can reduce the accumulation of lipofuscin in the retina, and thus delay or stop the vision loss in AMD or STGD caused by excessive accumulation of lipofuscin in the retina.The RBP4 inhibitor disclosed herein can inhibit RBP4 and delay bisretinoid / A2E accumulation.

[0051] Visual function assessment There are several approaches to assessing ocular disease or visual function for various purposes, including, but not limited to, selecting subjects for treatment, assessing disease progression in a subject, assessing the potential therapeutic effect of a treatment on a subject, assessing a subject's therapeutic or clinical response to a treatment, determining the dosage of a treatment for a subject, or a combination thereof. These approaches include, but are not limited to, retinal imaging, imaging modalities, and functional tests. Imaging modalities typically use specialized cameras with or without non-invasive laser light or fluorescent dyes. Imaging modalities include, but are not limited to, fundus photography, fundus angiography (FA), fundus autofluorescence (FAF), spectral-domain optical coherence tomography (SD-OCT), quantitative autofluorescence (qAF), infrared (IR) imaging, optical coherence tomography-angiography (OCT-A), and wide-field imaging. Functional tests typically assess visual function or its impact on daily activities or behavior. Functional tests include tests of visual acuity, functional vision questionnaires, microperimetry, perimetry, and other behavioral functional tests. These assessment approaches are used to measure several variables related to vision, visual function, visual structure, ocular anatomy, retinal atrophy, retinal degeneration, macular degeneration, retinal physiology or pathology, macular physiology or pathology, or changes therein. For example, these variables include, but are not limited to, visual acuity (VA), Functional Vision Questionnaire score, logarithm of minimum separation threshold angle (logMAR) chart score, Snellen chart score, best corrected visual acuity (BCVA) test score, Early Treatment Diabetic Retinopathy Study (ETDRS) letter test score, retinal sensitivity, size of questionable decrease in autofluorescence (QDAF), size of definite decrease in autofluorescence (DDAF), size of decrease in autofluorescence (DAF), retinal thickness, ellipsoid zone (EZ) defect width, central subfield retinal thickness (CST), outer subfield retinal thickness (OST), middle subfield retinal thickness (MST), or changes therein, or any other variable related to visual function.

[0052] Disclosed herein are methods, compositions, and systems for assessing visual function. In some embodiments, the methods, compositions, or systems disclosed herein can combine at least two variables to generate a composite biomarker. In some embodiments, the composite biomarker is used to assess ocular disease or visual function. In some embodiments, the composite biomarker is used to select a subject with an ocular disease for treatment, assess the progression of an ocular disease in a subject, evaluate the potential therapeutic efficacy of a treatment for a subject with an ocular disease, evaluate a subject's therapeutic response to a treatment for an ocular disease, determine the dosage of a treatment for a subject, or any other purpose related to the treatment or assessment of an ocular disease, or a combination thereof. In some embodiments, the at least two variables are obtained from at least two assessment approaches for ocular diseases disclosed herein, including, but not limited to, imaging methods, imaging modalities, or functional tests. In some embodiments, the at least two variables include measurements, images, analyses, test scores, values, or any other form of data obtained from the assessment approaches for ocular diseases. In some embodiments, the composite biomarker can be in the form of a score, a predicted score, a predictive model, or a combination thereof. In some embodiments, the composite biomarker includes a threshold value. In some embodiments, whether the composite biomarkers exceed a threshold correlates with a particular outcome of the methods disclosed herein. In some embodiments, the composite biomarkers are used to select a subject for a particular clinical treatment. In some embodiments, the composite biomarkers are used to assess disease progression in a subject. In some embodiments, the composite biomarkers are used to evaluate the potential therapeutic effect of a particular treatment on a subject prior to treatment. In some embodiments, the composite biomarkers are used to determine the dosage of treatment for a subject. In some embodiments, the composite biomarkers are used to evaluate the therapeutic effect of a subject during treatment. In some embodiments, the composite biomarkers are used for a combination of purposes disclosed herein. In some embodiments, if the composite biomarkers exceed a threshold, the subject may be selected for a particular clinical treatment.In some embodiments, if the composite biomarkers do not exceed a threshold, the subject may not be selected for a particular clinical treatment. In some embodiments, if the composite biomarkers exceed a threshold, the subject may be determined to likely have a particular disease state. In some embodiments, if the composite biomarkers do not exceed a threshold, the subject may be determined to be unlikely to have a particular disease state. In some embodiments, if the composite biomarkers exceed a threshold, the subject may be determined to be likely to benefit therapeutically from a treatment before receiving the treatment. In some embodiments, if the composite biomarkers do not exceed a threshold, the subject may be determined to be unlikely to benefit therapeutically from a treatment before receiving the treatment. In some embodiments, if the composite biomarkers exceed a threshold, the subject may be determined to be likely to have a particular therapeutic response to the treatment over the course of the treatment. In some embodiments, if the composite biomarkers do not exceed a threshold, the subject may be determined to be unlikely to have a particular therapeutic response to the treatment over the course of the treatment. In some embodiments, the dosage of a treatment for an ocular disease can be calculated based on the composite biomarkers.

[0053] In some embodiments, at least one of the at least two variables is correlated with the state of an ocular disease. In some embodiments, the at least two variables include at least one objective variable. In some embodiments, the at least one objective variable is correlated with the state of an ocular disease. In some embodiments, the at least one objective variable includes a change in ocular structure. In some embodiments, the at least one objective variable includes a pathological change in the eye. In some embodiments, at least one of the at least two variables is correlated with another of the at least two variables. In some embodiments, each of the at least two variables is correlated with the remaining of the at least two variables. In some embodiments, at least one of the at least two variables is correlated with visual acuity. In some embodiments, visual acuity may be an endpoint of a clinical evaluation or clinical treatment. In some embodiments, visual acuity may be a subjective measurement. In some embodiments, the at least two variables include vision, a visual questionnaire score, a measurement obtained from an imaging technique for evaluating an ocular disease, a change therein, or a combination thereof. In some embodiments, the imaging technique is used to detect and / or quantify changes in retinal atrophy. In some embodiments, the at least two variables include measurements from imaging techniques used to detect and / or quantify changes in visual acuity, changes in mean visual questionnaire scores, and changes in retinal atrophy. In some embodiments, one of the at least two variables is obtained from the right eye, the left eye, or both eyes of a subject. In some embodiments, the at least two variables are obtained from at least two subjects of different genders, ethnicities, ages, or combinations thereof. In some embodiments, the at least two variables are obtained during at least two clinical phases.

[0054] There are several signature variables for the assessment of ocular diseases, including, but not limited to, changes in visual acuity, changes in Functional Vision Questionnaire mean scores, and changes in measurements obtained from imaging modalities used to detect and / or quantify changes in retinal or macular structure / anatomy, such as retinal atrophy, macular atrophy, and macular degeneration in AMD and STGD. These signature variables are used to select patients for treatment, monitor disease progression, and / or evaluate treatment efficacy.

[0055] In some embodiments, visual acuity may be assessed using a logarithmic minimum separation threshold angle chart (logMAR chart). The logMAR chart includes a row of letters used to estimate visual acuity. A logMAR of zero may indicate normal visual acuity, a positive value may indicate poor visual acuity, and a negative value may indicate good vision. In some embodiments, the best corrected visual acuity (BCVA) Early Treatment Diabetic Retinopathy Study (ETDRS) letters score is calculated using the following formula: LogMAR score = -0.02 * letter score +1.7 It can be calculated using

[0056] In some embodiments, a modifier of -1 may be added to the change in visual acuity for interpretation of visual acuity improvement. In some embodiments, a Snellen chart may also be used to assess visual acuity.

[0057] In some embodiments, a functional visual questionnaire may be administered with several questions scored on a severity scale. An average score is obtained from one or more functional visual questionnaires. In some embodiments, the visual questionnaire's scoring scale may be any range between (or including) two numbers. In some embodiments, the scoring scale may be 0 to 4. In some embodiments, a response of "NEVER" to a question is assigned a score according to the scoring scale. In some embodiments, a response of "ALMOST NEVER" to a question is assigned a score according to the scoring scale. In some embodiments, a response of "SCOMETIMES" to a question is assigned a score according to the scoring scale. In some embodiments, a response of "ALMOST ALWAYS" to a question is assigned a score according to the scoring scale. In some embodiments, a response of "ALWAYS" to a question is assigned a score according to the scoring scale. In some embodiments, a response of "NEVER," "ALMOST NEVER," "SOMETIMES," "ALMOST ALWAYS," and "ALWAYS" to a question is assigned a score of 0, 1, 2, 3, and 4, respectively, according to a 0 to 4 scoring scale. In some embodiments, answers to questions of "NEVER," "ALMOST NEVER," "SOMETIMES," "ALMOST ALWAYS," and "ALWAYS" are assigned scores of 4, 3, 2, 1, and 0, respectively, according to a 0-4 scoring scale.

[0058] In some embodiments, the functional vision questionnaire includes any number of questions, such as about 1 to about 200 questions, for example, about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111 1, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158 , 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, or about 200, or any number therebetween. In some embodiments, the functional vision questionnaire includes about 24 questions.

[0059] In some embodiments, the questions in the vision questionnaire relate to visual function. In some embodiments, the visual function includes the subject's confidence in navigating to different locations during the day. In some embodiments, the visual function includes the subject's confidence in navigating to different locations at night. In some embodiments, the visual function includes the subject's confidence in navigating to different locations during the day and at night. In some embodiments, the visual function includes the subject's confidence in navigating to different locations during the day or at night. In some embodiments, the visual function includes the subject's ability to recognize people. In some embodiments, the visual function includes the subject's ability to participate in sports. In some embodiments, the visual function includes the subject's ability to obtain information. In some embodiments, the visual function includes the subject's ability to recognize people, participate in sports, or obtain information. In some embodiments, the visual function includes the subject's social interaction. In some embodiments, the visual function includes the subject's work efficiency. In some embodiments, the visual function includes the subject's social interaction and work efficiency. In some embodiments, the visual function includes the subject's social interaction or work efficiency.

[0060] Fundus autofluorescence (FAF) imaging is used as an endpoint in clinical trials. FAF is used to detect lesion growth at multiple time points. The change in lesion area measured by FAF is plotted against time to calculate lesion growth rate, e.g., how fast or slow a patient's macula or retina is degenerating compared to placebo. FAF imaging is used to compare the rate of anatomical or structural deterioration or change to evaluate the therapeutic effect of a drug or treatment, e.g., reducing the worsening of retinal degeneration.

[0061] In some embodiments, fundus autofluorescence (FAF) is used to evaluate ocular disease or visual function. In some embodiments, one or more retinal images of FAF are used to detect areas of atrophy. In some embodiments, one or more retinal images of FAF are used to gain detailed insight into the health of the retinal pigment epithelium (RPE). In some embodiments, one or more images of FAF may be high-contrast retinal images. In some embodiments, two types of decreased autofluorescence (DAF) may be quantified. In some embodiments, one type of DAF may be a clear DAF (DDAF), which includes areas with a level of darkness defined as qualitatively clear. In some embodiments, another type of DAF may be a suspicious DAF (QDAF), which includes areas with a level of darkness defined as qualitatively suspicious. In some embodiments, the size of a decreased autofluorescence (DAF) lesion may be the sum of all DDAF and QDAF. In some embodiments, DAF is measured in square millimeters (mm 2 ) units of area.

[0062] In some embodiments, spectral-domain optical coherence tomography (SD-OCT) is used to evaluate ocular disease or visual function. In some embodiments, SD-OCT provides in vivo cross-sectional and en face visualization of the retina and RPE. In some embodiments, SD-OCT is used to detect the presence of RPE atrophy. In some embodiments, SD-OCT is used to evaluate ellipsoid zone (EZ) defect width. In some embodiments, the EZ line provides information about photoreceptor integrity. In some embodiments, the EZ line provides useful information in early disease. In some embodiments, SD-OCT images are used to evaluate central subfield retinal thickness (CST). In some embodiments, SD-OCT images are used to evaluate middle subfield retinal thickness (MST). In some embodiments, SD-OCT images are used to evaluate outer subfield retinal thickness (OST).

[0063] In some embodiments, microperimetry is used to evaluate ocular disease or visual function. In some embodiments, microperimetry is used to measure mean retinal sensitivity. In some embodiments, retinal sensitivity can be the level of retinal response to light stimuli. In some embodiments, microperimetry is used to spatially map retinal sensitivity. In some embodiments, microperimetry can be a psychophysical visual function test. In some embodiments, microperimetry is used to identify correlations between anatomical features and visual function.

[0064] In some embodiments, methods for measuring quantitative autofluorescence (qAF) or assessing ocular disease or visual function are used. In some embodiments, qAF methods can incorporate an internal fluorescence reference to account for variable laser power and detector sensitivity. In some embodiments, the intensity of AF can be calculated relative to a calibrated internal fluorescent reference in the optical path.

[0065] Evaluation method for visual function using multiple biomarkers In one aspect, a method of treating a subject with an ocular disease is disclosed herein. In some embodiments, the method includes one or more steps disclosed herein. In some embodiments, the method includes one or more steps of a different method disclosed herein. In some embodiments, one or more steps of a method disclosed herein can be combined with one or more steps of another method disclosed herein. In some embodiments, the method includes administering to the subject a treatment for the ocular disease. In some embodiments, the treatment includes a pharmaceutical composition disclosed herein. In some embodiments, the treatment can be administered at a dosage disclosed herein. In some embodiments, the method includes performing an assay on the subject to obtain at least two variables. In some embodiments, at least one of the at least two variables is related to one or more selected from the group including vision, visual function, ocular anatomy, ocular physiology, and ocular pathology. In some embodiments, at least one of the at least two variables is related to one or more selected from the group including changes in vision, changes in visual function, changes in ocular anatomy, changes in ocular physiology, and changes in ocular pathology. In some embodiments, the assay includes at least two assays. In some embodiments, at least two assays may be performed at two or more time points to obtain at least two variables. In some embodiments, at least two assays may be performed at a first time point and a second time point. In some embodiments, the assays include any number of assays.In some embodiments, the assays include any number of assays ranging from 1 to 100, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, Including 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100, or any number in between. In some embodiments, the number of time points at which the assay is performed is any number ranging from 1 to 100, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48 , 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100, or any number therebetween. In some embodiments, at least one of the at least two variables is a variable disclosed herein. In some embodiments, the at least two variables include all variables disclosed herein. In some embodiments, the method includes calculating at least two variables to obtain a composite biomarker. In some embodiments, a composite biomarker can be calculated based on at least two variables. In some embodiments, the composite biomarkers may be calculated based on a formula or model disclosed herein.In some embodiments, the method includes determining whether the treatment is therapeutically effective for treating the subject based on the composite biomarkers. In some embodiments, if the composite biomarkers exceed a threshold, the treatment is therapeutically effective for treating the subject. In some embodiments, if the composite biomarkers do not exceed a threshold, the treatment is not therapeutically effective for treating the subject.

[0066] In some embodiments, a method of treating a subject with an ocular disease includes, after administering the treatment, performing a first assay on the subject to obtain a first set of at least two variables at a first time point. In some embodiments, the method includes calculating the first set of at least two variables to obtain a first composite biomarker. In some embodiments, the first composite biomarker can be calculated based on the first set of at least two variables. In some embodiments, the method includes performing a second assay on the subject to obtain a second set of at least two variables at a second time point. In some embodiments, the method includes calculating a second set of at least two variables to obtain a second composite biomarker. In some embodiments, the second composite biomarker can be calculated based on the second set of at least two variables. In some embodiments, the method includes determining whether the treatment is therapeutically effective to treat the subject based on the first composite biomarker and the second composite biomarker. In some embodiments, the method includes calculating a composite biomarker based on the first and second sets of at least two variables. In some embodiments, the method includes determining whether a treatment is therapeutically effective for treating a subject based on a composite biomarker calculated from a first and a second set of at least two variables. In some embodiments, the composite biomarker can be calculated from the first and the second set of at least two variables based on a formula or model disclosed herein. In some embodiments, the method includes comparing the first composite biomarker with the second composite biomarker to obtain a difference between the first composite biomarker and the second composite biomarker. In some embodiments, if the difference between the first composite biomarker and the second composite biomarker exceeds a threshold, the treatment is therapeutically effective for treating the subject. In some embodiments, if the difference between the first composite biomarker and the second composite biomarker does not exceed a threshold, the treatment is not therapeutically effective for treating the subject.

[0067] In some embodiments, a method for treating a subject with an ocular disease includes administering a first dose of treatment to the subject. In some embodiments, the method includes performing an assay on the subject after administering the first dose of treatment to obtain at least two variables. In some embodiments, the method includes calculating at least two variables to obtain a composite biomarker. In some embodiments, the composite biomarker can be calculated based on the at least two variables. In some embodiments, the method includes determining whether the first dose of treatment is therapeutically effective for treating the subject based on the composite biomarker. In some embodiments, the method includes administering a second dose of treatment to the subject. In some embodiments, if the first dose is determined to be ineffective for treating the subject, the second dose can be different from the first dose. In some embodiments, if the first dose is determined to be therapeutically effective for treating the subject, the second dose can be the same or approximately the same as the first dose. In some embodiments, the first dose of treatment is therapeutically effective for treating the subject if the composite biomarker exceeds a threshold. In some embodiments, if the composite biomarkers do not exceed the threshold value, the first dose of treatment is not therapeutically effective to treat the subject.

[0068] In some embodiments, the method includes performing a first assay on the subject to obtain a first set of at least two variables at a first time point after administering a first dose of treatment. In some embodiments, the method includes performing a second assay on the subject to obtain a second set of at least two variables at a second time point. In some embodiments, a first composite biomarker can be calculated based on the first set of at least two variables. In some embodiments, a second composite biomarker can be calculated based on the second set of at least two variables. In some embodiments, the method includes determining whether the treatment is therapeutically effective to treat the subject based on the first composite biomarker and the second composite biomarker. In some embodiments, the method includes calculating a composite biomarker based on the first and second sets of at least two variables. In some embodiments, the method includes determining whether the treatment is therapeutically effective to treat the subject based on a composite biomarker calculated from the first and second sets of at least two variables. In some embodiments, the composite biomarker can be calculated from the first and second sets of at least two variables based on a formula or model disclosed herein. In some embodiments, the method includes administering a second dose of treatment to the subject. In some embodiments, if the first dose is determined to be ineffective in treating the subject, the second dose can be different from the first dose. In some embodiments, if the first dose is determined to be effective in treating the subject, the second dose can be the same or approximately the same as the first dose. In some embodiments, the method includes comparing the first composite biomarker with the second composite biomarker to obtain a difference between the first composite biomarker and the second composite biomarker. In some embodiments, if the difference between the first composite biomarker and the second composite biomarker exceeds a threshold, the treatment is therapeutically effective in treating the subject.In some embodiments, if the difference between the first composite biomarker and the second composite biomarker does not exceed a threshold, the treatment is not therapeutically effective for treating the subject. In some embodiments, if the composite biomarker calculated from the first and second sets of at least two variables exceeds a threshold, the treatment is therapeutically effective for treating the subject. In some embodiments, if the composite biomarker calculated from the first and second sets of at least two variables does not exceed a threshold, the treatment is not therapeutically effective for treating the subject.

[0069] In some embodiments, a method of treating a subject with an ocular disease includes performing a first assay on the subject at a first time point to obtain a first set of at least two variables disclosed herein before administering the treatment. In some embodiments, the method includes calculating the first set of at least two variables to obtain a first composite biomarker before administering the treatment. In some embodiments, the method includes administering the treatment to the subject. In some embodiments, the method includes performing a second assay on the subject at a second time point to obtain a second set of at least two variables after administering the treatment. In some embodiments, the method includes calculating the second set of at least two variables to obtain a second composite biomarker. In some embodiments, the second composite biomarker can be calculated based on the second set of at least two variables. In some embodiments, the method includes determining whether the treatment is therapeutically effective to treat the subject based on the first composite biomarker and the second composite biomarker. In some embodiments, the method includes comparing a first composite biomarker with a second composite biomarker to obtain a difference between the first composite biomarker and the second composite biomarker. In some embodiments, if the difference between the first composite biomarker and the second composite biomarker exceeds a threshold, the treatment is therapeutically effective for treating the subject. In some embodiments, if the difference between the first composite biomarker and the second composite biomarker does not exceed a threshold, the treatment is not therapeutically effective for treating the subject.

[0070] In some embodiments, a method of treating a subject with an ocular disease includes, prior to administering the treatment, performing a first assay on the subject to obtain a first set of at least two variables disclosed herein. In some embodiments, the method includes calculating the first set of at least two variables to obtain a first composite biomarker. In some embodiments, the method includes, prior to administering the treatment, performing a second assay on the subject at a second time point to obtain a second set of at least two variables. In some embodiments, the method includes calculating the second set of at least two variables to obtain a second composite biomarker. In some embodiments, the method includes comparing the first composite biomarker with the second composite biomarker to obtain a difference between the first composite biomarker and the second composite biomarker. In some embodiments, the method includes calculating a fifth composite biomarker based on the first and second sets of at least two variables. In some embodiments, the method includes administering the treatment to the subject. In some embodiments, the method includes, after administering the treatment, performing a third assay on the subject at a third time point to obtain a third set of at least two variables. In some embodiments, the method includes performing a fourth assay on the subject at a fourth time point after administering the treatment to obtain a fourth set of at least two variables. In some embodiments, the method includes calculating the third set of at least two variables to obtain a third composite biomarker. In some embodiments, the method includes calculating the fourth set of at least two variables to obtain a fourth composite biomarker. In some embodiments, the method includes comparing the third composite biomarker with the fourth composite biomarker to obtain a difference between the third composite biomarker and the fourth composite biomarker. In some embodiments, the method includes calculating a sixth composite biomarker based on the third and fourth sets of at least two variables.In some embodiments, the method includes determining whether a treatment is therapeutically effective for treating a subject based on the first, second, third, and fourth composite biomarkers. In some embodiments, the method includes comparing the difference between the first composite biomarker and the second composite biomarker with the difference between the third composite biomarker and the fourth composite biomarker to generate a differential value. In some embodiments, if the differential value exceeds a threshold, the treatment is therapeutically effective for treating the subject. In some embodiments, if the differential value does not exceed a threshold, the treatment is not therapeutically effective for treating the subject. In some embodiments, the method includes determining whether a treatment is therapeutically effective for treating a subject based on a fifth and a sixth composite biomarker. In some embodiments, the method includes comparing the fifth and sixth composite biomarkers to obtain a difference therebetween. In some embodiments, if the difference between the fifth composite biomarker and the sixth composite biomarker exceeds a threshold, the treatment is therapeutically effective for treating the subject. In some embodiments, if the difference between the fifth composite biomarker and the sixth composite biomarker does not exceed a threshold value, the treatment is not therapeutically effective to treat the subject.

[0071] In some embodiments, the period between the first and second time points at which the first and second assays are performed, or the third and fourth time points at which the third and fourth assays are performed, can be any period suitable for measuring at least two variables as disclosed herein. In some embodiments, the time period is any time period from about 1 day to about 1 year, e.g., about 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 days, 32 days, 33 days, 34 days, 35 days, 36 days, 37 days, 38 days, 39 days, 40 days, 41 days, 42 days, 43 days, 44 days, 45 days, 46 days, 47 days, 48 ​​days, 49 days, 50 days, 51 days, 52 days, 53 days, 54 days, 55 days, 56 days, 57 days, 58 days, 59 days, 60 days, 61 days, 62 days, 63 days, 64 days, 65 days, 66 days, 67 days, 68 days, 69 days, 70 days, 71 days, 72 days, 73 days, 74 days, 75 days, 76 days, 77 days, 78 days, 79 days, 80 days, 81 days, 82 days, 83 days, 84 days, 85 days, 86 days, 87 days, 88 days, 89 days, 90 days, 91 days, 92 days, 93 days, 94 days, 95 days, 96 days, 97 days, 98 days, 9 , 50th, 51st, 52nd, 53rd, 54th, 55th, 56th, 57th, 58th, 59th, 60th, 61st, 62nd, 63rd, 64th, 65th, 66th, 67th, 68th, 69th, 70th, 71st, 72nd, 73rd, 74th, 75th, 76th, 77th, 78th, 79th, 80th, 81st, 82nd, 83rd, 84th, 85th, 86th, 87th, 88th, 89th, 90th, 91st, 92nd, 93rd, 94th, 95th, 96th, 97th, 98th, 99th, 100th, 101st, 102nd, 103rd , 104th, 105th, 106th, 107th, 108th, 109th, 110th, 111th, 112th, 113th, 114th, 115th, 116th, 117th, 118th, 119th, 120th, 121st, 122nd, 123rd, 124th, 125th, 126th, 127th, 128th, 129th, 130th, 131st, 132nd, 133rd, 134th, 135th, 136th, 137th, 138th, 139th, 140th, 141st, 142nd, 143rd, 144th, 145th, 146th, 147th , 148th, 149th, 150th, 151th, 152th, 153th, 154th, 155th, 156th, 157th, 158th, 159th, 160th, 161st, 162nd, 163rd, 164th, 165th, 166th, 167th, 168th, 169th, 170th, 171st, 172nd, 173rd, 174th, 175th, 176th, 177th, 178th, 179th, 180th, 181st, 182nd, 183rd, 184th, 185th, 186th, 187th, 188th, 189th, 190th, 191st,192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236 , 237th, 238th, 239th, 240th, 241st, 242nd, 243rd, 244th, 245th, 246th, 247th, 248th, 249th, 250th, 251st, 252nd, 253rd, 254th, 255th, 256th, 257th, 258th, 259th, 260th, 261st, 262nd, 263rd, 264th, 265th, 266th, 267th, 268th, 269th, 270th, 271st, 272nd, 273rd, 274th, 275th, 276th, 277th, 278th, 279th, 280th, 2 81st, 282nd, 283rd, 284th, 285th, 286th, 287th, 288th, 289th, 290th, 291st, 292nd, 293rd, 294th, 295th, 296th, 297th, 298th, 299th, 300th, 301st, 302nd, 303rd, 304th, 305th, 306th, 307th, 308th, 309th, 310th, 311th, 312th, 313th, 314th, 315th, 316th, 317th, 318th, 319th, 320th, 321st, 322nd, 323rd, 324th, 325th , 326, 327, 328, 329, 330, 331, 332, 333, 334, 335, 336, 337, 338, 339, 340, 341, 342, 343, 344, 345, 346, 347, 348, 349, 350, 351, 352, 353, 354, 355, 356, 357, 358, 359, 360, 361, 362, 363, 364, or 365 days, or any period in between. In some embodiments, the period is any period from about 1 week to about 530 weeks, e.g., about 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks,20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 ​​weeks, 49 weeks, 50 weeks, 51 weeks 1 week, 52 weeks, 53 weeks, 54 weeks, 55 weeks, 56 weeks, 57 weeks, 58 weeks, 59 weeks, 60 weeks, 61 weeks, 62 weeks, 63 weeks, 64 weeks, 65 weeks, 66 weeks, 67 weeks, 68 weeks, 69 weeks, 70 weeks, 71 weeks, 72 weeks, 73 weeks, 74 weeks, 75 weeks, 76 weeks, 77 weeks, 78 weeks, 79 weeks, 80 weeks, 81 weeks, 82 weeks 81 week, 82 week, 83 week, 84 week, 85 week, 86 week, 87 week, 88 week, 89 week, 90 week, 91 week, 92 week, 93 week, 94 week, 95 week, 96 week, 97 week, 98 week, 99 week, 100 week, 101 week, 102 week, 103 week, 104 week, 105 week, 106 week, 107 week, 108 week, 109 week, 110 week, 111 weeks, 112 weeks, 113 weeks, 114 weeks, 115 weeks, 116 weeks, 117 weeks, 118 weeks, 119 weeks, 120 weeks, 121 weeks, 122 weeks, 123 weeks, 124 weeks, 125 weeks, 126 weeks, 127 weeks, 128 weeks, 129 weeks, 130 weeks, 131 weeks, 132 weeks, 133 weeks, 134 weeks, 135 weeks, 136 weeks, 137 weeks, 138 weeks, 139 weeks, 140 weeks, 141 weeks, 142 weeks, 143 weeks, 144 weeks, 145 weeks, 146 weeks, 147 weeks, 148 weeks, 149 weeks, 150 weeks, 151 weeks, 152 weeks, 153 weeks, 154 weeks, 155 weeks, 156 weeks, 157 weeks, 158 weeks, 159 weeks, 160 weeks, 161 week, 162 week, 163 week, 164 week, 165 week, 166 week, 167 week, 168 week, 169 week, 170 week, 171 week, 172 week, 173 week, 174 week, 175 week, 176 week, 177 week, 178 week, 179 week, 180 week, 181 week, 182 week, 183 week, 184 week, 185 week, 186 weeks, 187 weeks, 188 weeks, 189 weeks, 190 weeks, 191 weeks, 192 weeks, 193 weeks, 194 weeks, 195 weeks, 196 weeks, 197 weeks, 198 weeks, 199 weeks, 200 weeks, 201 weeks, 202 weeks, 203 weeks, 204 weeks, 205 weeks, 206 weeks, 207 weeks, 208 weeks, 209 weeks, 210 weeks, 211 weeks, 212 weeks, 213 weeks, 214 weeks, 215 weeks, 216 weeks, 217 weeks, 218 weeks, 219 weeks, 220 weeks, 221 weeks, 222 weeks, 223 weeks, 224 weeks, 225 weeks, 226 weeks, 227 weeks, 228 weeks, 229 weeks, 230 weeks, 231 weeks, 232 weeks, 233 weeks, 234 weeks, 235 weeks,236 weeks, 237 weeks, 238 weeks, 239 weeks, 240 weeks, 241 weeks, 242 weeks, 243 weeks, 244 weeks, 245 weeks, 246 weeks, 247 weeks, 248 weeks, 249 weeks, 250 weeks, 251 weeks, 252 weeks, 253 weeks, 254 weeks, 255 weeks, 256 weeks, 257 weeks, 258 weeks, 259 weeks, 260 weeks, Week 261, Week 262, Week 263, Week 264, Week 265, Week 266, Week 267, Week 268, Week 269, Week 270, Week 271, Week 272, Week 273, Week 274, Week 275, Week 276, Week 277, Week 278, Week 279, Week 280, Week 281, Week 282, Week 283, Week 284, Week 285 Week, 286, 287, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301, 302, 303, 304, 305, 306, 307, 308, 309, 310 Week, 311, 312, 313, 314, 315, 316, 317, 318, 319, 320, 321, 322, 323, 324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334, 335 , 336 weeks, 337 weeks, 338 weeks, 339 weeks, 340 weeks, 341 weeks, 342 weeks, 343 weeks, 344 weeks, 345 weeks, 346 weeks, 347 weeks, 348 weeks, 349 weeks, 350 weeks, 351 weeks, 352 weeks, 353 weeks, 354 weeks, 355 weeks, 356 weeks, 357 weeks, 358 weeks, 359 weeks, 360 weeks , 361 week, 362 week, 363 week, 364 week, 365 week, 366 week, 367 week, 368 week, 369 week, 370 week, 371 week, 372 week, 373 week, 374 week, 375 week, 376 week, 377 week, 378 week, 379 week, 380 week, 381 week, 382 week, 383 week, 384 week, 385 week , 386 weeks, 387 weeks, 388 weeks, 389 weeks, 390 weeks, 391 weeks, 392 weeks, 393 weeks, 394 weeks, 395 weeks, 396 weeks, 397 weeks, 398 weeks, 399 weeks, 400 weeks, 401 weeks, 402 weeks, 403 weeks, 404 weeks, 405 weeks, 406 weeks, 407 weeks, 408 weeks, 409 weeks, 410 weeks , 411 weeks, 412 weeks, 413 weeks, 414 weeks, 415 weeks, 416 weeks, 417 weeks, 418 weeks, 419 weeks, 420 weeks, 421 weeks, 422 weeks, 423 weeks, 424 weeks, 425 weeks, 426 weeks, 427 weeks, 428 weeks, 429 weeks, 430 weeks, 431 weeks, 432 weeks, 433 weeks, 434 weeks, 435 weeks,436 weeks, 437 weeks, 438 weeks, 439 weeks, 440 weeks, 441 weeks, 442 weeks, 443 weeks, 444 weeks, 445 weeks, 446 weeks, 447 weeks, 44 8 weeks, 449 weeks, 450 weeks, 451 weeks, 452 weeks, 453 weeks, 454 weeks, 455 weeks, 456 weeks, 457 weeks, 458 weeks, 459 weeks, 460 weeks , 461 weeks, 462 weeks, 463 weeks, 464 weeks, 465 weeks, 466 weeks, 467 weeks, 468 weeks, 469 weeks, 470 weeks, 471 weeks, 472 weeks, 4 73 weeks, 474 weeks, 475 weeks, 476 weeks, 477 weeks, 478 weeks, 479 weeks, 480 weeks, 481 weeks, 482 weeks, 483 weeks, 484 weeks, 485 weeks, 486, 487, 488, 489, 490, 491, 492, 493, 494, 495, 496, 497, 498, 499, 500, 501, 502, 503, 504, 505, 506, 507, 508, 509, 510, 511, 512, 513, 514, 515, 516, 517, 518, 519, 520, 521, 522, 523, 524, 525, 526, 527, 528, 529, or 530 weeks, or any period in between. In some embodiments, the durations disclosed above are applicable to any two time points in the methods disclosed herein, including performing at least two assays to obtain at least two sets of at least two variables disclosed herein.

[0072] In some embodiments, the method of treating a subject with an ocular disease includes a process of selecting the subject for treatment prior to administering the treatment. In some embodiments, the method includes performing an assay on the subject to obtain at least two variables disclosed herein. In some embodiments, the method includes calculating at least two variables to obtain a composite biomarker. In some embodiments, the method includes determining whether to select the subject for treatment based on the composite biomarker. In some embodiments, the method includes selecting the subject for treatment if the composite biomarker exceeds a threshold. In some embodiments, the method includes not selecting the subject for treatment if the composite biomarker does not exceed a threshold. In some embodiments, the method includes administering the treatment to the subject if the subject is selected for treatment. In some embodiments, the method includes not administering the treatment to the subject if the subject is not selected for treatment.

[0073] In some embodiments, the process of selecting subjects for treatment comprises performing a first assay on the subjects to obtain a first set of at least two variables. In some embodiments, the process of selecting subjects for treatment comprises performing a second assay on the subjects to obtain a second set of at least two variables. In some embodiments, the process of selecting subjects for treatment comprises calculating a first set and a second set of at least two variables to obtain a first composite biomarker and a second composite biomarker. In some embodiments, the process of selecting subjects comprises calculating the first and second sets of at least two variables to obtain a composite biomarker. In some embodiments, the process of selecting subjects for treatment comprises determining whether to select the subject for treatment based on the first composite biomarker and the second composite biomarker. In some embodiments, the process of selecting subjects for treatment comprises determining whether to select the subject for treatment based on a composite biomarker calculated from the first and second sets of at least two variables. In some embodiments, the process of selecting subjects for treatment comprises comparing the first composite biomarker and the second composite biomarker to obtain a difference therebetween. In some embodiments, the process of selecting a subject for treatment comprises selecting the subject for treatment if the difference between the first composite biomarker and the second composite biomarker exceeds a threshold. In some embodiments, the process of selecting a subject for treatment comprises not selecting the subject for treatment if the difference between the first composite biomarker and the second composite biomarker does not exceed a threshold. In some embodiments, the method comprises selecting the subject for treatment if the composite biomarker calculated from the first and second sets of at least two variables exceeds a threshold. In some embodiments, the method comprises not selecting the subject for treatment if the composite biomarker calculated from the first and second sets of at least two variables does not exceed a threshold.In some embodiments, the threshold difference between the first composite biomarker and the second composite biomarker may be the same as or different from the threshold of the composite biomarker calculated from the first and second sets of at least two variables.

[0074] In some embodiments, the process of selecting a subject for treatment of an ocular disease may be combined with one or more steps of the methods disclosed herein, including, but not limited to, a process of determining whether a treatment or dosage of treatment is therapeutically effective for treating a subject based on one or more composite biomarkers calculated from at least two variables disclosed herein, and a process of administering a therapeutically effective dosage of treatment to a subject based on one or more composite biomarkers calculated from at least two variables measured after the subject receives a particular dosage of treatment.

[0075] In some embodiments, one or more steps of the methods disclosed herein are used to monitor the outcome of a treatment for an ocular disease in a subject. In some embodiments, the method comprises determining whether a dosage of a treatment administered to a subject is therapeutically effective for treating the subject by calculating at least two variables of the subject disclosed herein to obtain one or more composite biomarkers. In some embodiments, the method comprises other steps, including, but not limited to, performing one or more assays on the subject to obtain at least two variables, and calculating at least two variables of the subject to obtain one or more composite biomarkers.

[0076] In some embodiments, one or more steps of the methods disclosed herein are used to predict a subject's therapeutic response to a treatment for an ocular disease. In some embodiments, the method includes predicting a subject's therapeutic response to a treatment based on one or more composite biomarkers calculated from at least two variables disclosed herein. In some embodiments, the method includes determining whether a subject is likely to have a therapeutic response to a treatment based on the one or more composite biomarkers. In some embodiments, if the composite biomarkers exceed a threshold, the subject is likely to have a therapeutic response to the treatment. In some embodiments, if the composite biomarkers do not exceed a threshold, the subject is likely to not have a therapeutic response to the treatment. In some embodiments, if the difference between two or more composite biomarkers disclosed herein exceeds a threshold, the subject is likely to have a therapeutic response to the treatment. In some embodiments, if the difference between two or more composite biomarkers disclosed herein does not exceed a threshold, the subject is likely to not have a therapeutic response to the treatment. In some embodiments, the method includes other steps, including but not limited to, performing one or more assays on the subject to obtain at least two variables and calculating at least two variables of the subject to obtain one or more composite biomarkers.

[0077] In some embodiments, one or more steps of the methods disclosed herein are used to determine the dosage of a treatment for a subject with an ocular disease based on one or more composite biomarkers calculated from at least two variables disclosed herein. In some embodiments, the dosage of a treatment can be determined by calculating the composite biomarker or the difference between two or more composite biomarkers. In some embodiments, the dosage of a treatment is correlated with the value of the composite biomarker or the difference between the values ​​of two or more composite biomarkers. In some embodiments, the at least two variables disclosed herein are obtained after administering the treatment to the subject. In some embodiments, the at least two variables disclosed herein are obtained before administering the treatment to the subject.

[0078] In some embodiments, one or more steps of the methods disclosed herein are used to monitor the progression of ocular disease in a subject based on one or more composite biomarkers calculated from at least two variables disclosed herein. In some embodiments, the state of ocular disease can be determined by calculating the composite biomarker or the difference between two or more composite biomarkers. In some embodiments, the state of ocular disease is correlated with the value of the composite biomarker or the difference between the values ​​of two or more composite biomarkers. In some embodiments, the at least two variables disclosed herein are obtained after administering a treatment to the subject. In some embodiments, the at least two variables disclosed herein are obtained before administering a treatment to the subject.

[0079] In some embodiments, the at least two variables include any number of variables suitable for the methods disclosed herein. In some embodiments, the at least two variables include a number of variables ranging from 2 to 50, such as 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50, or any number therebetween. In some embodiments, at least one of the at least two variables disclosed herein relates to one or more selected from the group including visual acuity (VA), a functional vision questionnaire score, and a measurement obtained from an imaging technique disclosed herein. In some embodiments, at least one of the at least two variables is related to changes in ocular structure, changes in ocular pathology, changes in retinal atrophy, changes in macular atrophy, changes in macular degeneration, or a combination thereof. In some examples, the at least two variables include treatment (e.g., type of drug, dose, frequency, administration method), such as treatment with an RBP4 inhibitor. In some examples, the biomarkers provided herein predict therapeutic response to treatment.

[0080] In some embodiments, the functional vision questionnaire score comprises a mean score on the functional vision questionnaire. In some embodiments, the imaging technology comprises one or more imaging technologies disclosed herein. In some embodiments, at least one of the at least two variables relates to one or more selected from the group comprising a change in visual acuity, a change in the functional vision questionnaire score, and a change in a measurement obtained from the imaging technology. In some embodiments, the change in the functional vision questionnaire score comprises a change in the mean score on the functional vision questionnaire. In some embodiments, the imaging technology comprises a technology for assessing ocular structure or visual function. In some embodiments, the imaging technology comprises a technology for detecting or quantifying changes in ocular structure or visual function. In some embodiments, at least one of the at least two variables relates to a change in visual acuity, a change in the mean score on the functional vision questionnaire, and a change in a measurement obtained from an imaging technology for detecting or quantifying changes in optic atrophy or visual function. In some embodiments, the at least two variables relate to a change in visual acuity, a change in the mean score on the functional vision questionnaire, and a change in a measurement obtained from an imaging technology for detecting or quantifying changes in optic atrophy or visual function.

[0081] In some embodiments, at least two variables relate to visual acuity and the mean score of a functional vision questionnaire. In some embodiments, at least two variables relate to a change in visual acuity and a change in the mean score of a functional vision questionnaire. In some embodiments, at least two variables relate to visual acuity and a measurement obtained from an imaging technique for detecting or quantifying a change in optic atrophy or a change in visual function. In some embodiments, at least two variables relate to a change in visual acuity and a change in a measurement obtained from an imaging technique for detecting or quantifying a change in optic atrophy or a change in visual function. In some embodiments, at least two variables relate to the mean score of a functional vision questionnaire and a measurement obtained from an imaging technique for detecting or quantifying a change in optic atrophy or a change in visual function. In some embodiments, at least two variables relate to a change in the mean score of a functional vision questionnaire and a change in a measurement obtained from an imaging technique for detecting or quantifying a change in optic atrophy or a change in visual function. In some embodiments, at least two variables are all related to visual acuity. In some embodiments, at least two variables are all related to a change in visual acuity. In some embodiments, at least two variables are all related to a change in the mean score of a functional vision questionnaire. In some embodiments, at least two variables are all related to a change in the mean score of a functional vision questionnaire. In some embodiments, the at least two variables are all related to measurements obtained from an imaging technique for detecting or quantifying changes in optic atrophy or visual function. In some embodiments, the at least two variables are all related to changes in measurements obtained from an imaging technique for detecting or quantifying changes in optic atrophy or visual function.

[0082] In some embodiments, two of the at least two variables are correlated with each other. In some embodiments, the correlation between two of the at least two variables may be expressed using a correlation coefficient. In some embodiments, a correlation coefficient formula is used to assess the strength of the correlation between two of the at least two variables. In some embodiments, the correlation coefficient formula may generate a value between −1 and 1. In some embodiments, a value of one (1) may indicate a strong positive relationship. In some embodiments, a value of minus one (−1) may indicate a strong negative relationship. In some embodiments, a value of zero (0) may indicate no relationship. In some embodiments, one of the at least two variables is correlated with visual acuity. In some embodiments, one of the at least two variables is correlated with change in visual acuity. In some embodiments, one of the at least two variables is correlated with a score on a functional vision questionnaire. In some embodiments, one of the at least two variables is correlated with a change in functional vision questionnaire score. In some embodiments, one of the at least two variables is correlated with a mean score on a functional vision questionnaire. In some embodiments, one of the at least two variables is correlated with a change in mean score on a functional vision questionnaire. In some embodiments, one of the at least two variables is correlated with a measurement obtained from an imaging technique for detecting or quantifying optic atrophy or changes in visual function. In some embodiments, one of the at least two variables is correlated with a change in a measurement obtained from an imaging technique for detecting or quantifying optic atrophy or changes in visual function. In some embodiments, the at least two variables include two variables of visual acuity that are correlated with each other. In some embodiments, the at least two variables include two variables of change in visual acuity that are correlated with each other. In some embodiments, the at least two variables include two variables of mean scores on a functional vision questionnaire that are correlated with each other. In some embodiments, the at least two variables include two variables of change in mean scores on a functional vision questionnaire that are correlated with each other.In some embodiments, the at least two variables include two variables of measurements obtained from imaging techniques for detecting or quantifying changes in optic nerve atrophy or visual function that are correlated with each other. In some embodiments, the at least two variables include two variables of changes in measurements obtained from imaging techniques for detecting or quantifying changes in optic nerve atrophy or visual function that are correlated with each other. In some embodiments, all of the at least two variables are correlated with visual acuity. In some embodiments, all of the at least two variables are correlated with changes in visual acuity. In some embodiments, all of the at least two variables are correlated with the mean score on a functional vision questionnaire. In some embodiments, all of the at least two variables are correlated with changes in the mean score on a functional vision questionnaire. In some embodiments, all of the at least two variables are correlated with measurements obtained from imaging techniques for detecting or quantifying changes in optic nerve atrophy or visual function. In some embodiments, all of the at least two variables are correlated with changes in measurements obtained from imaging techniques for detecting or quantifying changes in optic nerve atrophy or visual function. In some embodiments, one of the at least two variables correlates with two selected from the group including visual acuity, mean score on a functional vision questionnaire, and a measurement obtained from an imaging technique for detecting or quantifying changes in optic atrophy or visual function. In some embodiments, one of the at least two variables correlates with two selected from the group including change in visual acuity, change in mean score on a functional vision questionnaire, and a change in a measurement obtained from an imaging technique for detecting or quantifying changes in optic atrophy or visual function. In some embodiments, one of the at least two variables correlates with each of visual acuity, mean score on a functional vision questionnaire, and a measurement obtained from an imaging technique for detecting or quantifying changes in optic atrophy or visual function. In some embodiments, one of the at least two variables correlates with each of change in visual acuity, change in mean score on a functional vision questionnaire, and a measurement obtained from an imaging technique for detecting or quantifying changes in optic atrophy or visual function. In some embodiments, one of the at least two variables correlates with the status of an ocular disease.In some embodiments, one of the at least two variables correlates with the progression of the ocular disease.

[0083] In some embodiments, the at least two variables include values ​​obtained from a logarithm of minimum separation threshold angle (logMAR) chart, a Snellen chart, a best corrected visual acuity (BCVA) test, an Early Treatment Diabetic Retinopathy Study (ETDRS) letter test, or a combination thereof. In some embodiments, the at least two variables include two values ​​obtained from a logarithm of minimum separation threshold angle (logMAR) chart, a Snellen chart, a best corrected visual acuity (BCVA) test, and an Early Treatment Diabetic Retinopathy Study (ETDRS) letter test.

[0084] In some embodiments, the at least two variables comprise a score on a functional vision questionnaire that includes one or more questions related to one or more of the following: the subject's confidence in navigating different locations during the day, the subject's confidence in navigating different locations at night, the subject's ability to recognize people, the subject's ability to participate in sports, the subject's ability to obtain information, the subject's ability for social interaction, and the subject's ability for work performance. In some embodiments, the at least two variables comprise a score on a functional vision questionnaire that includes one or more questions related to one or more of the following: the subject's confidence in navigating different locations during the day or night, the subject's ability to recognize people, participate in sports, or obtain information, and the subject's ability for social interaction or work performance. In some embodiments, each of the one or more questions can be scored for the subject. In some embodiments, an average score can be obtained from two or more questions on a vision questionnaire test, two or more functional vision questionnaires that include one or more questions, or both. In some embodiments, the score scale for the vision questionnaire can be any range between two numbers. In some embodiments, the score scale can be 0 to 4. In some embodiments, a response of "NEVER" to a question is assigned a score according to the score scale. In some embodiments, an answer of "ALMOST NEVER" to a question is assigned a score according to a scoring scale. In some embodiments, an answer of "SOMETIMES" to a question is assigned a score according to a scoring scale. In some embodiments, an answer of "ALMOST ALWAYS" to a question is assigned a score according to a scoring scale. In some embodiments, an answer of "ALWAYS" to a question is assigned a score according to a scoring scale. In some embodiments, answers of "NEVER," "ALMOST NEVER," "SOMETIMES," "ALMOST ALWAYS," and "ALWAYS" to a question are assigned scores of 0, 1, 2, 3, and 4, respectively, according to a 0-4 scoring scale.In some embodiments, answers to questions "NEVER," "ALMOST NEVER," "SOMETIMES," "ALMOST ALWAYS," and "ALWAYS" are assigned scores of 4, 3, 2, 1, and 0, respectively, according to a scoring scale of 0 to 4. In some embodiments, answers to questions "NEVER," "ALMOST NEVER," "SOMETIMES," "ALMOST ALWAYS," and "ALWAYS" are assigned scores according to an arbitrary scale.

[0085] In some embodiments, the at least two variables include two or more values ​​obtained from microperimetry (MP), perimetry, or both. In some embodiments, MP includes measuring a spatial map of the subject's retinal sensitivity. In some embodiments, MP includes measuring the subject's mean retinal sensitivity, its change, or both. In some embodiments, the at least two variables include two or more values ​​obtained from two or more selected from the group including fundus photography, fundus angiography (FA), fundus autofluorescence (FAF), spectral-domain optical coherence tomography (SD-OCT), quantitative autofluorescence (qAF), infrared (IR) imaging, optical coherence tomography-angiography (OCT-A), and wide-field imaging. In some embodiments, the at least two variables include at least two values ​​obtained from one of the group including fundus photography, fundus angiography (FA), fundus autofluorescence (FAF), spectral-domain optical coherence tomography (SD-OCT), quantitative autofluorescence (qAF), infrared (IR) imaging, optical coherence tomography-angiography (OCT-A), and wide-field imaging. In some embodiments, the at least two variables include two or more values ​​selected from the group including suspicious autofluorescence decreased area (QDAF), definite autofluorescence decreased area (DDAF), autofluorescence decreased area (DAF), retinal thickness, ellipsoid zone (EZ) defect width, central subfield retinal thickness (CST), outer subfield retinal thickness (OST), and middle subfield retinal thickness (MST). In some embodiments, the at least two variables comprise two or more values ​​selected from the group consisting of change in suspicious area of ​​decreased autofluorescence (QDAF), change in definite area of ​​decreased autofluorescence (DDAF), change in area of ​​decreased autofluorescence (DAF), change in retinal thickness, change in ellipsoid zone (EZ) defect width, change in central subfield retinal thickness (CST), change in outer subfield retinal thickness (OST), and change in middle subfield retinal thickness (MST). In some embodiments, the at least two variables comprise DAF and EZ defect width. In some embodiments, the at least two variables comprise change in DAF and change in EZ defect width.In some embodiments, the area of ​​decreased autofluorescence (DAF) includes a suspicious area of ​​decreased autofluorescence (QDAF) and a definite area of ​​decreased autofluorescence (DDAF). In some embodiments, the change in the area of ​​decreased autofluorescence (DAF) includes a change in the suspicious area of ​​decreased autofluorescence (QDAF) and a change in the definite area of ​​decreased autofluorescence (DDAF). In some embodiments, the at least two variables include two or more selected from the group including visual acuity, QDAF, DAF, and EZ defect width. In some embodiments, the at least two variables include two or more selected from the group including a change in visual acuity, a change in QDAF, a change in DAF, and a change in EZ defect width. In some embodiments, the at least two variables include visual acuity, QDAF, DAF, and EZ defect width. In some embodiments, the at least two variables include a change in visual acuity, a change in QDAF, a change in DAF, and a change in EZ defect width. In some embodiments, the EZ defect width correlates with visual acuity. In some embodiments, the change in EZ defect width correlates with a change in visual acuity. In some embodiments, EZ defect width is correlated with QDAF. In some embodiments, a change in EZ defect width is correlated with a change in QDAF. In some embodiments, EZ defect width is correlated with DAF. In some embodiments, a change in EZ defect width is correlated with a change in DAF. In some embodiments, visual acuity is correlated with QDAF. In some embodiments, QDAF comprises a measure of autofluorescence. In some embodiments, a change in visual acuity is correlated with a change in QDAF. In some embodiments, a change in QDAF comprises a measure of autofluorescence.

[0086] In some embodiments, EZ defect width correlates with visual acuity, QDAF, and DAF. In some embodiments, changes in EZ defect width correlate with changes in visual acuity, changes in QDAF, and changes in DAF. In some embodiments, EZ defect width correlates with visual acuity, QDAF, and DAF, with a correlation coefficient greater than about 0.8 and a p-value less than about 0.05. In some embodiments, changes in EZ defect width correlate with changes in visual acuity, changes in QDAF, and changes in DAF, with a correlation coefficient greater than about 0.8 and a p-value less than about 0.05. In some embodiments, visual acuity correlates with EZ defect width and QDAF. In some embodiments, changes in visual acuity correlate with changes in EZ defect width and QDAF. In some embodiments, visual acuity correlates with EZ defect width and QDAF with a p-value less than about 0.05. In some embodiments, changes in visual acuity correlate with changes in EZ defect width and QDAF with a p-value less than about 0.05. In some embodiments, at least two variables are obtained from both the right eye and the left eye of a subject. In some embodiments, at least two variables are obtained from at least two subjects with different genders, ethnicities, ages, or combinations thereof. In some embodiments, at least two variables are obtained from clinical trials. In some embodiments, at least two variables are obtained from at least two stages of clinical trials.

[0087] In some embodiments, one or more composite biomarkers disclosed herein are used as surrogate biomarkers or endpoints to detect or predict improvement in visual function. In some embodiments, the methods disclosed herein are used to detect and / or predict changes in visual function in clinical practice or clinical trials. In some embodiments, the methods disclosed herein are used to detect and / or predict visual improvement in clinical practice or clinical trials. In some embodiments, the methods disclosed herein are used to develop algorithms or software. In some embodiments, the methods disclosed herein may be applied to medical devices, virtual reality goggles, the Metaverse, video games, or combinations thereof.

[0088] In some embodiments, the methods disclosed herein can be applied to detect and measure multidimensional visual function. In some embodiments, the multidimensional visual function includes spatial awareness, eye-body coordination, or visuomotor function. In some embodiments, the methods disclosed herein can be applied to detect and measure vision loss or improvement as a multidimensional or multifactorial measure. In some embodiments, the methods disclosed herein can be applied to develop algorithms, software, or scoring systems for diagnosing ocular diseases, detecting improvement or loss of visual function, or detecting treatment response during clinical trials.

[0089] In some embodiments, the methods disclosed herein may be applied to develop predictive models related to the variables disclosed herein. In some embodiments, the predictive models may be constructed using a link function based on the magnitude of the variance of each response variable as a function of its predicted value. In some embodiments, the predictive model comprises three components. In some embodiments, the three components are the regressors (η i) In some embodiments, the three components include a predictor based on a function of the response variable Y given the values ​​of the explanatory variables in the model. i In some embodiments, the three components include a model structure that best fits the conditional distribution of the response variable μ i =E(Y i ) is calculated by the predictor g(μ i )=η i =α+β1X i1 +β2X i2 +···+β k X ik In some embodiments, a predictive model may be constructed using visual acuity (VA) and EZ width as follows: VA = -0.0896 EZ WIDTH + 0.0701, Z-score = -2.211, P-value = 0.027, and CI 95% [-0.169, -0.010]. In some embodiments, another univariate or multivariate model may be constructed using visual acuity and EZ width.

[0090] In some embodiments, the methods disclosed herein are used for any ocular disease. In some embodiments, the ocular disease comprises one or more selected from the group including maculopathy, retinopathy, retinal atrophy, macular atrophy, retinal degeneration, macular degeneration, age-related macular degeneration (AMD), RP (retinitis pigmentosa), ABCA4 gene mutation, Stargardt disease (STGD), and STGD1. In some embodiments, the ocular disease comprises retinal degeneration. In some embodiments, the ocular disease comprises macular degeneration. In some embodiments, the ocular disease comprises AMD. In some embodiments, the ocular disease comprises STGD. In some embodiments, the ocular disease comprises STGD1.

[0091] In some embodiments, ocular diseases can be diagnosed based on one or more factors disclosed herein. In some embodiments, a sample from a subject with ocular disease can have an expression level of retinol binding protein 4 (RBP4) at least at a threshold level. In some embodiments, the threshold level of RBP4 can be any value for diagnosing macular degenerative diseases disclosed herein. In some embodiments, the threshold level of RBP4 is at least 25 μg / mL. In some embodiments, the threshold level of RBP4 is at least 30 μg / mL. In some embodiments, the threshold level of RBP4 is at least 35 μg / mL. In some embodiments, the threshold level is from about 25 μg / mL to about 100 μg / mL. In some embodiments, the threshold value is about 25 μg / mL to about 30 μg / mL, about 25 μg / mL to about 35 μg / mL, about 25 μg / mL to about 40 μg / mL, about 25 μg / mL to about 50 μg / mL, about μg / mL to about μg / mL, about μg / mL to about μg / mL, about μg / mL to about μg / mL, about 25 μg / mL to about 80 μg / mL, about 25 μg / mL to about 90 μg / mL, about 25 μg / mL to about 100 μg / mL, about 30 μg / mL to about 35 μg / mL, about 30 μg / mL to about 40 μg / mL, or about 30 μg / mL to about 50 μg / mL , about 30 μg / mL to about 60 μg / mL, about 30 μg / mL to about 70 μg / mL, about 30 μg / mL to about 80 μg / mL, about 30 μg / mL to about 90 μg / mL, about 30 μg / mL to about 100 μg / mL, about 35 μg / mL to about 40 μg / mL, about 35 μg / mL to about 50 μg / mL, about 35 μg / mL to about 60 μg / mL, about 35 μg / mL to about 70 μg / mL, about 35 μg / mL to about 80 μg / mL, about 35 μg / mL to about 90 μg / mL, or about 35 μg / mL to about 100 μg / mL. In some embodiments, the threshold is about 25 μg / mL, about 30 μg / mL, or about 35 μg / mL. In some embodiments, the threshold level is at least about 25 μg / mL, about 30 μg / mL, or about 35 μg / mL. In some embodiments, the threshold level of RBP4 disclosed herein may be applicable to the ocular diseases disclosed herein. In some embodiments, the threshold level of RBP4 disclosed herein may be applicable to AMD, STGD, or STGD1.In some embodiments, the threshold is at most about 30 μg / mL, about 35 μg / mL, about 40 μg / mL, about 50 μg / mL, about 60 μg / mL, about 70 μg / mL, about 80 μg / mL, about 90 μg / mL, or about 100 μg / mL. In some embodiments, the level of RBP4 in a subject can be assessed by an assay. Any suitable assay for measuring the level of RBP4 can be used (e.g., an antibody assay, a mass spectrometry-based assay (e.g., LC / MS), a liquid chromatography assay (e.g., HPLC, UPLC), etc.). In some embodiments, the assay comprises an antibody assay, an electrophoresis assay, an immunoassay, a radioimmunoassay, a chromatography assay, a mass spectrometry assay, a microarray-based detection assay, a polymerase chain reaction assay, a sequencing assay, an immunohistochemistry assay, or any combination thereof. In some embodiments, the assay comprises an antibody assay. In some embodiments, the antibody assay comprises an enzyme-linked immunosorbent assay (ELISA).

[0092] In some embodiments, the RBP4 threshold may vary based on various individual characteristics, including, but not limited to, demographic data, sex, age, medical history, history of diagnosed eye disease, body mass index (BMI), height, weight, and general health conditions, including obesity, hyperlipidemia, hyperglycemia, hypertension, diabetes, erythritis, cardiovascular disease, or non-alcoholic fatty liver disease.

[0093] In some embodiments, a diagnosis of ocular disease is made when the level of RBP4 is above a threshold. In some embodiments, a risk score is calculated when the level of RBP4 is above a threshold.

[0094] In some embodiments, if the level of RBP4 is above a threshold, a treatment is administered. In some embodiments, a treatment is administered to reduce the level of RBP4. In some embodiments, the treatment comprises administering a pharmaceutical composition to the individual. In some embodiments, the treatment comprises administering a pharmaceutical compound to the individual. In some embodiments, the pharmaceutical composition comprises an RBP4 inhibitor. The RBP4 inhibitor can be any of the RBP4 inhibitors provided herein.

[0095] In some embodiments, a sample from a subject with an ocular disease may have at least a threshold vitamin A expression level. In some embodiments, the threshold vitamin A level is at least about 150 μg / mL. In some embodiments, the threshold vitamin A level is at least about 175 μg / mL. In some embodiments, the threshold vitamin A level is at least about 200 μg / mL. In some embodiments, the threshold vitamin A level is at least about 220 μg / mL. In some embodiments, the threshold vitamin A level is at least about 221 μg / mL. In some embodiments, the threshold vitamin A level is at least about 222 μg / mL. In some embodiments, the threshold vitamin A level is at least about 223 μg / mL. In some embodiments, the threshold vitamin A level is at least about 224 μg / mL. In some embodiments, the threshold vitamin A level is at least about 225 μg / mL. In some embodiments, the threshold vitamin A level is at least about 250 μg / mL. In some embodiments, the threshold level of vitamin A is at least about 300 μg / mL. In some embodiments, the threshold level of vitamin A is at least about 350 μg / mL. In some embodiments, the threshold level of vitamin A is at least about 390 μg / mL. In some embodiments, the threshold level of vitamin A is at least about 391 μg / mL. In some embodiments, the threshold level of vitamin A is at least about 392 μg / mL. In some embodiments, the threshold level of vitamin A is at least about 393 μg / mL. In some embodiments, the threshold level of vitamin A is at least about 394 μg / mL. In some embodiments, the threshold level of vitamin A is at least about 395 μg / mL. In some embodiments, the threshold level of vitamin A is between about 150 ng / mL and about 500 μg / mL.In some embodiments, the threshold level of vitamin A is about 150 ng / mL to about 175 ng / mL, about 150 ng / mL to about 200 ng / mL, about 150 ng / mL to about 225 ng / mL, about 150 ng / mL to about 250 ng / mL, about 150 ng / mL to about 300 ng / mL, about 150 ng / mL to about 350 ng / mL, about 150 ng / mL to about 400 ng / mL, about 150 ng / mL to about 450 ng / mL, about 150 ng / mL to about 500 ng / mL, about 175 ng / mL to about 2 ... mL~about 225ng / mL, about 175ng / mL~about 250ng / mL, about 175ng / mL~about 300ng / mL, about 175ng / mL~about 350ng / mL, about 175ng / mL~about 400ng / mL, about 175ng / mL~about 450ng / mL, about 17 5ng / mL to about 500ng / mL, about 200ng / mL to about 225ng / mL, about 200ng / mL to about 250ng / mL, about 200ng / mL to about 300ng / mL, about 200ng / mL to about 350ng / mL, about 200ng / mL to about 400ng / mL, Approximately 200ng / mL to approximately 450ng / mL, approximately 200ng / mL to approximately 500ng / mL, approximately 225ng / mL to approximately 250ng / mL, approximately 225ng / mL to approximately 300ng / mL, approximately 225ng / mL to approximately 350ng / mL, approximately 225ng / mL to approximately 400ng / mL, about 225ng / mL to about 450ng / mL, about 225ng / mL to about 500ng / mL, about 250ng / mL to about 300ng / mL, about 250ng / mL to about 350ng / mL, about 250ng / mL to about 400ng / mL, about 250ng / mL to about 45 0 ng / mL, about 250 ng / mL to about 500 ng / mL, about 300 ng / mL to about 350 ng / mL, about 300 ng / mL to about 400 ng / mL, about 300 ng / mL to about 450 ng / mL, about 300 ng / mL to about 500 ng / mL, about 350 ng / mL to about 400 ng / mL, about 350 ng / mL to about 450 ng / mL, about 350 ng / mL to about 500 ng / mL, about 400 ng / mL to about 450 ng / mL, about 400 ng / mL to about 500 ng / mL, or about 450 ng / mL to about 500 μg / mL.In some embodiments, the threshold level of vitamin A is about 150 ng / mL, about 175 ng / mL, about 200 ng / mL, about 225 ng / mL, about 250 ng / mL, about 300 ng / mL, about 350 ng / mL, about 400 ng / mL, about 450 ng / mL, or about 500 μg / mL. In some embodiments, the threshold level of vitamin A is at least about 150 ng / mL, about 175 ng / mL, about 200 ng / mL, about 225 ng / mL, about 250 ng / mL, about 300 ng / mL, about 350 ng / mL, about 400 ng / mL, or about 450 μg / mL. In some embodiments, the vitamin A threshold level is at most about 175ng / mL, about 200ng / mL, about 225ng / mL, about 250ng / mL, about 300ng / mL, about 350ng / mL, about 400ng / mL, about 450ng / mL, or about 500μg / mL.In some embodiments, the vitamin A threshold level disclosed herein can be applicable to the eye diseases disclosed herein.In some embodiments, the vitamin A threshold level disclosed herein can be applicable to AMD, STGD, or STGD1.

[0096] In some embodiments, the threshold value may vary based on various characteristics of an individual, including, but not limited to, demographic data, sex, age, medical history, history of diagnosed eye disease, body mass index (BMI), height, weight, and general health conditions, including obesity, hyperlipidemia, hyperglycemia, hypertension, diabetes, erythritis, cardiovascular disease, or non-alcoholic fatty liver disease.

[0097] In some embodiments, the threshold level of vitamin A depends on the age of the individual. In some embodiments, the threshold level of vitamin A is lower for adolescents (e.g., individuals aged 12-17 years) than for adults (e.g., individuals aged 18 years or older). In some embodiments, the threshold level of vitamin A for adolescents is at least about 150 ng / mL, at least about 175 ng / mL, at least about 200 ng / mL, at least about 210 ng / mL, at least about 220 ng / mL, at least about 221 ng / mL, at least about 222 ng / mL, at least about 223 ng / mL, at least about 224 ng / mL, at least about 225 ng / mL, at least about 230 ng / mL, or at least about 250 μg / mL. In some embodiments, the threshold for adults is at least about 300 ng / mL, at least about 325 ng / mL, at least about 350 ng / mL, at least about 375 ng / mL, at least about 380 ng / mL, at least about 385 ng / mL, at least about 390 ng / mL, at least about 391 ng / mL, at least about 392 ng / mL, at least about 393 ng / mL, at least about 394 ng / mL, at least about 395 ng / mL, or at least about 400 μg / mL.

[0098] In some embodiments, a diagnosis of eye disease is made when the level of vitamin A is above a threshold. In some embodiments, a risk score is calculated when the level of vitamin A is above a threshold.

[0099] In some embodiments, treatment is administered when the vitamin A level is above a threshold. In some embodiments, therapy is administered to reduce the vitamin A level. In some embodiments, the therapy comprises administering a pharmaceutical composition to the individual. In some embodiments, the therapy comprises administering a pharmaceutical compound to the individual. In some embodiments, the pharmaceutical composition comprises an RBP4 inhibitor. The RBP4 inhibitor can be any of the RBP4 inhibitors provided herein.

[0100] In some embodiments, the level of vitamin A in an individual is assessed by an assay. Any suitable assay for measuring vitamin A levels can be used (e.g., an antibody assay, a mass spectrometry-based assay (e.g., LC / MS), a liquid chromatography assay (e.g., HPLC, UPLC), etc.). In some embodiments, the assay comprises an antibody assay, an electrophoresis assay, an immunoassay, a radioimmunoassay, a chromatography assay, a mass spectrometry assay, a microarray-based detection assay, a polymerase chain reaction assay, a sequencing assay, an immunohistochemistry assay, or any combination thereof. In some embodiments, the assay comprises an antibody assay. In some embodiments, the antibody assay comprises an enzyme-linked immunosorbent assay (ELISA). In some embodiments, the assay is a chromatography assay. In some embodiments, the assay comprises high-performance liquid chromatography (HPLC), ultra-performance liquid chromatography (UPLC), or liquid chromatography / mass spectrometry (LC-MS).

[0101] In some embodiments, the sample comprises a blood sample from a subject. The blood sample may be further processed, such as to remove impurities or to retain serum and / or plasma. In some embodiments, the sample is a plasma or serum sample. In some embodiments, the sample is a plasma sample. In some embodiments, the sample is a serum sample. In some embodiments, the level is measured from plasma or serum derived from the blood sample. In some embodiments, the level is measured from plasma derived from the blood sample. In some embodiments, the level is measured from serum derived from the blood sample.

[0102] In some embodiments, the methods disclosed herein include assessing whether a subject has an eye disease disclosed herein or whether they are likely to develop an eye disease disclosed herein, such as AMD or STGD. In some embodiments, the methods include determining the presence or absence of one or more genomic variants by assay. In some embodiments, the one or more genomic variants include at least one of rs4147863, rs2275029, rs1800739, rs4147857, rs4147856, rs1801555, or rs1801574. In some embodiments, the methods include calculating a risk score for the eye disease using the presence or absence of the one or more genomic variants. In some embodiments, the methods include diagnosing the eye disease using the presence or absence of the one or more genomic variants. In some embodiments, the methods include determining the presence or absence of one or more genomic variants by assay. In some embodiments, the one or more genomic variants include at least one of rs4147863, rs2275029, rs1800739, rs4147857, rs4147856, rs1801555, or rs1801574. In some embodiments, the one or more genomic variants include at least two of rs4147863, rs2275029, rs1800739, rs4147857, rs4147856, rs1801555, or rs1801574. In some embodiments, the one or more genomic variants include at least three of rs4147863, rs2275029, rs1800739, rs4147857, rs4147856, rs1801555, or rs1801574. In some embodiments, the one or more genomic variants include at least four of rs4147863, rs2275029, rs1800739, rs4147857, rs4147856, rs1801555, or rs1801574. In some embodiments, the one or more genomic variants include at least five of rs4147863, rs2275029, rs1800739, rs4147857, rs4147856, rs1801555, or rs1801574.In some embodiments, the one or more genomic variants include at least six of rs4147863, rs2275029, rs1800739, rs4147857, rs4147856, rs1801555, or rs1801574. In some embodiments, the one or more genomic variants include each of rs4147863, rs2275029, rs1800739, rs4147857, rs4147856, rs1801555, or rs1801574. In some embodiments, the one or more genomic variants include rs4147863. In some embodiments, the one or more genomic variants include rs2275029. In some embodiments, the one or more genomic variants include rs1800739. In some embodiments, the one or more genomic variants include rs4147857. In some embodiments, the one or more genomic variants comprise rs4147856. In some embodiments, the one or more genomic variants comprise rs1801555. In some embodiments, the one or more genomic variants comprise rs1801574. In some embodiments, the one or more genomic variants comprise rs3747961, rs6666652, rs1800717, rs763108716, rs185601596, rs17110761, rs61748519, rs1801359, rs145766145, rs76258939, rs200551567, rs7547651 rs1762114, rs55860151, rs1800549, rs3112831, rs4147830, rs2297634, or rs4847281.In some embodiments, the one or more genomic variants are rs3747961, rs6666652, rs1800717, rs763108716, rs185601596, rs17110761, rs61748519, rs1801359, rs145766145, rs76258939, rs200551567, rs7547651 In some embodiments, the one or more genomic variants comprise at least five of rs1800549, rs3112831, rs4147830, rs2297634, or rs4847281. In some embodiments, the one or more genomic variants comprise at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 genomic variants. In some embodiments, the one or more genomic variants comprise at least one genomic variant from Table A. In some embodiments, the one or more genomic variants comprise at least five genomic variants from Table A. In some embodiments, the one or more genomic variants comprise at least 7 genomic variants from Table A. In some embodiments, the one or more genomic variants comprise at least 10 genomic variants from Table A. In some embodiments, the one or more genomic variants comprise at least 15 genomic variants from Table A. In some embodiments, the one or more genomic variants comprise at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 genomic variants from Table A.

[0103] In some embodiments, the treatment of ocular diseases disclosed herein comprises a pharmaceutical composition comprising an RBP4 inhibitor or a compound that reduces blood RBP4 levels in an individual. Further provided herein is a pharmaceutical composition comprising a compound of formula (I):

[0104] [ka] or a pharmaceutically acceptable salt thereof, In the formula, R A 1 , R A 2 , R A 3 , R A 4 , and R A 5 are each independently H, halogen, CF, or C-C alkyl; R A 1 , R A 2 , R A 3 , R A 4 , and R A 5 At least two of the groups are other than H, and R A 6 is H, OH, or a halogen, A A is the structure

[0105] [ka] and wherein α, β, χ, and δ are each independently absent or present, and when present, each is a bond; X is C or N; Z1 is N; and Z2 is N or NR A 9 and R A 9 is H, C1-C4 alkyl, or oxetane, and B A is a substituted or unsubstituted 5-, 6-, or 7-membered ring structure.

[0106] Further, as used herein, a compound may have the structure:

[0107] [ka] or a pharmaceutically acceptable salt thereof.

[0108] Further, as used herein, a compound may have the structure:

[0109] [ka] or a pharmaceutically acceptable salt thereof.

[0110] Further provided herein is a pharmaceutical composition comprising a compound of formula (II)

[0111] [ka] or a pharmaceutically acceptable salt thereof, In the formula, ring A B is an optionally further substituted benzene, and R B 1 is an optionally substituted branched C3-C6 alkyl group, and X B 1 is O, S, SO, SO2, or NH, and X B 2 is a bond or a C1-C3 alkylene group, and ring B B is azetidine or piperidine, and X B 3 is CO or SO2, and R B 2 is an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an optionally substituted hydroxy group, an optionally substituted mercapto group, a cyano group, a nitro group, an acyl group, or a halogen atom.

[0112] Further provided herein is a compound, such as 4-(3-(2-tert-butylphenoxy)azetidin-1-yl)-4-oxobutanoic acid, 3-{3-[(2-tert-butyl-4-fluorophenoxy)methyl]azetidin-1-yl}-3-oxopropanoic acid, 2-{[3-(2-tert-butyl-4-chlorophenoxy)azetidin-1-yl]carbonyl}pyridine, 4-[3-(2-tert-butyl-4-chlorophenoxy)azetidin-1-yl]-4-oxobutanoic acid, {3-[(2-tert-butyl-4-chlorophenoxy)methyl]azetidin-1-yl}(oxo) acetic acid, {3-[(2-tert-butylphenoxy)methyl]azetidin-1-yl}(oxo)acetic acid, 3-{3-[(2-tert-butylphenoxy)methyl]azetidin-1-yl}-3-oxopropanoic acid, {4-[(2-tert-butyl-4-chlorophenoxy)methyl]piperidin-1-yl}(oxo)acetic acid, [4-(2-tert-butylphenoxy)piperidin-1-yl](oxo)acetic acid, or {4-[(2-tert-butylphenoxy)methyl]piperidin-1-yl}(oxo)acetic acid, or a pharmaceutically acceptable salt thereof.

[0113] Further provided herein is a pharmaceutical composition comprising a compound of formula (III)

[0114] [ka] or a pharmaceutically acceptable salt thereof, In the formula, ring A C is a benzene ring optionally substituted with 1 to 3 substituents selected from the group consisting of (a) halogen atoms, and (b) C alkyl groups, and ring B C is a piperazine ring optionally substituted with 1 to 3 substituents selected from the group consisting of (a) a halogen atom, (b) a C1-C6 alkyl group optionally substituted with 1 to 3 halogen atoms, and (c) a C1-C6 alkoxy group optionally substituted with 1 to 3 halogen atoms, and R C(1) optionally substituted C1-C 10 alkyl group, (2) optionally substituted C-C 14 (1) an optionally substituted aryl group, (2) an optionally substituted 5- or 6-membered aromatic heterocyclic group, (3) an optionally substituted amino group, (4) an optionally substituted carboxy group, or (5) an optionally substituted carbamoyl group, or a pharmaceutically acceptable salt thereof.

[0115] Further provided herein are methods wherein the compound is N-{[4-(2-tert-butylphenyl)piperazin-1-yl]carbonyl}glycine, 3-[4-(2-tert-butylphenyl)piperazin-1-yl]-3-oxopropanoic acid, [4-(2-tert-butyl-4-chlorophenyl)piperazin-1-yl](oxo)acetic acid, 5-{2-[4-(2-tert-butylphenyl)piperazin-1-yl]-2-oxoethyl}imidazolidine-2,4-dione, [(5-{[4-(2-tert-butylphenyl)piperazin-1-yl]carbonyl}isoxazol-3-yl)oxy]acetic acid, or a pharmaceutically acceptable salt thereof.

[0116] Further provided herein is a pharmaceutical composition comprising a compound of formula (IV)

[0117] [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, Ring A D is a 5-membered non-aromatic heterocycle optionally further substituted with one oxo group, and ring B D is a benzene ring optionally further substituted with 1 to 4 substituents, and XD is O, CHO, OCH, CH, (CH), S, CHS, SCH, S(O), CHS(O), S(O)CH, S(O), CHS(O), or S(O)CH.

[0118] Further provided herein are methods wherein the compound is ({(3S)-1-[3,5-bis(trifluoromethyl)phenyl]pyrrolidin-3-yl}oxy)acetic acid, ({1-[4-chloro-3-(trifluoromethyl)phenyl]pyrrolidin-3-yl}sulfanyl)acetic acid, 3-{(2R,5S)-5-[3,5-bis(trifluoromethyl)phenyl]tetrahydrofuran-2-yl}propanoic acid, or a pharmaceutically acceptable salt thereof.

[0119] Further provided herein is a pharmaceutical composition comprising a compound of formula (V):

[0120] [ka] or a pharmaceutically acceptable salt thereof, wherein ring A E is a pyrazole ring, a pyridine ring, an oxazole ring, an imidazole ring, or a pyrimidine ring, and X E is S, optionally substituted alkylene, or O, and R E is a hydrogen atom or a C1-C6 alkyl group.

[0121] Further provided herein is a method, wherein the compound is ((4-(3,5-bis(trifluoromethyl)phenyl)-1,3-oxazol-2-yl)sulfanyl)acetic acid, ethyl ((6-(3,5-bis(trifluoromethyl)phenyl)-pyridin-3-yl)sulfanyl)acetic acid, ((6-(3,5-bis(trifluoromethyl)-phenyl)pyridin-3-yl)sulfanyl)acetic acid, 3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-pyrazol-1-yl)butanoic acid, or 3-{3-[3,5-bis(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}propanoic acid (also known as STG-001).

[0122] In some embodiments, treatments containing the compounds described herein are administered for prophylactic and / or therapeutic treatments. In certain therapeutic applications, treatments are administered to patients already suffering from a disease or condition in an amount sufficient to cure or at least partially halt at least one symptom of the disease or condition. Amounts effective for this use will depend on the severity and course of the disease or condition, previous treatments, the patient's health status, weight, and response to the drugs, and the judgment of the treating physician. Therapeutically effective amounts are optionally determined by methods including, but not limited to, dose escalation and / or dose ranging clinical trials.

[0123] In prophylactic applications, compositions containing the compounds described herein are administered to a patient susceptible to or otherwise at risk of a particular disease, disorder, or condition. Such an amount is defined to be a "prophylactically effective amount or dose." For this use, the precise amount also depends on the patient's health, weight, and the like. When used in a patient, the effective amount for this use will depend on the severity and course of the disease, disorder, or condition, previous treatments, the patient's health status and response to the drugs, and the judgment of the treating physician. In one aspect, prophylactic treatment involves administering to a mammal a pharmaceutical composition containing a compound described herein, or a pharmaceutically acceptable salt thereof, to prevent the recurrence of symptoms of the disease or condition when the mammal has previously experienced at least one symptom of the disease being treated and is currently in remission.

[0124] In certain embodiments where the patient's disease does not improve, at the physician's discretion, administration of the compound is administered chronically, i.e., for an extended period of time, including for the life of the patient, to improve or otherwise control or limit the symptoms of the patient's disease or disorder.

[0125] Oral doses typically range from about 1.0 mg to about 1000 mg, one to four times per day or more. However, in general, doses used for adult human treatment typically range from 0.01 mg to 5000 mg per day. In one aspect, doses used for adult human treatment are from about 1 mg to about 1000 mg per day. In one embodiment, the desired dose is conveniently administered simultaneously in a single or divided dose, or as subdoses at appropriate intervals, for example, two, three, four or more times per day.

[0126] In one embodiment, a suitable daily dosage for a compound described herein, or a pharmaceutically acceptable salt thereof, is about 0.01 to about 50 mg / kg of body weight. In some embodiments, the daily dosage or amount of active in a dosage form will be lower or higher than the ranges set forth herein, depending on many variables related to the particular treatment regime. In various embodiments, the daily dose and unit dose will vary depending on numerous variables, including, but not limited to, the activity of the compound used, the disease or condition being treated, the mode of administration, the requirements of the individual subject, the severity of the disease or condition being treated, and the judgment of the practitioner.

[0127] Once improvement of the patient's disease occurs based on the clinical evaluation methods described herein, a maintenance dose is administered as needed. Thereafter, in certain embodiments, the dosage or frequency of administration, or both, is reduced as a function of symptoms to a level at which the improved disease, disorder, or condition is maintained. However, in certain embodiments, the patient requires intermittent treatment on a long-term basis upon recurrence of symptoms.

[0128] Toxicity and therapeutic efficacy of such treatment regimens are determined by standard pharmaceutical procedures in cell cultures or experimental animals, including, but not limited to, determination of the LD50 and ED50. The dose ratio between toxic and therapeutic effects is the therapeutic index, which is expressed as the ratio between LD50 and ED50. In certain embodiments, data obtained from cell culture assays and animal studies are used in formulating a therapeutically effective daily dosage range and / or a therapeutically effective unit dosage amount for use in mammals, including humans. In some embodiments, the daily dosage of the compounds described herein lies within a range of circulating concentrations that include the ED50 with minimal toxicity. In certain embodiments, the daily dose range and / or unit dose will vary within this range depending on the dosage form employed and the route of administration utilized.

[0129] In any of the aforementioned aspects, there are further embodiments in which an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof is (a) administered systemically to a mammal, and / or (b) administered orally to a mammal, and / or (c) administered intravenously to a mammal, and / or (d) administered by injection to a mammal, and / or (e) administered locally to a mammal, and / or (f) administered non-systemically or locally to a mammal. In some embodiments, an RBP4 inhibitor, a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, is administered orally or parenterally to a subject in need thereof. Parenteral administration, as used herein, includes intravenous administration, intraarterial administration, intraperitoneal administration, intrathecal administration, intraventricular administration, intraurethral administration, intrasternal administration, intracranial administration, intramuscular administration, intrasynovial administration, intravesical administration, and subcutaneous administration. In some embodiments, the RBP4 inhibitor, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, is administered orally or intravenously to a subject in need thereof. In some embodiments, the RBP4 inhibitor, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, is administered orally to a subject in need thereof. In some embodiments, the RBP4 inhibitor, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, is administered intravenously to a subject in need thereof.

[0130] In any of the above aspects, there are further embodiments that comprise a single administration of an effective amount of the compound, including further embodiments where (i) the compound is administered once a day, or (ii) the compound is administered to a mammal multiple times throughout the day, for example, two, three, four or more times daily. In some embodiments, the RBP4 inhibitor compounds described herein are administered daily, every other day, every other day three times a week, every two weeks, every three weeks, every four weeks, every five weeks, every three days, every four days, every five days, every six days, every week, every other week three times a week, four times a week, five times a week, six times a week, once a month, twice a month, three times a month, once every two months, once every three months, once every four months, once every five months, or once every six months. In some embodiments, the RBP4 inhibitor compound described herein, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, is administered daily.

[0131] In any of the foregoing aspects, there are further embodiments that include multiple administrations of an effective amount of the compound, where (i) the compound is administered continuously or intermittently, as in the case of a single administration, (ii) the time between the multiple administrations is every 3 hours, (iii) the time between the multiple administrations is every 6 hours, (iv) the compound is administered to the mammal every 8 hours, (v) the compound is administered to the mammal every 12 hours, or (vi) the compound is administered to the mammal every 24 hours.

[0132] In certain embodiments where the patient's condition improves, the administered dose of drug is temporarily reduced or temporarily suspended for a period of time (e.g., a "drug holiday"). In specific embodiments, the length of the drug holiday is between 2 days and 1 year, including, by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, or more than 28 days. The dose reduction during the drug holiday is, by way of example only, between 10% and 100%, including, by way of example only, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, and 100%. In further or alternative embodiments, the method includes a drug holiday, during which administration of the compound is temporarily suspended or the dose of the administered compound is temporarily reduced, and at the end of the drug holiday, administration of the compound is resumed. In one embodiment, the length of the drug holiday ranges from 2 to 7 days. In one embodiment, the length of the drug holiday is 7 days. In one embodiment, the length of the drug holiday is 14 days. In one embodiment, the length of the drug holiday is 28 days.

[0133] Retinol-binding protein 4 In one aspect, provided herein is a method for diagnosing or assessing the risk of developing age-related macular degeneration (AMD) in an individual who needs to be diagnosed or assessed, the method comprising: determining the level of retinol-binding protein 4 (RBP4) in a sample from the individual by assay.In some embodiments, the diagnosis or risk assessment step is accompanied by a treatment step, such as administering a treatment to reduce the level of RBP4 in the individual, thereby treating or preventing AMD in the individual.In some embodiments, if the level of RBP4 in the sample is greater than a threshold (for example, 25 μg / mL), a treatment is administered.In some embodiments, if the level of RBP4 in the sample is greater than a threshold (for example, 25 μg / mL), the individual is diagnosed or assessed as having a risk of developing AMD.

[0134] In another aspect, provided herein is a method for assessing the likelihood of age-related macular degeneration in an individual, the method comprising: determining by assay that the level of retinol-binding protein 4 (RBP4) in a sample from the individual exceeds a threshold value of RBP4; and assessing the likelihood of developing macular degeneration based on the level of RBP4.In some embodiments, the method also comprises determining the age and / or medical history of the individual.Therefore, in some embodiments, the assessment of the likelihood of developing macular degeneration is based on the level of RBP4, age, and medical history of the individual.

[0135] In another aspect, provided herein is a method for assessing the severity of age-related macular degeneration in an individual, the method comprising: determining by assay that the level of retinol-binding protein 4 (RBP4) in a sample from the individual exceeds a threshold value for RBP4; and assessing the severity of macular degeneration based on the level of RBP4. In some embodiments, the method also comprises determining the age and / or medical history of the individual. Thus, in some embodiments, the assessment of the severity of macular degeneration is based on the level of RBP4, age, and medical history of the individual.

[0136] In another aspect, a method for assessing the diagnosis of age-related macular degeneration in an individual is provided herein, comprising: determining by assay that the level of retinol-binding protein 4 (RBP4) in a sample from the individual exceeds a threshold value for RBP4; and assessing the diagnosis of macular degeneration based on the level of RBP4. In some embodiments, the method also comprises determining the age and / or medical history of the individual. Thus, in some embodiments, the diagnosis of macular degeneration is based on the level of RBP4, age, and medical history of the individual.

[0137] In another aspect, the present disclosure provides a method for assessing a dosage regimen for an individual with age-related macular degeneration, the method comprising: determining by assay that the level of retinol-binding protein 4 (RBP4) in a sample from the individual exceeds a threshold value for RBP4; and assessing the diagnosis of macular degeneration based on the level of RBP4. In some embodiments, the method also comprises determining the age and / or medical history of the individual. Thus, in some embodiments, the assessment of a dosage regimen for an individual with macular degeneration is based on the level of RBP4, age, and medical history of the individual.

[0138] In some embodiments, the threshold level of RBP4 is at least 25 μg / mL. In some embodiments, the threshold level of RBP4 is at least 30 μg / mL. In some embodiments, the threshold level of RBP4 is at least 35 μg / mL. In some embodiments, the threshold is between about 25 μg / mL and about 100 μg / mL. In some embodiments, the threshold value is about 25 μg / mL to about 30 μg / mL, about 25 μg / mL to about 35 μg / mL, about 25 μg / mL to about 40 μg / mL, about 25 μg / mL to about 50 μg / mL, about μg / mL to about μg / mL, about μg / mL to about μg / mL, about μg / mL to about μg / mL, about 25 μg / mL to about 80 μg / mL, about 25 μg / mL to about 90 μg / mL, about 25 μg / mL to about 100 μg / mL, about 30 μg / mL to about 35 μg / mL, about 30 μg / mL to about 40 μg / mL, or about 30 μg / mL to about 50 μg / mL , about 30 μg / mL to about 60 μg / mL, about 30 μg / mL to about 70 μg / mL, about 30 μg / mL to about 80 μg / mL, about 30 μg / mL to about 90 μg / mL, about 30 μg / mL to about 100 μg / mL, about 35 μg / mL to about 40 μg / mL, about 35 μg / mL to about 50 μg / mL, about 35 μg / mL to about 60 μg / mL, about 35 μg / mL to about 70 μg / mL, about 35 μg / mL to about 80 μg / mL, about 35 μg / mL to about 90 μg / mL, or about 35 μg / mL to about 100 μg / mL. In some embodiments, the threshold is about 25 μg / mL, about 30 μg / mL, or about 35 μg / mL. In some embodiments, the threshold is at least about 25 μg / mL, about 30 μg / mL, or about 35 μg / mL, hi some embodiments, the threshold is at most about 30 μg / mL, about 35 μg / mL, about 40 μg / mL, about 50 μg / mL, about 60 μg / mL, about 70 μg / mL, about 80 μg / mL, about 90 μg / mL, or about 100 μg / mL.

[0139] In some embodiments, the threshold value may vary based on various characteristics of an individual, including, but not limited to, demographic data, sex, age, medical history, history of diagnosed eye disease, body mass index (BMI), height, weight, and general health conditions, including obesity, hyperlipidemia, hyperglycemia, hypertension, diabetes, erythritis, cardiovascular disease, or non-alcoholic fatty liver disease.

[0140] In some embodiments, a diagnosis of AMD is made when the level of RBP4 is above a threshold. In some embodiments, a risk score is calculated when the level of RBP4 is above a threshold.

[0141] In some embodiments, if the level of RBP4 is above a threshold, a treatment is administered. In some embodiments, a treatment is administered to reduce the level of RBP4. In some embodiments, the treatment comprises administering a pharmaceutical composition to the individual. In some embodiments, the treatment comprises administering a pharmaceutical compound to the individual. In some embodiments, the pharmaceutical composition comprises an RBP4 inhibitor. The RBP4 inhibitor can be any of the RBP4 inhibitors provided herein.

[0142] In some embodiments, if the level of RBP4 is below the threshold, further steps can be taken or recommended. Such readings below the threshold may still indicate that the individual has some risk of developing AMD in the future, and therefore future monitoring may be recommended, or additional testing may be required to confirm or complete the diagnosis of AMD.

[0143] Further, in some embodiments, the method includes assessing the likelihood of developing AMD based on the level of RBP4. In some embodiments, assessing the likelihood of developing AMD includes generating a risk score. In some embodiments, if the risk score exceeds a threshold, treatment for AMD is administered (e.g., treatment with an RBP4 inhibitor). In some embodiments, the risk score reflects the probability that an individual will develop AMD at some point in the future based on the measurements provided herein.

[0144] In some embodiments, the method includes providing a recommendation to re-evaluate the individual for AMD after a certain period of time (e.g., if a risk score for developing AMD has been calculated, or if the level of RBP4 is below a threshold but there are other indicators that AMD may develop). In some embodiments, if the level or risk score is below a threshold, the method includes providing a recommendation to re-evaluate the individual for AMD after a certain period of time. The period of time can be any suitable period of time. In some embodiments, the period of time is from about 1 month to about 24 months. In some embodiments, the duration is about 1 month to about 3 months, about 1 month to about 6 months, about 1 month to about 9 months, about 1 month to about 12 months, about 1 month to about 18 months, about 1 month to about 24 months, about 3 months to about 6 months, about 3 months to about 9 months, about 3 months to about 12 months, about 3 months to about 18 months, about 3 months to about 24 months, about 6 months to about 9 months, about 6 months to about 12 months, about 6 months to about 18 months, about 6 months to about 24 months, about 9 months to about 12 months, about 9 months to about 18 months, about 9 months to about 24 months, about 12 months to about 18 months, about 12 months to about 24 months, or about 18 months to about 24 months. In some embodiments, the duration is about 1 month, about 3 months, about 6 months, about 9 months, about 12 months, about 18 months, or about 24 months. In some embodiments, the period is at least about 1 month, about 3 months, about 6 months, about 9 months, about 12 months, or about 18 months, hi some embodiments, the period is up to about 3 months, about 6 months, about 9 months, about 12 months, about 18 months, or about 24 months.

[0145] A recommendation to reevaluate includes performing additional testing after a period of time, including, but not limited to, reevaluating the level of RBP4 in the individual, or performing any of the other tests or evaluations for AMD provided herein, such as following up with a physician for a physical eye examination.

[0146] In some embodiments, the level of RBP4 in an individual is assessed by an assay. Any suitable assay for measuring the level of RBP4 can be used (e.g., an antibody assay, a mass spectrometry-based assay (e.g., LC / MS), a liquid chromatography assay (e.g., HPLC, UPLC), etc.). In some embodiments, the assay comprises an antibody assay, an electrophoresis assay, an immunoassay, a radioimmunoassay, a chromatography assay, a mass spectrometry assay, a microarray-based detection assay, a polymerase chain reaction assay, a sequencing assay, an immunohistochemistry assay, or any combination thereof. In some embodiments, the assay comprises an antibody assay. In some embodiments, the antibody assay comprises an enzyme-linked immunosorbent assay (ELISA).

[0147] In some embodiments, the sample comprises a blood sample from an individual. The blood sample may be further processed, such as to remove impurities or to retain serum and / or plasma. In some embodiments, the sample is a plasma or serum sample. In some embodiments, the sample is a plasma sample. In some embodiments, the sample is a serum sample. In some embodiments, the level is measured from plasma or serum from the blood sample. In some embodiments, the level is measured from plasma from the blood sample. In some embodiments, the level is measured from serum from the blood sample.

[0148] In some embodiments, the determination of a diagnosis of AMD, the assessment of the risk of developing AMD, and / or the decision to administer treatment is based on additional considerations in addition to the level of RBP4. In some embodiments, the determination is based on the individual's age and / or medical history. In some embodiments, the determination is based at least in part on the individual's age. In some embodiments, the determination is based at least in part on the individual's medical history. In some embodiments, the individual's medical history may include information such as previous diagnoses of eye disease, body mass index (BMI), height, weight, systemic diseases including obesity, hyperlipidemia, hyperglycemia, hypertension, diabetes, cardiovascular disease, or non-alcoholic fatty liver disease. In some embodiments, the determination is based at least in part on the level of vitamin A in the individual (e.g., in the individual's blood sample).

[0149] In addition, the methods provided herein may further include any of the additional tests or diagnostics provided herein for assessing the presence of AMD in an individual, including measuring the presence or absence of any of the genomic variants provided herein, or any other measurement that can be used to diagnose AMD. In some embodiments, the method further includes performing at least one of color fundus photography, fundus autofluorescence, spectral-domain optical coherence tomography, or microperimetry.

[0150] In some embodiments, the method further comprises classifying the progression of age-related macular degeneration. Classification can be based on the level of RBP4 measured as provided herein, or can be combined with other methods provided herein, such as by classification using the Age-Related Eye Disease Study (AREDS) classification.

[0151] Predicting Vitamin A Levels in AMD In one aspect, provided herein is a method for diagnosing or assessing the risk of developing age-related macular degeneration (AMD) in an individual in need thereof, comprising determining the level of vitamin A in a sample from the individual by assay.In some embodiments, the diagnosing or risk assessment step is accompanied by a treatment step, such as administering a treatment to reduce the level of vitamin A or RBP4 in the individual, thereby treating or preventing AMD in the individual.In some embodiments, if the level of vitamin A in the sample exceeds a threshold value (for example, 150ng / mL), a treatment is administered.In some embodiments, if the level of vitamin A in the sample exceeds a threshold value (for example, 150ng / mL), the individual is diagnosed or assessed as having a risk of developing AMD.

[0152] In another aspect, provided herein is a method for assessing the likelihood of age-related macular degeneration in an individual, the method comprising: determining by assay that the vitamin A level in a sample from the individual exceeds a vitamin A threshold; and assessing the likelihood of developing macular degeneration based on the vitamin A level. In some embodiments, the method also comprises determining the age and / or medical history of the individual. Thus, in some embodiments, the assessment of the likelihood of developing macular degeneration is based on the vitamin A level, age, and medical history of the individual.

[0153] In another aspect, provided herein is a method for assessing the severity of age-related macular degeneration in an individual, the method comprising: determining by assay that the vitamin A level in a sample from the individual exceeds a vitamin A threshold; and assessing the severity of macular degeneration based on the vitamin A level. In some embodiments, the method also comprises determining the age and / or medical history of the individual. Thus, in some embodiments, the assessment of the severity of macular degeneration is based on the vitamin A level, age, and medical history of the individual.

[0154] In another aspect, provided herein is a method for assessing the diagnosis of age-related macular degeneration in an individual, comprising determining by assay that the vitamin A level in a sample from the individual exceeds a vitamin A threshold, and assessing the diagnosis of macular degeneration based on the vitamin A level. In some embodiments, the method also comprises determining the age and / or medical history of the individual. Thus, in some embodiments, the assessment of the diagnosis of macular degeneration is based on the vitamin A level, age, and medical history of the individual.

[0155] In another aspect, provided herein is a method for assessing a dosage regimen for an individual with age-related macular degeneration, the method comprising: determining by assay that the vitamin A level in a sample from the individual exceeds a vitamin A threshold; and assessing a diagnosis of macular degeneration based on the vitamin A level. In some embodiments, the method also comprises determining the age and / or medical history of the individual. Thus, in some embodiments, the assessment of a dosage regimen for an individual with macular degeneration is based on the vitamin A level, age, and medical history of the individual.

[0156] In some embodiments, the threshold level of vitamin A is at least about 150 μg / mL. In some embodiments, the threshold level of vitamin A is at least about 175 μg / mL. In some embodiments, the threshold level of vitamin A is at least about 200 μg / mL. In some embodiments, the threshold level of vitamin A is at least about 220 μg / mL. In some embodiments, the threshold level of vitamin A is at least about 221 μg / mL. In some embodiments, the threshold level of vitamin A is at least about 222 μg / mL. In some embodiments, the threshold level of vitamin A is at least about 223 μg / mL. In some embodiments, the threshold level of vitamin A is at least about 224 μg / mL. In some embodiments, the threshold level of vitamin A is at least about 225 μg / mL. In some embodiments, the threshold level of vitamin A is at least about 250 μg / mL. In some embodiments, the threshold level of vitamin A is at least about 300 μg / mL. In some embodiments, the threshold level of vitamin A is at least about 350 μg / mL. In some embodiments, the threshold level of vitamin A is at least about 390 μg / mL. In some embodiments, the threshold level of vitamin A is at least about 391 μg / mL. In some embodiments, the threshold level of vitamin A is at least about 392 μg / mL. In some embodiments, the threshold level of vitamin A is at least about 393 μg / mL. In some embodiments, the threshold level of vitamin A is at least about 394 μg / mL. In some embodiments, the threshold level of vitamin A is at least about 395 μg / mL. In some embodiments, the threshold level of vitamin A is between about 150 ng / mL and about 500 μg / mL.In some embodiments, the threshold level of vitamin A is about 150 ng / mL to about 175 ng / mL, about 150 ng / mL to about 200 ng / mL, about 150 ng / mL to about 225 ng / mL, about 150 ng / mL to about 250 ng / mL, about 150 ng / mL to about 300 ng / mL, about 150 ng / mL to about 350 ng / mL, about 150 ng / mL to about 400 ng / mL, about 150 ng / mL to about 450 ng / mL, about 150 ng / mL to about 500 ng / mL, about 175 ng / mL to about 2 ... mL~about 225ng / mL, about 175ng / mL~about 250ng / mL, about 175ng / mL~about 300ng / mL, about 175ng / mL~about 350ng / mL, about 175ng / mL~about 400ng / mL, about 175ng / mL~about 450ng / mL, about 17 5ng / mL to about 500ng / mL, about 200ng / mL to about 225ng / mL, about 200ng / mL to about 250ng / mL, about 200ng / mL to about 300ng / mL, about 200ng / mL to about 350ng / mL, about 200ng / mL to about 400ng / mL, Approximately 200ng / mL to approximately 450ng / mL, approximately 200ng / mL to approximately 500ng / mL, approximately 225ng / mL to approximately 250ng / mL, approximately 225ng / mL to approximately 300ng / mL, approximately 225ng / mL to approximately 350ng / mL, approximately 225ng / mL to approximately 400ng / mL, about 225ng / mL to about 450ng / mL, about 225ng / mL to about 500ng / mL, about 250ng / mL to about 300ng / mL, about 250ng / mL to about 350ng / mL, about 250ng / mL to about 400ng / mL, about 250ng / mL to about 45 0 ng / mL, about 250 ng / mL to about 500 ng / mL, about 300 ng / mL to about 350 ng / mL, about 300 ng / mL to about 400 ng / mL, about 300 ng / mL to about 450 ng / mL, about 300 ng / mL to about 500 ng / mL, about 350 ng / mL to about 400 ng / mL, about 350 ng / mL to about 450 ng / mL, about 350 ng / mL to about 500 ng / mL, about 400 ng / mL to about 450 ng / mL, about 400 ng / mL to about 500 ng / mL, or about 450 ng / mL to about 500 μg / mL.In some embodiments, the threshold level of vitamin A is about 150 ng / mL, about 175 ng / mL, about 200 ng / mL, about 225 ng / mL, about 250 ng / mL, about 300 ng / mL, about 350 ng / mL, about 400 ng / mL, about 450 ng / mL, or about 500 μg / mL. In some embodiments, the threshold level of vitamin A is at least about 150 ng / mL, about 175 ng / mL, about 200 ng / mL, about 225 ng / mL, about 250 ng / mL, about 300 ng / mL, about 350 ng / mL, about 400 ng / mL, or about 450 μg / mL. In some embodiments, the threshold level of vitamin A is up to about 175 ng / mL, about 200 ng / mL, about 225 ng / mL, about 250 ng / mL, about 300 ng / mL, about 350 ng / mL, about 400 ng / mL, about 450 ng / mL, or about 500 μg / mL.

[0157] In some embodiments, the threshold value may vary based on various characteristics of the individual, including, but not limited to, demographic data, sex, age, medical history, history of diagnosed eye disease, body mass index (BMI), height, weight, and general health conditions, including obesity, hyperlipidemia, hyperglycemia, hypertension, diabetes, erythritis, cardiovascular disease, or non-alcoholic fatty liver disease.

[0158] In some embodiments, the threshold level of vitamin A depends on the age of the individual. In some embodiments, the threshold level of vitamin A is lower for adolescents (e.g., individuals aged 12-17 years) than for adults (e.g., individuals aged 18 years or older). In some embodiments, the threshold level of vitamin A for adolescents is at least about 150 ng / mL, at least about 175 ng / mL, at least about 200 ng / mL, at least about 210 ng / mL, at least about 220 ng / mL, at least about 221 ng / mL, at least about 222 ng / mL, at least about 223 ng / mL, at least about 224 ng / mL, at least about 225 ng / mL, at least about 230 ng / mL, or at least about 250 μg / mL. In some embodiments, the threshold for adults is at least about 300 ng / mL, at least about 325 ng / mL, at least about 350 ng / mL, at least about 375 ng / mL, at least about 380 ng / mL, at least about 385 ng / mL, at least about 390 ng / mL, at least about 391 ng / mL, at least about 392 ng / mL, at least about 393 ng / mL, at least about 394 ng / mL, at least about 395 ng / mL, or at least about 400 μg / mL.

[0159] In some embodiments, a diagnosis of AMD is made when the level of vitamin A is above a threshold. In some embodiments, a risk score is calculated when the level of vitamin A is above a threshold.

[0160] In some embodiments, treatment is administered when vitamin A levels are above a threshold. In some embodiments, treatment is administered to reduce vitamin A levels. In some embodiments, treatment comprises administering a pharmaceutical composition to the individual. In some embodiments, treatment comprises administering a pharmaceutical compound to the individual. In some embodiments, the pharmaceutical composition comprises an RBP4 inhibitor. The RBP4 inhibitor can be any of the RBP4 inhibitors provided herein.

[0161] In some embodiments, if the vitamin A level is below the threshold, further steps may be taken or recommended. Such a reading below the threshold may still indicate that the individual has some risk of developing AMD in the future, and therefore future monitoring may be recommended, or additional testing may be required to confirm or complete the diagnosis of AMD.

[0162] Further, in some embodiments, the method comprises assessing the likelihood of developing AMD based on the level of vitamin A. In some embodiments, assessing the likelihood of developing AMD comprises generating a risk score. In some embodiments, if the risk score exceeds a threshold, treatment for AMD is administered (e.g., treatment with an RBP4 inhibitor). In some embodiments, the risk score reflects the probability that an individual will develop AMD at some point in the future based on the measurements provided herein.

[0163] In some embodiments, the method includes providing a recommendation to re-evaluate the individual for AMD after a certain period of time (e.g., if a risk score for developing AMD has been calculated, or if the vitamin A level is below a threshold but there are other indicators that AMD may develop). In some embodiments, if the level or risk score is below a threshold, the method includes providing a recommendation to re-evaluate the individual for AMD after a certain period of time. The period of time can be any suitable period of time. In some embodiments, the period of time is from about 1 month to about 24 months. In some embodiments, the duration is about 1 month to about 3 months, about 1 month to about 6 months, about 1 month to about 9 months, about 1 month to about 12 months, about 1 month to about 18 months, about 1 month to about 24 months, about 3 months to about 6 months, about 3 months to about 9 months, about 3 months to about 12 months, about 3 months to about 18 months, about 3 months to about 24 months, about 6 months to about 9 months, about 6 months to about 12 months, about 6 months to about 18 months, about 6 months to about 24 months, about 9 months to about 12 months, about 9 months to about 18 months, about 9 months to about 24 months, about 12 months to about 18 months, about 12 months to about 24 months, or about 18 months to about 24 months. In some embodiments, the duration is about 1 month, about 3 months, about 6 months, about 9 months, about 12 months, about 18 months, or about 24 months. In some embodiments, the period is at least about 1 month, about 3 months, about 6 months, about 9 months, about 12 months, or about 18 months, hi some embodiments, the period is at most about 3 months, about 6 months, about 9 months, about 12 months, about 18 months, or about 24 months.

[0164] A recommendation to reevaluate may include performing additional testing after a period of time, including, but not limited to, reevaluating the individual's vitamin A levels or performing any of the other tests or evaluations for AMD provided herein, such as following up with a physician for a physical eye examination.

[0165] In some embodiments, the level of vitamin A in an individual is assessed by an assay. Any suitable assay for measuring vitamin A levels can be used (e.g., an antibody assay, a mass spectrometry-based assay (e.g., LC / MS), a liquid chromatography assay (e.g., HPLC, UPLC), etc.). In some embodiments, the assay comprises an antibody assay, an electrophoresis assay, an immunoassay, a radioimmunoassay, a chromatography assay, a mass spectrometry assay, a microarray-based detection assay, a polymerase chain reaction assay, a sequencing assay, an immunohistochemistry assay, or any combination thereof. In some embodiments, the assay comprises an antibody assay. In some embodiments, the antibody assay comprises an enzyme-linked immunosorbent assay (ELISA). In some embodiments, the assay is a chromatography assay. In some embodiments, the assay comprises high-performance liquid chromatography (HPLC), ultra-performance liquid chromatography (UPLC), or liquid chromatography / mass spectrometry (LC-MS).

[0166] In some embodiments, the sample comprises a blood sample from an individual. The blood sample may be further processed, such as to remove impurities or to retain serum and / or plasma. In some embodiments, the sample is a plasma or serum sample. In some embodiments, the sample is a plasma sample. In some embodiments, the sample is a serum sample. In some embodiments, the level is measured from plasma or serum from the blood sample. In some embodiments, the level is measured from plasma from the blood sample. In some embodiments, the level is measured from serum from the blood sample.

[0167] In some embodiments, the determination of a diagnosis of AMD, the assessment of a risk of developing AMD, and / or the decision to administer treatment is based on additional considerations in addition to vitamin A levels. In some embodiments, the determination is based on the individual's age and / or medical history. In some embodiments, the determination is based at least in part on the individual's age. In some embodiments, the determination is based at least in part on the individual's medical history. In some embodiments, the individual's medical history may include information such as previous diagnosis of eye disease, body mass index (BMI), height, weight, systemic disease including obesity, hyperlipidemia, hyperglycemia, hypertension, diabetes, cardiovascular disease, or non-alcoholic fatty liver disease. In some embodiments, the determination is based at least in part on the level of RBP4 in the individual (e.g., in the individual's blood sample).

[0168] In addition, the methods provided herein may further comprise any of the additional tests or diagnostics provided herein for assessing the presence of AMD in individuals, including measuring the presence or absence of any of the genomic variants provided herein, or any other measurements that can be used to diagnose AMD. In some embodiments, the method further comprises performing at least one of color fundus photography, fundus autofluorescence, spectral domain optical coherence tomography, or microperimetry.

[0169] In some embodiments, the method further comprises classifying the progression of age-related macular degeneration. Classification can be based on the vitamin A level measured as provided herein, or can be combined with other methods provided herein, such as by classification using the Age-Related Disease Study (AREDS) classification.

[0170] Genomic Variants Predictive of AMD Also provided herein are genomic variants that indicate an individual's propensity to develop AMD. In some embodiments, the genomic variants include single nucleotide polymorphisms (SNPs) in the gene encoding ATP-binding cassette, subfamily A, member 4 (ABCA4) in an individual. ABCA4 is a protein encoded by the ABCA4 gene in humans and other eukaryotes. The ABCA4 protein is expressed almost exclusively in the retina and is involved in Stargardt syndrome and other ocular diseases, including, but not limited to, fundus flavimaculatus, cone-rod dystrophy, retinitis pigmentosa, and age-related macular degeneration. Decreased ABCA4 activity is associated with the excessive accumulation of toxic retinoids and lipofuscin. Such mutations are, in some instances, detected by sequencing the subject's DNA or RNA. In some embodiments, the genomic variants provided herein, either alone or in combination with other factors, predict the likelihood of a subject developing AMD. Genomic variants herein include SNPs that are missense SNPs, intronic SNPs, synonymous SNPs, or any other type of SNP. An individual contains one or more of the SNPs provided herein, either in the same allele or in different alleles. Examples of such genomic variants and SNPs can be found in Table A below.

[0171] [Table 1]

[0172] In one aspect, provided herein are methods for assessing whether an individual has AMD, whether an individual is likely to develop AMD, and, in some examples, methods for treating or preventing AMD. In some embodiments, the method includes determining the presence or absence of one or more genomic variants by assay. In some embodiments, the one or more genomic variants include at least one of rs4147863, rs2275029, rs1800739, rs4147857, rs4147856, rs1801555, or rs1801574. In some embodiments, the method includes calculating a risk score for age-related macular degeneration using the presence or absence of one or more genomic variants. In some embodiments, the method includes diagnosing age-related macular degeneration using the presence or absence of one or more genomic variants. In some embodiments, the method further includes administering a therapy for treating age-related macular degeneration in the individual. In some embodiments, the method further includes administering a therapy for preventing age-related macular degeneration in the individual.

[0173] In some embodiments, the method comprises determining the presence or absence of one or more genomic variants by assay. In some embodiments, the one or more genomic variants comprise at least one of rs4147863, rs2275029, rs1800739, rs4147857, rs4147856, rs1801555, or rs1801574. In some embodiments, the one or more genomic variants comprise at least two of rs4147863, rs2275029, rs1800739, rs4147857, rs4147856, rs1801555, or rs1801574. In some embodiments, the one or more genomic variants include at least three of rs4147863, rs2275029, rs1800739, rs4147857, rs4147856, rs1801555, or rs1801574. In some embodiments, the one or more genomic variants include at least four of rs4147863, rs2275029, rs1800739, rs4147857, rs4147856, rs1801555, or rs1801574. In some embodiments, the one or more genomic variants include at least five of rs4147863, rs2275029, rs1800739, rs4147857, rs4147856, rs1801555, or rs1801574. In some embodiments, the one or more genomic variants include at least six of rs4147863, rs2275029, rs1800739, rs4147857, rs4147856, rs1801555, or rs1801574. In some embodiments, the one or more genomic variants include each of rs4147863, rs2275029, rs1800739, rs4147857, rs4147856, rs1801555, or rs1801574.

[0174] In some embodiments, the one or more genomic variants comprise rs4147863. In some embodiments, the one or more genomic variants comprise rs2275029. In some embodiments, the one or more genomic variants comprise rs1800739. In some embodiments, the one or more genomic variants comprise rs4147857. In some embodiments, the one or more genomic variants comprise rs4147856. In some embodiments, the one or more genomic variants comprise rs1801555. In some embodiments, the one or more genomic variants comprise rs1801574.

[0175] In some embodiments, the one or more genomic variants are rs3747961, rs6666652, rs1800717, rs763108716, rs185601596, rs17110761, rs61748519, rs1801359, rs145766145, rs76258939, rs200551567, rs7547651 rs1762114, rs55860151, rs1800549, rs3112831, rs4147830, rs2297634, or rs4847281. In some embodiments, the one or more genomic variants are rs3747961, rs6666652, rs1800717, rs763108716, rs185601596, rs17110761, rs61748519, rs1801359, rs145766145, rs76258939, rs200551567, rs7547651 In some embodiments, the one or more genomic variants comprise at least five of rs1800549, rs3112831, rs4147830, rs2297634, or rs4847281. In some embodiments, the one or more genomic variants comprise at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 genomic variants.

[0176] In some embodiments, the one or more genomic variants comprise at least one genomic variant from Table A. In some embodiments, the one or more genomic variants comprise at least five genomic variants from Table A. In some embodiments, the one or more genomic variants comprise at least seven genomic variants from Table A. In some embodiments, the one or more genomic variants comprise at least ten genomic variants from Table A. The one or more genomic variants comprise at least fifteen genomic variants from Table A. In some embodiments, the one or more genomic variants comprise at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 genomic variants from Table A.

[0177] In some embodiments, detecting the presence or absence of one or more genomic variants further comprises determining the allele frequency of the one or more genomic variants in the individual. In some embodiments, the one or more genomic variants are present on a single copy of the gene in the individual. In some embodiments, the one or more genomic variants are present on multiple copies of the gene in the individual.

[0178] In some embodiments, determining the presence or absence of one or more genomic variants comprises performing an assay on genetic material from an individual.In some cases, genetic material is obtained from blood, serum, plasma, sweat, hair, tears, urine, and other techniques known to those skilled in the art.In some embodiments, genetic material is obtained from the blood, serum, or plasma of an individual.

[0179] In some embodiments, a method for detecting the presence, absence, or level of a genomic variant in a sample obtained from an individual includes detecting a nucleic acid sequence. In some cases, the nucleic acid sequence includes deoxyribonucleic acid (DNA), such as when detecting complementary DNA (cDNA) of an mRNA transcript. In some examples, the nucleic acid sequence includes a denatured DNA molecule or a fragment thereof. In some examples, the nucleic acid sequence includes DNA selected from genomic DNA, amplified DNA, circular DNA, circulating DNA, cell-free DNA, or exosomal DNA. In some examples, the DNA is single-stranded DNA (ssDNA), double-stranded DNA, denatured double-stranded DNA, synthetic DNA, and combinations thereof. The circular DNA may be cleaved or fragmented. In some examples, the nucleic acid sequence includes ribonucleic acid (RNA). In some examples, the nucleic acid sequence includes fragmented RNA. In some examples, the nucleic acid sequence includes partially degraded RNA.

[0180] In some embodiments, genomic variants are detected by subjecting a sample obtained from a subject to a nucleic acid-based detection assay. In some examples, the nucleic acid-based detection assay includes quantitative polymerase chain reaction (qPCR), gel electrophoresis (e.g., Northern or Southern blot), immunochemistry, in situ hybridization such as fluorescent in situ hybridization (FISH), cytochemistry, microarray, or sequencing. In some embodiments, the sequencing technique includes next-generation sequencing. In some embodiments, the method includes a hybridization assay such as fluorogenic qPCR (e.g., TaqMan™, SYBR Green, SYBR Green I, SYBR Green II, SYBR Gold, ethidium bromide, methylene blue, pyronin Y, DAPI, acridine orange, Blue View, or phycoerythrin), which involves a nucleic acid amplification reaction using a specific primer pair and hybridization of the amplified nucleic acid probe containing a detectable moiety or molecule specific to the target nucleic acid sequence. In some examples, the number of amplification cycles for detecting a target nucleic acid in a qPCR assay is about 5 to about 30 cycles. In some examples, the number of amplification cycles for detecting a target nucleic acid is at least about 5 cycles. In some examples, the number of amplification cycles for detecting a target nucleic acid is at most about 30 cycles. In some examples, the number of amplification cycles for detecting a target nucleic acid is about 5 to about 10, about 5 to about 15, about 5 to about 20, about 5 to about 25, about 5 to about 30, about 10 to about 15, about 10 to about 20, about 10 to about 25, about 10 to about 30, about 15 to about 20, about 15 to about 25, about 15 to about 30, about 20 to about 25, about 20 to about 30, or about 25 to about 30 cycles. In the case of TaqMan™ methods, the probe may be a hydrolyzable probe comprising a fluorophore and a quencher that is hydrolyzed by a DNA polymerase when hybridized to a target nucleic acid.In some cases, the presence of the target nucleic acid is determined when the number of amplification cycles to reach the threshold is less than 30, 29, 28, 27, 26, 25, 24, 23, 22, 21, or 20. In some cases, hybridization can occur in a standard PCR buffer at a standard hybridization temperature, e.g., from about 35°C to about 65°C.

[0181] Further exemplary nucleic acid-based detection assays include the use of nucleic acid probes conjugated or otherwise immobilized on beads, multiwell plates, or other substrates, where the nucleic acid probes are configured to hybridize with target nucleic acid sequences. In some examples, the nucleic acid probes are specific to one or more gene products (of the PRSs) described herein. In some examples, biomarker-specific nucleic acid probes comprise nucleic acid probe sequences sufficiently complementary to the polynucleotide sequence of the biomarker. In some examples, the biomarkers comprise transcribed polynucleotide sequences (e.g., RNA, cDNA). In some embodiments, the nucleic acid probes can be full-length cDNAs, or portions thereof, such as oligonucleotides at least about 7, 8, 9, 10, 11, 12, 13, 14, 15, 20, 25, 30, 35, 40, 45, or 50 nucleotides in length, and sufficient to specifically hybridize to the target nucleic acid sequence under standard hybridization conditions. In some embodiments, the target nucleic acid sequence is immobilized on a solid surface and contacted with a probe, for example, by running the isolated target nucleic acid sequence on an agarose gel and transferring the target nucleic acid sequence from the gel to a membrane such as nitrocellulose. In some embodiments, the probe is immobilized on a solid surface, for example, an Affymetrix gene chip array, and the probe is contacted with the target nucleic acid sequence.

[0182] In some embodiments, the term "probe" with respect to nucleic acids refers to any nucleic acid molecule capable of selectively binding to a specific intended target nucleic acid sequence. In some examples, the probe is specifically designed to be labeled with, for example, a radioactive label, a fluorescent label, an enzyme, a chemiluminescent tag, a colorimetric tag, or other labels or tags known in the art. In some examples, the fluorescent label comprises a fluorophore. In some examples, the fluorophore is an aromatic or heteroaromatic compound. In some examples, the fluorophore is pyrene, anthracene, naphthalene, acridine, stilbene, benzoxazole, indole, benzoindole, oxazole, thiazole, benzothiazole, indole, carbocyanine, salicylate, anthranilate, xanthene dye, or coumarin. Exemplary xanthene dyes include, for example, fluorescein and rhodamine dyes. Fluorescein and rhodamine dyes include, but are not limited to, 6-carboxyfluorescein (FAM), 2'7'-dimethoxy-4'5'-dichloro-6-carboxyfluorescein (JOE), tetrachlorofluorescein (TET), 6-carboxyrhodamine (R6G), N,N,N,N'-tetramethyl-6-carboxyrhodamine (TAMRA), and 6-carboxy-X-rhodamine (ROX). Suitable fluorescent probes also include naphthylamine dyes with an amino group at the α or β position. For example, naphthylamino compounds include 1-dimethylaminonaphthyl-5-sulfonate, 1-anilino-8-naphthalene sulfonate, and 2-p-toluidinyl-6-naphthalene sulfonate, 5-(2'-aminoethyl)aminonaphthalene-1-sulfonic acid (EDANS).Exemplary coumarins include, for example, 3-phenyl-7-isocyanatocoumarin, acridines such as 9-isothiocyanatoacridine and acridine orange, N-(p-(2-benzoxazolyl)phenyl)maleimide, indodicarbocyanine 3 (Cy3), indodicarbocyanine 5 (Cy5), indodicarbocyanine Cyanines such as 5.5 (Cy5.5), 3-(-carboxy-pentyl)-3'-ethyl-5,5'-c(-dimethyloxacarbocyanine (CyA), 1H,5H,11H,15H-xantheno[2,3,4-ij:5,6,7-i'j']diquinolizin-18-ium,9-[2](or 4)-[[[6-[2,5-dioxo-1-pyrrolidinyl)oxy]-6-oxohexyl]amino]sulfonyl]-4(or 2)-sulfophenyl]-2,3),6,7,12,13,16,17-octahydro-inner salt (TR or Texas Red), or BODIPY™ dyes. In some cases, the probe contains FAM as the dye label.

[0183] In some embodiments, detecting one or more genomic variants comprises sequencing genetic material obtained from a sample from a subject. Sequencing of the sequencing library can be performed using any suitable sequencing technology, including single molecule real-time (SMRT) sequencing, polony sequencing, ligation sequencing, reversible terminator sequencing, proton detection sequencing, ion semiconductor sequencing, nanopore sequencing, electronic sequencing, pyrosequencing, Maxam-Gilbert sequencing, chain termination (e.g., Sanger) sequencing, +S sequencing, or sequencing by synthesis. Sequencing methods also include advanced sequencing technologies such as next-generation sequencing, e.g., Illumina sequencing (e.g., Solexa), Roche 454 sequencing, Ion torrent sequencing, and SOLiD sequencing. In some cases, next-generation sequencing includes high-throughput sequencing methods. Additional sequencing methods available to those skilled in the art can also be used.

[0184] In some embodiments, when a genomic variant provided herein is identified in an individual, a treatment is administered. In some embodiments, a treatment is administered to reduce the level of RBP4 in the individual. In some embodiments, the treatment comprises administering a pharmaceutical composition to the individual. In some embodiments, the treatment comprises administering a pharmaceutical compound to the individual. In some embodiments, the pharmaceutical composition comprises an RBP4 inhibitor. The RBP4 inhibitor can be any of the RBP4 inhibitors provided herein.

[0185] In addition, the methods provided herein may further include any of the additional tests or diagnostics provided herein for assessing the presence of AMD in an individual, including measuring the level of RBP4 and comparing it with a threshold value provided herein, measuring the level of vitamin A and comparing it with a threshold value provided herein, or any other measurement that can be used to diagnose AMD. In some embodiments, the method further includes performing at least one of color fundus photography, fundus autofluorescence, spectral domain optical coherence tomography, or microperimetry.

[0186] In some embodiments, the method also includes determining the individual's age and medical history. Thus, in some embodiments, the assessment of the likelihood of developing macular degeneration is based on the presence of one or more genomic variants, the individual's age, and medical history.

[0187] In some embodiments, a determination of a diagnosis of AMD, an assessment of the risk of developing AMD, or a treatment decision is made based on additional considerations in addition to the presence or absence of one or more genomic variants. In some embodiments, the decision is based on the individual's age and / or medical history. In some embodiments, the decision is based at least in part on the individual's age. In some embodiments, the decision is based at least in part on the individual's medical history. In some embodiments, the individual's medical history may include information such as a previous diagnosis of eye disease, body mass index (BMI), height, weight, systemic diseases including obesity, hyperlipidemia, hyperglycemia, hypertension, diabetes, cardiovascular disease, or non-alcoholic fatty liver disease.

[0188] In some embodiments, the identification of one or more genomic variants provided herein in an individual does not require immediate intervention with treatment, but may prompt the treating physician to recommend increased monitoring for the onset of AMD or related symptoms that indicate the onset of AMD. In some embodiments, the method comprises providing a recommendation to reassess the individual for AMD after a certain period of time. In some embodiments, if the level or risk score falls below a threshold, the method comprises providing a recommendation to reassess the individual for AMD after a certain period of time. The period of time can be any suitable period of time. In some embodiments, the period of time is from about 1 month to about 24 months. In some embodiments, the duration is about 1 month to about 3 months, about 1 month to about 6 months, about 1 month to about 9 months, about 1 month to about 12 months, about 1 month to about 18 months, about 1 month to about 24 months, about 3 months to about 6 months, about 3 months to about 9 months, about 3 months to about 12 months, about 3 months to about 18 months, about 3 months to about 24 months, about 6 months to about 9 months, about 6 months to about 12 months, about 6 months to about 18 months, about 6 months to about 24 months, about 9 months to about 12 months, about 9 months to about 18 months, about 9 months to about 24 months, about 12 months to about 18 months, about 12 months to about 24 months, or about 18 months to about 24 months. In some embodiments, the duration is about 1 month, about 3 months, about 6 months, about 9 months, about 12 months, about 18 months, or about 24 months. In some embodiments, the period is at least about 1 month, about 3 months, about 6 months, about 9 months, about 12 months, or about 18 months.In some embodiments, the period is at most about 3 months, about 6 months, about 9 months, about 12 months, about 18 months, or about 24 months.The period can also be longer, for example, at least about 2 years, at least about 3 years, at least about 5 years, at least about 10 years, or more.In some embodiments, it can be recommended that individuals be regularly monitored for the development of AMD.

[0189] A recommendation for re-evaluation may include performing additional testing after a period of time, including assessing the level of RBP4 in the individual, or performing any of the other tests or evaluations for AMD provided herein, such as following up with a physician for a physical eye examination.

[0190] In addition, the methods provided herein may further include any of the additional tests or diagnostics provided herein for assessing the presence of AMD in an individual, including measuring the level of RBP4 and comparing it with the thresholds provided herein, measuring the level of vitamin A and comparing it with the thresholds provided herein, or any other measurement that can be used to diagnose AMD. In some embodiments, the method further includes performing at least one of color fundus photography, fundus autofluorescence, spectral domain optical coherence tomography, or microperimetry.

[0191] In some embodiments, the method further comprises classifying the progression of age-related macular degeneration. Classification can be based on the level of RBP4 measured as provided herein, or can be combined with other methods provided herein, such as by classification using the Age-Related Disease Study (AREDS) classification.

[0192] Combinations of RBP4 levels / vitamin A levels and genomic variants predictive of AMD The biomarker levels (e.g., blood levels of RBP4 and / or vitamin A) and genomic variants (e.g., ABCA4 variants) provided herein can also be simultaneously probed to provide a diagnosis, risk score, or recommendation for treatment of AMD in an individual. In some embodiments, this combined approach results in a more reliable diagnosis or risk score than either method alone. In some embodiments, this allows for a specific diagnosis or risk assessment of AMD without the need for a more invasive physical examination of the eye, since the diagnosis or risk score can be calculated from a single sample (e.g., a blood sample) from the individual.

[0193] In one aspect of the present disclosure, there is provided a method for assessing the likelihood of age-related macular degeneration in an individual in need thereof, the method comprising: obtaining a blood sample from the individual; extracting a protein fraction from the blood sample; extracting a nucleic acid fraction from the blood sample; determining a retinol binding protein 4 (RBP4) level and / or a vitamin A level from the protein fraction by a first assay; determining the allele frequency of one or more genomic variants from nucleic acids in the nucleic acid fraction by a second assay; and assessing the likelihood of age-related macular degeneration based on the RBP4 level and / or the vitamin A level and the allele frequency of the one or more genomic variants. In some embodiments, the one or more genomic variants include at least one of rs4147863, rs2275029, rs1800739, rs4147857, rs4147856, rs1801555, or rs1801574.

[0194] Another aspect of the present disclosure is a method of treating age-related macular degeneration in an individual in need thereof, comprising: a) providing a level of retinol binding protein 4 (RBP4) and / or a level of vitamin A, wherein the level is determined by assaying a protein fraction of a sample from the individual; b) providing an allele frequency of one or more genomic variants, wherein the allele frequency is determined by assaying a nucleic acid fraction of the sample from the individual; and c) administering a treatment based on the assessment of the level of RBP4 and / or the level of vitamin A and the allele frequency of the one or more genomic variants. In some embodiments, the one or more genomic variants include at least one of rs4147863, rs2275029, rs1800739, rs4147857, rs4147856, rs1801555, or rs1801574.

[0195] In some embodiments, the level of RBP4 is compared with the RBP4 threshold value provided elsewhere herein.Any of the RBP4 threshold values ​​provided herein are used in diagnosis / assessment protocol in conjunction with detecting genomic variants.In addition, any of the methods or assays used to determine the level of RBP4 in sample provided herein are equally applicable to the diagnosis of AMD, the assessment of the risk of developing AMD, or the method of determining the treatment of AMD based on the combination of genomic variants and RBP4 levels.

[0196] In some embodiments, the method herein provides for detecting the presence or absence of one or more genomic variants.The evaluation of any combination or number of genomic variants provided herein can be used in conjunction with the information provided by the level of RBP4 when diagnosing, risk assessment or treating AMD as provided herein.

[0197] In embodiments in which both RBP4 levels and genomic variants are measured, the measurement of RBP4 levels with an assay and the determination of the presence or absence (or allele frequency) of one or more genomic variants with a second assay are performed on a sample from the individual. In some embodiments, the assay and the second assay are performed on the same sample. In some embodiments, the assay and the second assay are performed on different samples from the individual. The samples need not be collected from the individual at the same time, and the samples need not be of the same type. In some embodiments, the assay and the second assay are performed on the same sample from the individual. In some embodiments, the assay and the second assay are performed on two separate samples from the individual. In some embodiments, the two separate samples are the same type of sample (e.g., a blood sample). In some embodiments, the two separate samples are different types of sample (e.g., a blood sample and a urine sample). In some embodiments, the two separate samples are two blood samples. The two separate samples need not be collected from the individual at the same time. In some embodiments, the two separate samples are collected from the individual at the same time. In some embodiments, the two separate samples are taken at different times, hi some embodiments, the two separate samples are taken at most about 1 day, at most about 2 days, at most about 3 days, at most about 1 week, at most about 2 weeks, at most about 1 month, at most about 2 months, at most about 3 months, or at most about 6 months apart.

[0198] Just as the methods provided herein based on the measured RBP4 level or the presence or absence of a genomic variant may further include additional testing or diagnosis to confirm the presence of AMD in an individual, methods may also utilize both the RBP4 level and the presence or absence of a genomic variant. In some embodiments, the diagnosis, risk assessment, or decision to administer treatment is further based on additional criteria, such as the subject's age and medical history. In some embodiments, the decision is based on the individual's age and / or medical history. In some embodiments, the decision is based at least in part on the individual's age. In some embodiments, the decision is based at least in part on the individual's medical history. In some embodiments, the individual's medical history may include information such as eye condition, body mass index (BMI), height, weight, general condition including obesity, and previous diagnosis of hyperlipidemia, hyperglycemia, hypertension, diabetes, cardiovascular disease, or non-alcoholic fatty liver disease.

[0199] In addition, the methods provided herein may further comprise any of the additional tests or diagnostics provided herein for assessing the presence of AMD in an individual. In some embodiments, the method further comprises performing at least one of color fundus photography, fundus autofluorescence, spectral domain optical coherence tomography, or microperimetry.

[0200] In some embodiments, the method further comprises classifying the progression of age-related macular degeneration. Classification can be based on the level of RBP4 measured as provided herein, or can be combined with other methods provided herein, such as by classification using the Age-Related Eye Disease Study (AREDS) classification.

[0201] In some embodiments, the risk score reflects the probability that an individual will develop AMD at some point in the future based on the measurements provided herein.

[0202] In some embodiments, the identification of one or more genomic variants provided herein and the measurement of RBP4 levels in an individual do not require immediate intervention with treatment, but may prompt the treating physician to recommend increased monitoring for the onset of AMD or related symptoms that indicate the onset of AMD. In some embodiments, the method includes providing a recommendation to re-evaluate the individual for AMD after a certain period of time. In some embodiments, if the level or risk score is below a threshold, the method includes providing a recommendation to re-evaluate the individual for AMD after a certain period of time. The period of time can be any suitable period of time. In some embodiments, the period of time is from about 1 month to about 24 months. In some embodiments, the duration is about 1 month to about 3 months, about 1 month to about 6 months, about 1 month to about 9 months, about 1 month to about 12 months, about 1 month to about 18 months, about 1 month to about 24 months, about 3 months to about 6 months, about 3 months to about 9 months, about 3 months to about 12 months, about 3 months to about 18 months, about 3 months to about 24 months, about 6 months to about 9 months, about 6 months to about 12 months, about 6 months to about 18 months, about 6 months to about 24 months, about 9 months to about 12 months, about 9 months to about 18 months, about 9 months to about 24 months, about 12 months to about 18 months, about 12 months to about 24 months, or about 18 months to about 24 months. In some embodiments, the duration is about 1 month, about 3 months, about 6 months, about 9 months, about 12 months, about 18 months, or about 24 months. In some embodiments, the period is at least about 1 month, about 3 months, about 6 months, about 9 months, about 12 months, or about 18 months. In some embodiments, the period is at most about 3 months, about 6 months, about 9 months, about 12 months, about 18 months, or about 24 months. The period can be longer, such as at least about 2 years, at least about 3 years, at least about 5 years, at least about 10 years, or more. In some embodiments, it can be recommended that individuals be regularly monitored for the development of AMD.

[0203] A recommendation for re-evaluation may include performing additional testing after a period of time, including, but not limited to, assessing the individual's levels of RBP4, or performing any of the other tests or evaluations for AMD provided herein, such as following up with a physician for a physical eye examination.

[0204] In some embodiments, when a genomic variant provided herein is identified in an individual, a treatment is administered. In some embodiments, a treatment is administered to reduce the level of RBP4 in the individual. In some embodiments, the treatment comprises administering a pharmaceutical composition to the individual. In some embodiments, the treatment comprises administering a pharmaceutical compound to the individual. In some embodiments, the pharmaceutical composition comprises an RBP4 inhibitor. The RBP4 inhibitor can be any of the RBP4 inhibitors provided herein.

[0205] Further considerations for predicting or diagnosing AMD In some embodiments, the diagnosis of AMD, the risk assessment of AMD development, or the treatment decision is based on the additional test that can be optionally carried out in addition to measuring the level of RBP4 in a subject and / or determining whether or not the genomic variants provided herein exist.Therefore, the method provided herein can further provide the additional test that is used in conjunction with the biomarkers that indicate AMD provided herein.

[0206] The methods provided herein can further comprise the additional test used to assess the existence or risk of developing AMD in individuals.A variety of such additional tests and diagnostics are known in the art, including color fundus photography, fundus autofluorescence, spectral domain optical coherence tomography and microperimetry.

[0207] In some embodiments, the methods provided herein further include analysis of at least one of color fundus photography, fundus autofluorescence, spectral domain optical coherence tomography, or microperimetry. In some embodiments, the methods further include analysis of color fundus photography. In some embodiments, the methods further include analysis of fundus autofluorescence. In some embodiments, the methods further include spectral domain optical coherence tomography. In some embodiments, the methods further include microperimetry. In some embodiments, the diagnosis of AMD, the assessment of risk for developing AMD, or the decision to administer therapy for AMD is based at least in part on one of these assessments.

[0208] In addition, the methods provided herein may also include determining the age or medical history of the individual. In some embodiments, the determination is based at least in part on the age of the individual. In some embodiments, the determination is based at least in part on the medical history of the individual. In some embodiments, the medical history of the individual may include information such as eye condition, body mass index (BMI), height, weight, general condition including obesity, previous diagnosis of hyperlipidemia, hyperglycemia, hypertension, diabetes, cardiovascular disease, or non-alcoholic fatty liver disease.

[0209] In some embodiments, the methods herein include classifying the progression of AMD, in some embodiments, the classification is based on Age-Related Eye Disease Study Research categories (Age-Related Eye Disease Study Research G. The Age-Related Eye Disease Study (AREDS): design implications. AREDS report no. 1. Control Clin Trials. 1999;20(6):573-600) (AREDS). AREDS categories include category 1 (defined as few (1-15), small (<63 μm), or no drusen and no pigmentary changes); category 2 (early AMD characterized by a few small, few intermediate-sized (63-124 μm) drusen and / or pigmentary changes in one or both eyes); category 3 (intermediate AMD characterized by extensive (20 soft or 65 hard, but not soft) intermediate-sized drusen, one large (>125 μm) drusen, and / or geographic atrophy not involving the macula in one or both eyes); and category 4 (advanced unilateral AMD consisting of an advanced dry form with geographic atrophy involving the macula or an exudative form with choroidal neovascularization in one eye).

[0210] RBP4 inhibitor compounds and compounds with lower RBP4 in the blood In some embodiments, the present disclosure provides RBP4 inhibitory compounds, compounds that reduce blood RBP4 levels, and pharmaceutical compositions comprising the compounds. In some embodiments, the compounds are RBP4 inhibitors. In some embodiments, the compounds reduce blood RBP4 levels. The compounds and compositions are useful for inhibiting RBP4 and treating various disorders, including age-related macular degeneration and STGD. In some embodiments, an individual is administered a treatment comprising an RBP4 inhibitor compound provided herein upon diagnosis of AMD or STGD, or upon assessment of the individual as being at risk for developing AMD or STGD using the methods provided herein. Examples of RBP4 inhibitor compounds can be found in U.S. Patent Publication No. US2010 / 0292206, PCT Publication No. WO2010119992, US Publication No. US2011 / 0251187, US Publication No. US2018 / 0237404, US Patent 10,273,243, US Patent 8,980,924, US Patent 9,637,450, US Patent 9,944,644, US Patent 9,938,291, US Patent 10,072,016, PCT Publication No. WO2018232154, each of which is incorporated by reference.

[0211] Some embodiments provided herein include a compound represented by formula (I):

[0212] [ka] or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, for use in treating age-related macular degeneration, having the structure: During the ceremony, Each R A 1 , R A 2 , R A 3 , R A 4 and R A 5are independently selected from halogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heterocycloalkyl, -COR A 7 , -CON(R A 7 )2, optionally substituted (C0-C4 alkylene)-CN, optionally substituted (C0-C4 alkylene)-OR a 7 , optionally substituted (C0-C4 alkylene)-N(R A 7 )2, optionally substituted (C0-C4 alkylene)N(R A 8 )-COR A 7 , optionally substituted (C0-C4 alkylene)-SON(R A 7 )2, optionally substituted (C0-C4 alkylene)-SO2R A 7 , optionally substituted (C0-C4 alkylene)N(R A 8 )-SO2N(R A 7 )2, or optionally substituted (C0-C4 alkylene)N(R A 8 )-SO2R A 7 , Each R A 7 is independently selected from H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl; Or two R's A 11 groups joined together with the nitrogen to which they are attached to form an optionally substituted N-heterocyclyl; Each R A 8 is independently selected from H or optionally substituted alkyl; R A 6 is —H, —OH, optionally substituted alkyl, or halogen; p is 0, 1, 2, 3, 4, or 5; A A is the structure

[0213] [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, α, β, χ, and δ are each independently absent or present, and when present, each is a bond; X is C, Z1 is S, O, or N, and Z2 is S, O, N, or NR A 9 and R A 9 is H, optionally substituted alkyl, or oxetane; B A is a substituted or unsubstituted fused 5-, 6-, or 7-membered ring structure.

[0214] In certain embodiments, the compound of formula (I) has the structure

[0215] [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, R A 1 , R A 2 , R A 3 , R A 4 , and R A 5 are each independently H, halogen, CF, or C-C alkyl, where RA 2 , R A 3 , R A 4 , and R A 5 two or more of are other than H, R A 6 is H, OH, or a halogen, A A is the structure

[0216] [ka] and During the ceremony, α, β, χ, and δ are each independently absent or present, and if present, each is a bond f; X is C or N; Z1 is N, Z2 is N or NR A 9 and where R A 9 is H, C1-C4 alkyl, or oxetane; B A is a substituted or unsubstituted 5-, 6-, or 7-membered ring structure.

[0217] In some embodiments, the compound of formula (I) is 1-(3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)ethan-1-one. In certain embodiments, the compound of formula (I) is 1-(3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)ethan-1-one, 1-(3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-yl)ethan-1-one. phen-1-one, (4-(3-fluoro-2,5-bis(trifluoromethyl)phenyl)piperidin-1-yl)(4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)methanone, (4-(2-chloro-3-fluorophenyl)piperidin-1-yl)(5-(2-methoxyethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)methanone, (4-(2-chloro-3-fluorophenyl)piperidin-1-yl)(5-(2-methoxyethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)methanone piperidin-1-yl)(5-(3,3,3-trifluoropropyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)methanone, (4-(2-chloro-3-fluorophenyl)piperidin-1-yl)(5-(2,2,2-trifluoroethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)methanone, (4-(2-chloro-3-fluorophenyl)piperidin-1-yl)(5 -(oxetan-3-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)methanone, (4-(4-fluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)methanone, (4-(4-fluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)methanone, (4-(2-chloro-3-fluorophenyl)piperidin-1-yl)(5-(cyclopropylmethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)methanone, (4-(2-chloro-3-fluorophenyl)piperidin-1-yl)(5-ethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)methanone, (4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(6-ethyl-4, 5,6,7-Tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)methanone, (4-(4-fluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(5-(methylsulfonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)methanone, 1-(3-(4-(2-fluoro-6-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)ethan-1-one, (4-(3-fluoro 4-(2-chloro-3-fluorophenyl)piperidin-1-yl)(6-(cyclopropylmethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)methanone, (4-(3,5-bis(trifluoromethyl)phenyl)piperidin-1-yl)(5-(methylsulfonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[ 4,3-c]pyridin-3-yl)methanone, (4-(2-chloro-3-fluorophenyl)piperidin-1-yl)(5-(methylsulfonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)methanone, (4-(2-chloro-3-fluorophenyl)piperidin-1-yl)(6-(oxetan-3-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)methanone, 3-(4-(2-chloro-3-fluorophenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine-6-carbonitrile (4-(5-fluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl) (5-(methylsulfonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)methanone, 3-(4-(3,5-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-N-methyl-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine-6-carboxamide (6-(cyclopropylmethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl) (4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, Methyl 3-(4-(3,5-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine-6-carboxylate, (4-(3,5-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(5-(3,3,3-trifluoropropyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)methanone, (4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl) (4-(3,5-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(6-(2,2,2-trifluoroethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-yl)methanone, (4-(2-chloro-5-fluorophenyl)piperidin-1-yl)(5-(methylsulfonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)methanone, (4-(3,5-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(6-(2,2,2-trifluoroethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine ... -yl)methanone, 3-(4-(3,5-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine-6-carbonitrile, (4-(3,5-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(6-(oxetan-3-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)methanone, 3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine- 1-carbonyl)-N-methyl-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine-6-carboxamide, (4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(6-neopentyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)methanone, (4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(6-(2,2,2-trifluoroethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)methanone, methyl 3-(4-(2-chloro-3-fluorophenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine-6-carboxylate, 1-(3-(4-(3,5-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)ethan-1-one, (6-(cyclopropylmethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)(4-( 3,5-Difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(6-(2-methoxyethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)methanone, 1-(3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-3-methyl Loubutan-1-one, 1-(3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)propan-1-one, 1-(3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-2-methylpropan-1-one, 3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-2-methylpropan-1-one, (4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-yl)(6-(3,3,3-trifluoropropyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)methanone, (4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(5-(2-methoxyethyl)-4,5,6,7-Tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)methanone, (4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(5-(3,3,3-trifluoropropyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)methanone, 3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl) (4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(6-(oxetan-3-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)methanone, methyl 3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine-6-carboxylate, 2-(3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)acetic acid, (4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(5-(oxetan-3-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)methanone, (5-(cyclopropylmethyl)-4,5,6,7-tetrahydro- 1H-pyrazolo[4,3-c]pyridin-3-yl)(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(5-ethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)methanone, 3-(4-(3-fluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-N-methyl-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxamide, (4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(6-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)methanone, methyl 3-(4-(3,5-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate, (4-(3,5-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(5-ethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)methanone, (4-(3,5-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(5-(2-methoxyethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)methanone, 3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carbonitrile, methyl 3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate, (4-(3-fluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(6-(3,3,3-trifluoropropyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)methanone , (6-ethyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)(4-(3-fluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (4-(3-fluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(5-(oxetan-3-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)methanone, (4-(3-fluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone (4-(3-fluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(5-(3,3,3-trifluoropropyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)methanone, (4-(3-fluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(5-(3,3,3-trifluoropropyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)methanone, 4-(2-chloro-5-fluorophenyl)piperidin-1-yl)(4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)methanone, imidazo[1,2-a]pyridin-2-yl(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (4-(5-fluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)methanone, 1-(3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)ethan-1-one, (5-ethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)(4-(3-fluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, 3-(4-(3-fluoro-2-(trifluoromethyl)phenyl)piperidine-1- carbonyl)-N-methyl-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine-6-carboxamide, (4-(3-fluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(5-(methylsulfonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)methanone, (4-(3,5-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)methanone, (4-(3,5 -difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)methanone, (4-(2-chloro-3-fluorophenyl)piperidin-1-yl)(4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)methanone, (4-(2-chloro-3-fluorophenyl)piperidin-1-yl)(4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)methanone, (4-(3,4-difluoro- 2-(trifluoromethyl)phenyl)piperidin-1-yl)(4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)methanone, (4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)methanone, (4-(3,5-bis(trifluoromethyl)phenyl)piperidin-1-yl)(4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)methanone, (4-(3,5-bis(trifluoromethyl)phenyl)piperidin-1-yl)(4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)methanone, (4-(3-fluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)methanone, (4-(3-fluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3 -yl)methanone, 1-(3-(4-(2-chloro-3-fluorophenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)ethan-1-one, 1-(3-(4-(3-fluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)ethan-1-one, 1-(3-(4-(5-fluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)ethan-1-one, 1-(3-(4-(3,5-bis(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)ethan-1-one, 1-(3-(4-(4-fluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)ethan-1-one, 1-(3-(4-(4-fluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)ethan-1-one, phenyl)-1-one, (4-(2-fluoro-6-(trifluoromethyl)phenyl)piperidin-1-yl)(4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)methanone, (4-(3-fluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(5-(2,2,2-trifluoroethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)methanone, (5-(cyclopropylmethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)(4-(3-fluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, methyl 3-(4-(3-fluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate, 3-(4-(3-fluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carbonitrile, 1-(3-(4-(2-chloro-5-fluorophenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)ethan-1-one, (4-(2-fluoro-6-(trifluoromethyl)phenyl)piperidin-1-yl)(4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)methanone, tert-butyl 2-(3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)acetate, tert-butyl 3-(4-(3,5-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate, tert-butyl 3-(4-(3,5-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine-6-carboxylate, tert-butyl 3-(4-(2-fluoro-6-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate, tert-butyl 3-(4-(5-fluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate, tert-butyl 3-(4-(5-fluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,5,7-Tetrahydro-6H-pyrazolo[3,4-c]pyridine-6-carboxylate, tert-butyl 3-(4-(2-chloro-3-fluorophenyl)piperidine-1-carbonyl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate, tert-butyl 3-(4-(2-fluoro-6-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine-6-carboxylate tert-butyl 3-(4-(3,5-bis(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate, tert-butyl tert-butyl 3-(4-(3,5-bis(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine-6-carboxylate tert-butyl 3-(4-(2-chloro-5-fluorophenyl)piperidine-1-carbonyl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate tert-butyl 3-(4-(2-chloro-5-fluorophenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine-6-carboxylate tert-butyl 3-(4-(4-fluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine-6-carboxylate tert-butyl 3-(4-(3-fluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine-6-carboxylate tert-butyl 3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate tert-butyl 3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine-6-carboxylate, tert-butyl 3-(4-(3-fluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate, tert-butyl 3-(4-(4-fluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,6,7-tetrahydro-5, H-pyrazolo[4,3-c]pyridine-5-carboxylate, tert-butyl 3-(4-(2-chloro-3-fluorophenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine-6-carboxylate, (6,6-dimethyl-1,4,6,7-tetrahydropyrano[4,3-c]pyrazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (6,6-dioxide-1,4,5,7-tetrahydrothiopyrano[3,4-c]pyrazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone); (1,4,6,7-tetrahydropyrano[4,3-c]pyrazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (1-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (1-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone Hydro-1H-pyrazolo[3,4-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, 1-ethyl-N,N-dimethyl-3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine-6-carboxamide, (5-(2,2,2-trifluoroethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone (6-(2,2,2-trifluoroethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (5-chloro-1H-indazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (1H-pyrazolo[3,4-b]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (6-chloro-1H-indazol- 3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (5-(methylsulfonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, 1-(3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)ethan-1-one, (4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (6-fluoro-1-(oxetan-3-yl)-1H-indazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (1-ethyl-6-fluoro-1H-indazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (6-fluoro-1-isopropyl-1H-indazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone 1-(3-(4-fluoro-4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)ethan-1-one, (5-fluoro-1-methyl-1H-indazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (6-fluoro-1H-indazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidine-1-yl)methanone, 1-(3-(4-fluoro-4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)ethan-1-one, (5-fluoro-1-methyl-1H-indazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (6-fluoro-1H-indazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidine (6-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (6-(methylsulfonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, 1-(3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,5,7 -tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)ethan-1-one, (5-fluoro-1H-indazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (5-((chloromethyl)sulfonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (5-(2-methoxyethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (4-fluoro-4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)(4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)methanone, 1-(3-(4-(4-fluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)ethane-1 -one, (1-ethyl-5-fluoro-1H-indazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (6-fluoro-1-methyl-1H-indazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, 3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[4,3-c]pyridin-6- ... 6-methyl-3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,6,7-tetrahydro-5H-pyrazolo[3,4-c]pyridin-5-one, 6-methyl-3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,6,7-tetrahydro-5H-pyrazolo[3,4-c]pyridin-5-one, 5-methyl-3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[4,3-c]pyridin-6-one (5,5-dioxide-1,4,6,7-tetrahydrothiopyrano[4,3-c]pyrazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone), (1-methyl-5-(methylsulfonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (1-methyl-6-(methylsulfonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, 1-(1-ethyl-3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)ethan-1-one, (5-(methoxymethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (6-(methoxymethyl) (5-methoxy-1H-indazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (5-(oxetan-3-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (5-isobutyl-4,5,6 ,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, 1-(3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)propan-1-one, (5-ethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, 3 -methyl-1-(3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)butan-1-one, 2-methyl-1-(3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)propan-1-one, 2,2-dimethyl-1-(3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,6,7-Tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)propan-1-one, (5-(isopropylsulfonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (5-(isobutylsulfonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (5-(ethyl sulfonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, 3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1H-indazole-5-carbonitrile, (7-chloro-1H-indazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (5,6-difluoro-1H-indazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone (6-(2-methoxyethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, 3,3,3-trifluoro-1-(3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)propan-1-one, (5-(tert-butyl) (4-(2-(trifluoromethyl)phenyl)piperidine-1-yl)methanone, (5-isopropyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, N-methyl-3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxamide, N-methyl-3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine-6-carboxamide, (5-bromo-1H-indazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, tert-butyl 3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine-6-carboxylate, tert-butyl 3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl, )-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate, (5-fluoro-1-isopropyl-1H-indazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (7-fluoro-1H-indazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (1H-pyrazolo[4,3-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (1H-pi Pyrazolo[3,4-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (1H-pyrazolo[4,3-b]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (6-methoxy-1H-indazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (5-fluoro-1-(oxetan-3-yl)-1H-indazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (1-ethyl-5-(methylsulfonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (1-ethyl-6-(methylsulfonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, 1-(1-methyl-3-(4-(2-(trifluoromethyl)phenyl)piperidine-1 -carbonyl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)ethan-1-one, 1-(1-methyl-3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)ethan-1-one, N,N-dimethyl-3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxamide, N,N-dimethyl-3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine-6-carboxamide, (1-methyl-5,5-dioxide-1,4,6,7-tetrahydrothiopyrano[4,3-c]pyrazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone), (4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)(1,6,6-trimethylthiopyrano[4,3-c]pyrazol-3-yl)( ... trimethyl-1,4,6,7-tetrahydropyrano[4,3-c]pyrazol-3-yl)methanone, (1-methyl-1,4,6,7-tetrahydropyrano[4,3-c]pyrazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, 2-methyl-1-(3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)propan-1-one, (6- (Isopropylsulfonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (6-(ethylsulfonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, 1-(3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1 ,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)propan-1-one, 2-methoxy-1-(3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)ethan-1-one, 3,3,3-trifluoro-1-(3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)propan-1-one, (1H-indazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (1-methyl-1H-indazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (6-(oxetan-3-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (6-(tert-butylsulfonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, 2,2-dimethyl-1-(3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)propan-1-one, (6-(tert-butyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone (6-(isobutylsulfonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, 3-methyl-1-(3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)butan-1-one, (6-isobutyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4 -c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (6-isopropyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (6-ethyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (5-(tert-butylsulfonyl)-4,5,6,7-Tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, tert-butyl 3-(4-fluoro-4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate, (4-hydroxy-4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)(1-methyl-1H-indazol-3-yl)methanone, 1-(3-(4-hydroxy-4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,6,7-tetrahydro- 5H-Pyrazolo[4,3-c]pyridin-5-yl)ethan-1-one, 3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-N-methyl-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide, (4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(5-neopentyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)methanone, (4-(3 ,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(5-(oxetan-3-yl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)methanone, (5-(cyclopropylmethyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone )piperidin-1-yl)(5-ethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)methanone, 1-(3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-yl)-3-methylbutan-1-one, 1-(3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-yl)-2-methylpropan-1-one, (4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(5-picolinoyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)methanone, 3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carbonitrile, (4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl) (5-(2-methoxyethyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)methanone, (4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(5-(3,3,3-trifluoropropyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)methanone, (5-benzoyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, methyl 3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxylate, (4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)methanone, (4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(5-(2,2,2-trifluoroethyl)-1,4 ,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)methanone, (4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(5-(pyrrolidine-1-carbonyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)methanone, (4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(5-isonicotinoyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)methanone, (4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(5-isonicotinoyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)methanone,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(5-nicotinoyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)methanone, (4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(5-(piperidine-1-carbonyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)methanone, (4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(5-(piperazine-1-carbonyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyra, (4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, 1-(3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-yl)propan-1-one, (5,5-dioxide-4,6-dihydro-1H-thieno[3,4-c]pyrazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone; (4,6-Dihydro-1H-furo[3,4-c]pyrazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (1-ethyl-5-(methylsulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (1-methyl-5-(methylsulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone (1-methyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, 2-methoxy-1-(3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-yl)ethan-1-one, (5-(2-methoxyethyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, pyrrolo[3,4-c]pyrazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, 3,3,3-trifluoro-1-(3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-yl)propan-1-one, (5-(oxetan-3-yl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)(4-(2-(trifluoromethyl)phenyl) piperidin-1-yl)methanone, (5-(isobutylsulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (5-(isopropylsulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (5-(ethylsulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, tert-butyl 3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxylate, (5-methyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (5-(methylsulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone 1-(3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-yl)ethan-1-one, (5-(tert-butylsulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (5-(tert-butyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone (5-isobutyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (5-isopropyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (5-isopropyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (5-ethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone 1-(1-methyl-3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-yl)ethan-1-one, 2-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-yl)methanone, 2-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-yl)ethan-1- ...2-dimethyl-1-(3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-yl)propan-1-one, 3-methyl-1-(3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-yl)butane -1-one, 2-methyl-1-(3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-yl)propan-1-one, 1-(3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-yl)propane- 1-one, N,N-dimethyl-3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide, (5-(2,2,2-trifluoroethyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidine-1 -yl)methanone, (5-(methoxymethyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, tert-butyl 4-(3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-5-carbonyl)piperazine-1-carboxylate, tert-butyl 3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxylate, (5,5-dioxide-4,6,7,8-tetrahydro-1H-thiepino[4,3-c]pyrazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone), (4,6,7,8-tetrahydro-1H-oxepino[4,3-c]pyrazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, N-methyl-3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4,6,7,8-tetrahydropyrazolo[4,3-c]azepine-5(1H)-carboxamide, (5-(2,2, 2-Trifluoroethyl)-1,4,5,6,7,8-hexahydropyrazolo[4,3-c]azepin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (5-(tert-butylsulfonyl)-1,4,5,6,7,8-hexahydropyrazolo[4,3-c]azepin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, 2,2-dimethyl-1-(3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-yl)- (5-(tert-butyl)-1,4,5,6,7,8-hexahydropyrazolo[4,3-c]azepin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidine-1-yl)methanone, (5-(isobutylsulfonyl)-1,4,5,6,7,8-hexahydropyrazolo[4,3-c]azepin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidine-1-yl)methanone yl)methanone, 3-methyl-1-(3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4,6,7,8-tetrahydropyrazolo[4,3-c]azepin-5(1H)-yl)butan-1-one, (5-isobutyl-1,4,5,6,7,8-hexahydropyrazolo[4,3-c]azepin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (5-(isopropylsulfonyl)-1,4,5,6,7,8-hexahydropyrazolo[4,3-c]azepin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, 2-methyl-1-(3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4,6,7,8-tetrahydropyrazolo[4,3-c]azepin-5(1H)-yl)propan-1-one, (1-ethyl-5-(methylsulfonyl)-1,4,5,6,7,8-hexahydropyrazolo[4,3-c]azepin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone 1-(1-methyl-3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4,6,7,8-tetrahydropyrazolo[4,3-c]azepin-5(1H)-yl)ethan-1-one, (5-(methoxymethyl)-1,4,5,6,7,8-hexahydropyrazolo[4,3-c]azepin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (5-methyl-1,4,5,6,7,8-hexahydropyrazolo[4,3-c]azepin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone Hydropyrazolo[4,3-c]azepin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (5-isopropyl-1,4,5,6,7,8-hexahydropyrazolo[4,3-c]azepin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (5-(ethylsulfonyl)-1,4,5,6,7,8-hexahydropyrazolo[4,3-c]azepin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone 1-(3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4,6,7,8-tetrahydropyrazolo[4,3-c]azepin-5(1H)-yl)propan-1-one, (5-ethyl-1,4,5,6,7,8-hexahydropyrazolo[4,3-c]azepin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (5-(methylsulfonyl)-1,4,5,6,7,8-hexahydropyrazolo[4,3-c]azepin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, 1-(3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4,6,7,8-tetrahydropyrazolo[4,3-c]azepin-5(1H)-yl)ethan-1-one, (1,4,5,6,7,8-hexahydropyrazolo[4,3-c]azepin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone N,N-dimethyl-3-(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (1-methyl-5-(methylsulfonyl)-1,4,5,6,7,8-hexahydropyrazolo[4,3-c]azepin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (1-methyl-1,4,5,6,7,8-hexahydropyrazolo[4,3-c]azepin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, )piperidine-1-carbonyl)-4,6,7,8-tetrahydropyrazolo[4,3-c]azepine-5(1H)-carboxamide, (5-(2-methoxyethyl)-1,4,5,6,7,8-hexahydropyrazolo[4,3-c]azepin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, 2-methoxy-1-(3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4,6,7,8-tetrahydropyrazolo[4,3-c]azepine-5(1H)-carboxamide 3,3,3-Trifluoro-1-(3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4,6,7,8-tetrahydropyrazolo[4,3-c]azepin-5(1H)-yl)propan-1-one, (5-(oxetan-3-yl)-1,4,5,6,7,8-hexahydropyrazolo[4,3-c]azepin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, tert-butyl 3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4,6,7,8-tetrahydropyrazolo[4,3-c]azepine-5(1H)-carboxylate, (6-(trifluoromethyl)imidazo[1,2-b]pyridazin-2-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (6-fluoroimidazo[1,2-b]pyridazin-2-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (6-(pyrrolidin-1-yl)imidazo[1,2-b]pyridazine-2 -yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (6-methoxyimidazo[1,2-b]pyridazin-2-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (6-methylimidazo[1,2-b]pyridazin-2-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (6-chloroimidazo[1,2-b]pyridazin-2-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, imidazo[1,2-b]pyridazin-2-yl(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (6-chloro-2-methylimidazo[1,2-b]pyridazin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (1H-benzo[d]imidazol-2-yl)(4-(2-(trifluoromethyl)phenyl)piperidine-1-yl)methanone yl)methanone, (1H-imidazo[4,5-b]pyridin-2-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (4-(5-fluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)methanone, (4-(3-fluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(6-(2-methoxyethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)methanone, 6-methyl-2-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)pyrimidine-4-carboxylic acid, methyl 6-methyl-2-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)pyrimidine-4-carboxylate, N-(cyclopropylsulfonyl)-2-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)benzamide, N-(phenylsulfonyl)-2-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)benzamide, N-(methylsulfonyl)-2-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl) carboxy)benzamide, 3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)benzamide, 2-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)benzamide, 4-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)benzoic acid, 3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)benzoic acid, 2-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)benzo Benzamide, 4-(4-(2-(tert-butyl)phenyl)piperidine-1-carbonyl)benzoic acid, 2-(4-(2-(tert-butyl)phenyl)piperidine-1-carbonyl)benzoic acid, 3-(4-(2-(tert-butyl)phenyl)piperidine-1-carbonyl)benzoic acid, 4-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)benzamide, 1-(3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4,7-dihydroisothiazolinone (4,5,6,7-tetrahydroisothiazolo[5,4-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (4,5,6,7-tetrahydroisothiazolo[4,5-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, 1-(3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-6,7-Dihydroisoxazolo[4,5-c]pyridin-5(4H)-yl)ethan-1-one, 1-(3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4,7-dihydroisoxazolo[5,4-c]pyridin-6(5H)-yl)ethan-1-one, (4,5,6,7-tetrahydroisoxazolo[4,5-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl) benzo[c]isothiazol-3-yl(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, benzo[d]thiazol-2-yl(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, benzo[d]isoxazol-3-yl(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone 1-(3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-6,7-dihydroisothiazolo[4,5-c]pyridin-5(4H)-yl)ethan-1-one, benzo[d]oxazol-2-yl(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (3-methyloxetan-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone 2-(2-hydroxyphenyl)-1-(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)ethan-1-one, (4-(2-(tert-butyl)phenyl)piperidin-1-yl)(tetrahydrothiophen-2-yl)methanone, rac-tert-butyl (2R,3R)-2-(4-(2-(tert-butyl)phenyl)piperidine-1-carbonyl)-3-hydroxypyrrolidine-1-carboxylate, rac-tert-butyl (2R,4R)-2-(4-(2-(tert-butyl)phenyl)piperidine-1-carbonyl)-4-hydroxypyrrolidine-1-carboxylate 2-(2-oxo-2-(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)ethyl)phenylsulfamate, (4-(2-(tert-butyl)phenyl)piperidin-1-yl) (1,1-dioxidotetrahydrothiophen-2-yl)methanone, rac-(4-(2-(tert-butyl)phenyl)piperidin-1-yl)((2R,3R)-3-hydroxypyrrolidin-2-yl)methanone, rac-(4-(2-(tert-butyl)phenyl)piperidin-1-yl)((2R,4R)-4-hydroxypyrrolidin-2-yl)methanone, rac-(R)-1-(2-(4-(2-(tert-butyl)phenyl)piperidine-1-carbonyl)pyrrolidin-1-yl)ethan-1-one, (6- Bromo-1H-pyrrolo[3,2-b]pyridin-2-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (5-morpholino-1H-pyrrolo[3,2-b]pyridin-2-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (5-(1H-imidazol-1-yl)-1H-pyrrolo[3,2-b]pyridin-2-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (5-chloro-1H-pyrrolo[3,2-b]pyridin-2-yl)(4-( 2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (5-fluoro-1H-pyrrolo[3,2-b]pyridin-2-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (5-methyl-1H-pyrrolo[3,2-b]pyridin-2-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (6-methoxy-1H-pyrrolo[3,2-b]pyridin-2-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, imidazo[1,2-a ]pyridin-2-yl(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (6-chloro-2-methylimidazo[1,2-b]pyridazin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, imidazo[1,2-b]pyridazin-6-yl(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (1H-pyrrolo[2,3-b]pyridin-2-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (1H-pyrrolo[3,2-c]pyridin-2-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (6-chloro-1H-pyrrolo[3,2-b]pyridin-2-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (6-morpholino-1H-pyrrolo[3,2-b]pyridin-2-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone (6-(1H-imidazol-1-yl)-1H-pyrrolo[3,2-b]pyridin-2-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (1-methyl-1H-pyrrolo[3,2-b]pyridin-2-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (5-methoxy-1H-pyrrolo[3,2-b]pyridin-2-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, si-1H-pyrrolo[3,2-b]pyridin-2-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (6-fluoro-1H-pyrrolo[3,2-b]pyridin-2-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (1H-imidazo[4,5-b]pyridin-2-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone )phenyl)piperidin-1-yl)methanone, (6-methyl-1H-pyrrolo[3,2-b]pyridin-2-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (1H-indol-2-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (1H-pyrrolo[3,2-b]pyridin-2-yl)(4-(2, -(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (1H-pyrrolo[2,3-c]pyridin-2-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (1H-pyrazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (1H-1,2,3-triazol-5-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, pyrazin-2-yl(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (6-methoxypyridazin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (6-methylpyridazin-3-yl)(4-(2-( (4-methyl-1,2,3-thiadiazol-5-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (6-chloropyridazin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, pyridazin-3-yl(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, pyridazin-4-yl(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, 4-(2-(trifluoromethyl)phenyl)piperidine-1-carboxylic acid, or 3-oxo-3-(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)propanoic acid.

[0218] Some embodiments provided herein provide a compound of formula (II) for use in the treatment of age-related macular degeneration.

[0219] [ka] or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, having the structure: During the ceremony, Ring A B is optionally further substituted benzene, R B 1 is an optionally substituted branched C alkyl group; X B 1 is O, S, SO, SO2, or NH, X B 2 is a bond or a C1-C3 alkylene group, Ring B B is azetidine, pyrrolidine or piperidine, X B 3 is CO or SO2, R B 2 is a substituent.

[0220] In some embodiments, the compound of Formula (II) has the structure

[0221] [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, Ring A B is optionally further substituted benzene, R B 1 is an optionally substituted branched C3-C6 alkyl group, and X B 1 is O, S, SO, SO2, or NH, X B 2 is a bond or a C1-C3 alkylene group, Ring B B is azetidine or piperidine, X B 3 is CO or SO2, R B 2is an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an optionally substituted hydroxy group, an optionally substituted mercapto group, a cyano group, a nitro group, an acyl group, or a halogen atom.

[0222] In some embodiments, the compound of Formula (II) is 4-(3-(2-tert-butylphenoxy)azetidin-1-yl)-4-oxobutanoic acid, 3-{3-[(2-tert-butyl-4-fluorophenoxy)methyl]azetidin-1-yl}-3-oxopropanoic acid, 2-{[3-(2-tert-butyl-4-chlorophenoxy)azetidin-1-yl]carbonyl}pyridine, 4-[3-(2-tert-butyl-4-chlorophenoxy)azetidin-1-yl]-4-oxobutanoic acid, {3-[(2-tert-butyl-4-chlorophenoxy)methyl]azetidin- 1-yl}(oxo)acetic acid, {3-[(2-tert-butylphenoxy)methyl]azetidin-1-yl}(oxo)acetic acid, 3-{3-[(2-tert-butylphenoxy)methyl]azetidin-1-yl}-3-oxopropanoic acid, {4-[(2-tert-butyl-4-chlorophenoxy)methyl]piperidin-1-yl}(oxo)acetic acid, [4-(2-tert-butylphenoxy)piperidin-1-yl](oxo)acetic acid, or {4-[(2-tert-butylphenoxy)methyl]piperidin-1-yl}(oxo)acetic acid, or a pharmaceutically acceptable salt thereof.

[0223] Some embodiments provided herein provide a compound of formula (III) for use in the treatment of age-related macular degeneration.

[0224] [ka] or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, having the structure: During the ceremony, Ring A C is a further optionally substituted benzene ring, Ring BC is a further optionally substituted piperazine ring; R C is a substituent.

[0225] In some embodiments, the compound of formula (III) has the structure

[0226] [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, Ring A C is a benzene ring optionally substituted with 1 to 3 substituents selected from the group consisting of (a) halogen atoms and (b) C alkyl groups; Ring B C is a piperazine ring optionally substituted with 1 to 3 substituents selected from the group consisting of (a) a halogen atom, (b) a C1-C6 alkyl group optionally substituted with 1 to 3 halogen atoms, and (c) a C1-C6 alkoxy group optionally substituted with 1 to 3 halogen atoms; R C (1) optionally substituted C1-C 10 alkyl group, (2) optionally substituted C-C 14 (3) an optionally substituted 5- or 6-membered aromatic heterocyclic group; (4) an optionally substituted amino group; (5) an optionally substituted carboxy group; or (6) an optionally substituted carbamoyl group.

[0227] In some embodiments, the compound of Formula (III) is N-{[4-(2-tert-butylphenyl)piperazin-1-yl]carbonyl}glycine, 3-[4-(2-tert-butylphenyl)piperazin-1-yl]-3-oxopropanoic acid, [4-(2-tert-butyl-4-chlorophenyl)piperazin-1-yl](oxo)acetic acid, 5-{2-[4-(2-tert-butylphenyl)piperazin-1-yl]-2-oxoethyl}imidazolidine-2,4-dione, [(5-{[4-(2-tert-butylphenyl)piperazin-1-yl]carbonyl}isoxazol-3-yl)oxy]acetic acid, or a pharmaceutically acceptable salt thereof.

[0228] Some embodiments provided herein provide a compound of formula (IV) for use in the treatment of age-related macular degeneration.

[0229] [ka] or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, having the structure: During the ceremony, Ring A D is a 5-membered non-aromatic heterocycle optionally further substituted by one substituent; Ring B D is a further optionally substituted benzene ring, XD is a bond, O, CH2O, OCH2, CH2, (CH2)2, S, CH2S, SCH2, S(O), CH2S(O), S(O)CH2, S(O)2, CH2S(O)2, or S(O)2CH2.

[0230] In some embodiments, the compound of formula (IV) has the structure

[0231] [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, Ring A D is a 5-membered non-aromatic heterocycle optionally further substituted with one oxo group; Ring B D is a benzene ring optionally further substituted with 1 to 4 substituents; XD is O, CH2O, OCH2, CH2, (CH2)2, S, CH2S, SCH2, S(O), CH2S(O), S(O)CH2, S(O)2, CH2S(O)2, or S(O)2CH2.

[0232] In some embodiments, the compound of formula (IV) is ({(3S)-1-[3,5-bis(trifluoromethyl)phenyl]pyrrolidin-3-yl}oxy)acetic acid, ({1-[4-chloro-3-(trifluoromethyl)phenyl]pyrrolidin-3-yl}sulfanyl)acetic acid, 3-{(2R,5S)-5-[3,5-bis(trifluoromethyl)phenyl]tetrahydrofuran-2-yl}propanoic acid, or a pharmaceutically acceptable salt thereof.

[0233] Some embodiments provided herein provide a compound of formula (V):

[0234] [ka] or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, having the structure: During the ceremony, Ring A E is a further optionally substituted monocyclic nitrogen-containing aromatic heterocycle, X E is CH2 or O, In the formula, R E is a hydrogen atom or a C1-C6 alkyl group.

[0235] In some embodiments, the compound of formula (V) has the structure

[0236] [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, Ring A E is a pyrazole ring, a pyridine ring, an oxazole ring, an imidazole ring or a pyrimidine ring, X E is S, optionally substituted alkylene, or O; R E is a hydrogen atom or a C1-C6 alkyl group.

[0237] In some embodiments, the compound of Formula (V) is ((4-(3,5-bis(trifluoromethyl)phenyl)-1,3-oxazol-2-yl)sulfanyl)acetic acid, ethyl ((6-(3,5-bis(trifluoromethyl)phenyl)-pyridin-3-yl)sulfanyl)acetic acid, ((6-(3,5-bis(trifluoromethyl)-phenyl)pyridin-3-yl)sulfanyl)acetic acid, or 3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-pyrazol-1-yl)butanoic acid.

[0238] In some embodiments, the RBP4 inhibitor is an RBP4 inhibitor provided in Table B.

[0239] [Table 2-1]

[0240] [Table 2-2]

[0241] [Table 2-3]

[0242] [Table 2-4]

[0243] Preparation of compounds The compounds used in the chemical reactions described herein are made according to organic synthesis techniques known to those skilled in the art, starting from commercially available chemicals and / or compounds described in the chemical literature.Commercially available chemicals include Acros Organics (Pittsburgh,PA),Aldrich Chemical (Milwaukee,WI,including Sigma Chemical and Fluka),Apin Chemicals Ltd.(Milton Park,UK),Avocado Research(Lancashire,UK),BDH Inc.(Toronto,Canada),Bionet(Cornwall,UK),Chemservice Inc.(West Chester,PA),Crescent Chemical Co.(Hauppauge, NY),Eastman Organic Chemicals,Eastman Kodak Company(Rochester,NY),Fisher Scientific Co.(Pittsburgh,PA),Fisons Chemicals(Leicestershire,UK),Frontier Scientific(Logan,UT),ICN Biomedicals,Inc.(Costa Mesa,CA),Key Organics(Cornwall,UK),Lancaster Synthesis(Windham,NH),Maybridge Chemical Co. Ltd.(Cornwall,UK),Parish Chemical Co.(Orem,UT),Pfaltz & Bauer, Inc.(Waterbury,CN),Polyorganix(Houston,TX),Pierce Chemical Co.(Rockford,IL),Riedel de Haen AG(Hanover,Germany),Spectrum Quality Product,Inc.(New Brunswick,NJ),TCI America(Portland,OR),Trans World Chemicals,Inc.(Rockville,MD),and Wako Chemicals USA,Inc.(Richmond,VA) is a very popular company.

[0244] Suitable references and articles detailing the synthesis of reactants useful in the preparation of the compounds described herein or providing references to articles describing the preparation include, for example, "Synthetic Organic Chemistry," John Wiley & Sons, Inc., New York; S.R. Sandler et al., "Organic Functional Group Preparations," 2nd Ed., Academic Press, New York, 1983; H.O. House, "Modern Synthetic Reactions," 2nd Ed., W.A. Benjamin, Inc. Menlo Park, Calif., 1972; T.L.G. Gilchrist, "Heterocyclic Chemistry," 2nd Ed., John Wiley & Sons, New York, 1992; J. March, "Advanced Organic Chemistry: Reactions, Mechanisms and Structure," 4th Ed., Wiley Interscience, New York, 1992. Further suitable reference books and articles detailing the synthesis of reactants useful in the preparation of the compounds described herein or providing references to articles describing the preparation include, for example, Fuhrhop, J. and Penzlin G. "Organic Synthesis: Concepts, Methods, Starting Materials", Second, Revised and Enlarged Edition (1994) John Wiley & Sons, ISBN: 3 527-29074-5; Hoffman, RV "Organic Chemistry, An Intermediate Text" (1996) Oxford University Press, ISBN 0-19-509618-5; Larock, RC "Comprehensive Organic Transformations: A Guide to Functional Group Preparations", 2nd Edition (1999) Wiley-VCH, ISBN: 0-471-19031-4; March, J. "Advanced Organic Chemistry: Reactions, Mechanisms, and Structure", 4th Edition(1992)John Wiley & Sons,ISBN:0-471-60180-2;Otera, J.(editor)“Modern Carbonyl Chemistry”(2000)Wiley-VCH,ISBN:3-527-29871-1;Patai,S.“Patai's 1992 Guide to the Chemistry of Functional Groups”(1992)Interscience ISBN:0-471-93022-9;Solomons,TWG“Organic Chemistry”7th Edition(2000)John Wiley & Sons,ISBN:0-471-19095-0;Stowell,JC,“Intermediate Organic Chemistry”2nd Edition(1993)Wiley-Interscience,ISBN:0-471-57456-2;“Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann's Encyclopedia”(1999)John Wiley & Sons,ISBN:3-527-29645-X,in 8 volumes;“Organic Reactions” (1942-2000) John Wiley & Sons, in over 55 volumes; and “Chemistry of Functional Groups” John Wiley & Sons, in 73 volumes. .

[0245] Alternatively, specific and similar reactants can be identified through the index of known chemicals and reactions prepared by the Chemical Abstract Service of the American Chemical Society, available in most public and university libraries, and through online databases (for more information, contact the American Chemical Society, Washington, DC). Known but not commercially available chemicals in catalogs can optionally be prepared by custom chemical synthesis houses, and many standard chemical supply houses (e.g., those listed above) offer custom synthesis services. A reference for the preparation and selection of pharmaceutical salts of the heterocyclic RBP4 inhibitor compounds described herein is PH Stahl & CG Wermuth "Handbook of Pharmaceutical Salts", Verlag Helvetica Chimica Acta, Zurich, 2002.

[0246] Retinol-binding protein 4 (RBP4) Retinol-binding protein 4 (RBP4), the only retinol transporter in the blood, is secreted by adipocytes and the liver. A reduction in RBP4 levels can reduce the accumulation of lipofuscin, which leads to vision loss in diseases such as STGD, AMD, and dry (atrophic) age-related macular degeneration. In some instances, reducing RBP4 reduces lipofuscin accumulation in the retina. In some embodiments, the compounds and formulations described herein reduce serum or plasma RBP4, thereby slowing or halting vision loss from excessive lipofuscin accumulation in the retina. In some embodiments, the compounds and formulations described herein reduce serum or plasma RBP4, thereby slowing or halting vision loss from age-related macular degeneration.

[0247] In some embodiments, 48 ​​hours after administration of an RBP4 inhibitor, a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, serum or plasma levels of RBP4 are reduced by at least 30% from baseline. In some embodiments, 48 ​​hours after administration of an RBP4 inhibitor, a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, serum or plasma levels of RBP4 are reduced by at least 40% from baseline. In some embodiments, 48 ​​hours after administration of an RBP4 inhibitor, a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, serum or plasma levels of RBP4 are reduced by at least 50% from baseline. In other embodiments, 48 ​​hours after administration of the RBP4 inhibitor, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, serum or plasma levels of RBP4 are reduced by at least 65% from baseline. In certain embodiments, 48 ​​hours after administration of an RBP4 inhibitor, a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, serum or plasma levels of RBP4 are reduced by at least 80% from baseline. In some embodiments, 48 ​​hours after administration of an RBP4 inhibitor, a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, serum or plasma levels of RBP4 are reduced by at least 85% from baseline.

[0248] In some embodiments, 36 hours after administration of an RBP4 inhibitor, a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, serum or plasma levels of RBP4 are reduced by at least 30% from baseline. In some embodiments, 36 hours after administration of an RBP4 inhibitor, a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, serum or plasma levels of RBP4 are reduced by at least 40% from baseline. In some embodiments, 36 hours after administration of an RBP4 inhibitor, a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, serum or plasma levels of RBP4 are reduced by at least 50% from baseline. In other embodiments, 36 hours after administration of an RBP4 inhibitor, a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, serum or plasma levels of RBP4 are reduced by at least 65% from baseline. In certain embodiments, 36 hours after administration of an RBP4 inhibitor, a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, serum or plasma levels of RBP4 are reduced by at least 80% from baseline. In some embodiments, 36 hours after administration of an RBP4 inhibitor, a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, serum or plasma levels of RBP4 are reduced by at least 85% from baseline.

[0249] In some embodiments, 24 hours after administration of an RBP4 inhibitor, a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, serum or plasma levels of RBP4 are reduced by at least 30% from baseline. In some embodiments, 24 hours after administration of an RBP4 inhibitor, a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, serum or plasma levels of RBP4 are reduced by at least 40% from baseline. In some embodiments, 24 hours after administration of an RBP4 inhibitor, a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, serum or plasma levels of RBP4 are reduced by at least 50% from baseline. In other embodiments, 24 hours after administration of an RBP4 inhibitor, a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, serum or plasma levels of RBP4 are reduced by at least 65% from baseline. In certain embodiments, 24 hours after administration of an RBP4 inhibitor, a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, serum or plasma levels of RBP4 are reduced by at least 80% from baseline. In some embodiments, 24 hours after administration of an RBP4 inhibitor, a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, serum or plasma levels of RBP4 are reduced by at least 85% from baseline.

[0250] In some embodiments, 12 hours after administration of an RBP4 inhibitor, a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, serum or plasma levels of RBP4 are reduced by at least 30% from baseline. In some embodiments, 12 hours after administration of an RBP4 inhibitor, a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, serum or plasma levels of RBP4 are reduced by at least 40% from baseline. In some embodiments, 12 hours after administration of an RBP4 inhibitor, a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, serum or plasma levels of RBP4 are reduced by at least 50% from baseline. In other embodiments, 12 hours after administration of an RBP4 inhibitor, a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, serum or plasma levels of RBP4 are reduced by at least 65% from baseline. In certain embodiments, 12 hours after administration of an RBP4 inhibitor, a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, serum or plasma levels of RBP4 are reduced by at least 80% from baseline. In some embodiments, 12 hours after administration of an RBP4 inhibitor, a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, serum or plasma levels of RBP4 are reduced by at least 85% from baseline.

[0251] In some embodiments, 6 hours after administration of an RBP4 inhibitor, a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, serum or plasma levels of RBP4 are reduced by at least 20% from baseline. In some embodiments, 6 hours after administration of an RBP4 inhibitor, a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, serum or plasma levels of RBP4 are reduced by at least 25% from baseline. In some embodiments, 6 hours after administration of an RBP4 inhibitor, a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, serum or plasma levels of RBP4 are reduced by at least 30% from baseline. In some embodiments, 6 hours after administration of an RBP4 inhibitor, a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, serum or plasma levels of RBP4 are reduced by at least 40% from baseline. In some embodiments, 6 hours after administration of an RBP4 inhibitor, a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, serum or plasma levels of RBP4 are reduced by at least 50% from baseline. In other embodiments, 6 hours after administration of an RBP4 inhibitor, a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, serum or plasma levels of RBP4 are reduced by at least 65% from baseline. In certain embodiments, 6 hours after administration of an RBP4 inhibitor, a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, serum or plasma levels of RBP4 are reduced by at least 80% from baseline. In some embodiments, 6 hours after administration of an RBP4 inhibitor, a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, serum or plasma levels of RBP4 are reduced by at least 85% from baseline.

[0252] In some embodiments, 48 ​​hours after administration of an RBP4 inhibitor, a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, serum or plasma levels of RBP4 are reduced by at least 1 mg / dL. In other embodiments, 48 ​​hours after administration of an RBP4 inhibitor, a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, serum or plasma levels of RBP4 are reduced by at least 2 mg / dL. In some embodiments, 48 ​​hours after administration of an RBP4 inhibitor, a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, serum or plasma levels of RBP4 are reduced by at least 5 mg / dL. In certain embodiments, 48 ​​hours after administration of an RBP4 inhibitor, a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, serum or plasma levels of RBP4 are reduced by at least 10 mg / dL. In some embodiments, 48 ​​hours after administration of an RBP4 inhibitor, a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, serum or plasma levels of RBP4 are reduced by at least 15 mg / dL.

[0253] In some embodiments, 36 hours after administration of an RBP4 inhibitor, a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, serum or plasma levels of RBP4 are reduced by at least 1 mg / dL. In other embodiments, 36 hours after administration of an RBP4 inhibitor, a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, serum or plasma levels of RBP4 are reduced by at least 2 mg / dL. In some embodiments, 36 hours after administration of an RBP4 inhibitor, a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, serum or plasma levels of RBP4 are reduced by at least 5 mg / dL. In certain embodiments, 36 hours after administration of an RBP4 inhibitor, a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, serum or plasma levels of RBP4 are reduced by at least 10 mg / dL. In some embodiments, 36 hours after administration of an RBP4 inhibitor, a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, serum or plasma levels of RBP4 are reduced by at least 15 mg / dL.

[0254] In some embodiments, 24 hours after administration of an RBP4 inhibitor, a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, serum or plasma levels of RBP4 are reduced by at least 1 mg / dL. In other embodiments, 24 hours after administration of an RBP4 inhibitor, a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, serum or plasma levels of RBP4 are reduced by at least 2 mg / dL. In some embodiments, 24 hours after administration of an RBP4 inhibitor, a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, serum or plasma levels of RBP4 are reduced by at least 5 mg / dL. In certain embodiments, 24 hours after administration of an RBP4 inhibitor, a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, serum or plasma levels of RBP4 are reduced by at least 10 mg / dL. In some embodiments, 24 hours after administration of an RBP4 inhibitor, a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, serum or plasma levels of RBP4 are reduced by at least 15 mg / dL.

[0255] In some embodiments, 12 hours after administration of an RBP4 inhibitor, a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, serum or plasma levels of RBP4 are reduced by at least 1 mg / dL. In other embodiments, 12 hours after administration of an RBP4 inhibitor, a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, serum or plasma levels of RBP4 are reduced by at least 2 mg / dL. In some embodiments, 12 hours after administration of an RBP4 inhibitor, a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, serum or plasma levels of RBP4 are reduced by at least 5 mg / dL. In certain embodiments, 12 hours after administration of an RBP4 inhibitor, a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, serum or plasma levels of RBP4 are reduced by at least 10 mg / dL. In some embodiments, 12 hours after administration of an RBP4 inhibitor, a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, serum or plasma levels of RBP4 are reduced by at least 15 mg / dL.

[0256] In some embodiments, 6 hours after administration of an RBP4 inhibitor, a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, serum or plasma levels of RBP4 are reduced by at least 1 mg / dL. In other embodiments, 6 hours after administration of an RBP4 inhibitor, a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, serum or plasma levels of RBP4 are reduced by at least 2 mg / dL. In some embodiments, 6 hours after administration of an RBP4 inhibitor, a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, serum or plasma levels of RBP4 are reduced by at least 5 mg / dL. In certain embodiments, 6 hours after administration of an RBP4 inhibitor, a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, serum or plasma levels of RBP4 are reduced by at least 10 mg / dL. In some embodiments, 6 hours after administration of an RBP4 inhibitor, a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, serum or plasma levels of RBP4 are reduced by at least 15 mg / dL.

[0257] Treatment method In some embodiments, the compounds disclosed herein, when administered to a subject in need of treatment or amelioration of a disease associated with an alteration in the RBP4 pathway, such as AMD or STGD, are used to treat or ameliorate the effects of a disease associated with an alteration in the RBP4 pathway, such as AMD or STGD. In some cases, the compounds disclosed herein, when administered to a subject in need of treatment or amelioration of the effects of a disease associated with an alteration in the RBP4 pathway, such as age-related macular degeneration or STGD, are used to treat or ameliorate the effects of a disease associated with an alteration in the RBP4 pathway, such as age-related macular degeneration or STGD.

[0258] Age-related macular degeneration Age-related macular degeneration (AMD) is a common eye disease among people over 50 and is a leading cause of vision loss. It causes damage to the macula, a small spot near the center of the retina and the part of the eye required for sharp central vision. As AMD progresses, a blurred area near the center of vision is a common symptom. Over time, the blurred area can grow larger, and the subject may develop a blank spot in their central vision.

[0259] Some embodiments provided herein describe the use of an RBP4 inhibitor described herein to treat AMD in a subject in need thereof. In some embodiments, the RBP4 inhibitor inhibits AMD. In certain embodiments, the RBP4 inhibitor halts the onset of AMD or its clinical symptoms. In certain embodiments, the RBP4 inhibitor reduces the onset of AMD or its clinical symptoms. In certain embodiments, the RBP4 inhibitor alleviates AMD in a subject. In certain embodiments, the RBP4 inhibitor causes regression, reversal, or improvement of AMD. In certain embodiments, the RBP4 inhibitor reduces the number, frequency, duration, or severity of AMD clinical symptoms.

[0260] In some embodiments, RBP4 inhibitor is used prophylactically.In certain embodiments, RBP4 inhibitor is used to prevent or reduce the risk of developing AMD.In certain embodiments, RBP4 inhibitor can prevent the clinical symptoms of AMD from developing in subjects who may be predisposed to AMD but have not yet experienced or shown symptoms of AMD.

[0261] Dry (atrophic) Age-related Macular Degeneration Approximately 85% to 90% of macular degeneration cases are of the "dry" (atrophic) type. It is estimated that 62.9 million individuals worldwide have this form of AMD, 8 million of whom are Americans. Due to increased life expectancy and current demographics, this number is expected to triple by 2020. Currently, there are no FDA-approved treatments for dry AMD. Given the lack of treatment and high prevalence, drug development for dry AMD is of paramount importance. Clinically, atrophic AMD represents a slowly progressive neurodegenerative disorder in which specialized neurons (rod and cone photoreceptors) die in the central part of the retina, called the macula. Histopathological and clinical imaging studies indicate that photoreceptor alterations in dry AMD are caused by abnormalities in the retinal pigment epithelium (RPE), which is located beneath the photoreceptors and provides critical metabolic support for these light-sensing neuronal cells. Experimental and clinical data indicate that excessive accumulation of cytotoxic autofluorescent lipid-protein-retinoid aggregates (lipofuscin) in the RPE is a major trigger of dry AMD. The primary cytotoxic component of RPE lipofuscin is the pyridinium bisretinoid A2E. Additional cytotoxic bisretinoids are isoA2E, atRAL di-PE, and A2-DHP-PE. The formation of A2E and other lipofuscin bisretinoids, such as A2-DHP-PE (A2-dihydropyridine-phosphatidylethanolamine) and atRAL di-PE (all-trans-retinal dimer-phosphatidylethanolamine), is initiated nonenzymatically in photoreceptor cells and can be considered a by-product of a properly functioning visual cycle.

[0262] Some embodiments provided herein describe the use of an RBP4 inhibitor described herein to treat dry (atrophic) AMD in a subject in need thereof. In some embodiments, the RBP4 inhibitor inhibits dry (atrophic) AMD. In certain embodiments, the RBP4 inhibitor halts the development of dry (atrophic) AMD or its clinical symptoms. In certain embodiments, the RBP4 inhibitor reduces the development of dry (atrophic) AMD or its clinical symptoms. In certain embodiments, the RBP4 inhibitor alleviates dry (atrophic) AMD in a subject. In certain embodiments, the RBP4 inhibitor causes regression, reversal, or improvement of dry (atrophic) AMD. In certain embodiments, the RBP4 inhibitor reduces the number, frequency, duration, or severity of dry (atrophic) AMD clinical symptoms.

[0263] In some embodiments, RBP4 inhibitor is used preventively.In certain embodiments, RBP4 inhibitor is used to prevent or reduce the risk of developing dry (atrophic) AMD.In certain embodiments, RBP4 inhibitor can prevent the clinical symptoms of dry (atrophic) AMD from developing in the subject who may be predisposed to dry (atrophic) AMD but has not yet experienced or shown the symptoms of dry (atrophic) AMD.

[0264] Pharmaceutical Composition In certain embodiments, the RBP4 inhibitory compounds described herein are administered as pure chemicals. In other embodiments, the RBP4 inhibitory compounds described herein are combined with a pharmaceutically suitable or acceptable carrier (also referred to herein as a pharmaceutically suitable (or acceptable) excipient, a physiologically suitable (or acceptable) excipient, or a physiologically suitable (or acceptable) carrier), selected based on the selected route of administration and standard pharmaceutical practice, for example, as described in Remington: The Science and Practice of Pharmacy (Gennaro, 21st Ed. Mack Pub. Co., Easton, PA (2005)).

[0265] Provided herein are pharmaceutical compositions comprising at least one RBP4 inhibitor compound, or its stereoisomer, pharmaceutically acceptable salt, or N-oxide, together with one or more pharmaceutically acceptable carriers. A carrier (or excipient) is acceptable or suitable if it is compatible with the other ingredients of the composition and not harmful to the recipient (i.e., subject or patient) of the composition.

[0266] In one embodiment, a pharmaceutical composition is provided comprising an RBP4 inhibitor or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient. In one embodiment, the pharmaceutical composition is provided in an oral dosage form comprising a compound provided herein and one or more pharmaceutically acceptable excipients or carriers.

[0267] In certain embodiments, the RBP4 inhibitor compound is substantially pure in that it contains less than about 5%, or less than about 1%, or less than about 0.1% of other small organic molecules, e.g., unreacted intermediates or synthesis by-products produced in one or more steps of the synthetic method.

[0268] Suitable oral dosage forms include, for example, tablets, pills, sachets, or capsules made of hard or soft gelatin, methylcellulose, or another suitable material that dissolves easily in the digestive tract. In some embodiments, suitable nontoxic solid carriers are used, including, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose, magnesium carbonate, and the like. (See, e.g., Remington: The Science and Practice of Pharmacy (Gennaro, 21st Ed. Mack Pub. Co., Easton, PA (2005)).

[0269] In some embodiments, the pharmaceutical compositions provided herein are formulated for oral administration in tablet, capsule, powder, or liquid form. In some embodiments, tablets contain a solid carrier or adjuvant. Liquid pharmaceutical compositions generally contain a liquid carrier such as water, petroleum, animal or vegetable oils, mineral oil, or synthetic oil. In some embodiments, saline, dextrose or other sugar solution, or glycol is optionally included. In some embodiments, capsules contain a solid carrier such as gelatin.

[0270] In another embodiment, the pharmaceutical composition is provided in a dosage form for parenteral administration, which comprises a compound provided herein and one or more pharmaceutically acceptable excipients or carriers.When the pharmaceutical composition is formulated for intravenous, cutaneous or subcutaneous injection, the active ingredient is in the form of a parenterally acceptable aqueous solution, which is pyrogen-free and has appropriate pH, isotonicity and stability.Those skilled in the art can easily prepare an appropriate solution using an isotonic vehicle such as sodium chloride injection, Ringer's injection, or lactated Ringer's injection.In some embodiments, preservatives, stabilizers, buffers, antioxidants, and / or other additives are included.

[0271] In yet another embodiment, a pharmaceutical composition is provided in a dosage form for topical administration, which comprises a compound provided herein and one or more pharmaceutically acceptable excipients or carriers.

[0272] Methods of Administration and Treatment Regimen The dosage of the compositions comprising at least one RBP4 inhibitor compound described herein will vary depending on the patient's disease, ie, the stage of the disease, general health, age, and other factors.

[0273] The pharmaceutical composition is administered in a manner appropriate for the disease to be treated (or prevented).The appropriate dose and the appropriate duration and frequency of administration are determined by factors such as the patient's condition, including the type and severity of the patient's disease, the specific form of the active ingredient, and the method of administration.In general, the appropriate dose and treatment regimen provide the composition in an amount sufficient to provide therapeutic and / or preventive benefits (e.g., improved clinical outcome) or reduce the severity of symptoms.The optimal dose is generally determined using experimental models and / or clinical trials.The optimal dose depends on the patient's size, weight, or blood volume.

[0274] In one embodiment, the compounds described herein or pharmaceutically acceptable salts thereof are used in the preparation of a medicament for the treatment of a disease or condition in a mammal that would benefit from the administration of any one of the disclosed compounds. A method of treating any of the diseases or conditions described herein in a mammal in need thereof comprises administering to the mammal a pharmaceutical composition comprising a therapeutically effective amount of at least one compound described herein, or a pharmaceutically acceptable salt, active metabolite, prodrug, or pharmaceutically acceptable solvate thereof.

[0275] In certain embodiments, compositions containing the compounds described herein are administered for prophylactic and / or therapeutic treatment. In certain therapeutic applications, the compositions are administered to a patient already suffering from a disease or condition in an amount sufficient to cure or at least partially halt at least one symptom of the disease or condition. Amounts effective for this use will depend on the severity and course of the disease or condition, previous treatments, the patient's health status, weight, and response to the drugs, and the judgment of the treating physician. Therapeutically effective amounts are optionally determined by methods including, but not limited to, dose escalation and / or dose ranging clinical trials.

[0276] In prophylactic applications, compositions containing the compounds describe...

Claims

1. A method for selecting a subject having an eye disease for treatment, wherein the method is: (a) A step of calculating at least two variables of the subject in order to obtain a composite biomarker, wherein at least one of the at least two variables relates to one or more selected from the group including vision, visual function, anatomical structure of the eye, physiological function of the eye, pathology of the eye, and changes therein. (b) If the composite biomarker exceeds the threshold, a step of selecting the subject for the treatment, or optionally, if the composite biomarker does not exceed the threshold, a step of not selecting the subject for the treatment. Methods that include...

2. The method according to claim 1, wherein the eye disease includes maculopathy, retinopathy, retinal atrophy, macular atrophy, macular degeneration, age-related macular degeneration (AMD), Stargardt disease (STGD), RP (retinitis pigmentosa), ABCA4 gene mutation, or a combination thereof.

3. The sample derived from the subject having the eye disease has at least a threshold expression level of retinol-binding protein 4 (RBP4), The threshold is approximately 25 μg / ml to approximately 100 μg / ml. The method according to claim 1, wherein the expression level of RBP4 is measured by an assay comprising an antibody assay, electrophoresis assay, immunoassay, radioimmunoassay, chromatography assay, mass spectrometry assay, microarray-based detection assay, polymerase chain reaction assay, sequencing assay, immunohistochemistry assay, or any combination thereof.

4. The sample derived from the subject having the eye disease has at least a threshold level of vitamin A expression, The threshold is approximately 150 ng / mL to approximately 500 ng / mL. The method according to claim 1, wherein the expression level of vitamin A is measured by an assay comprising an antibody assay, electrophoresis assay, immunoassay, radioimmunoassay, chromatography assay, mass spectrometry assay, microarray-based detection assay, polymerase chain reaction assay, sequencing assay, immunohistochemistry assay, or any combination thereof.

5. The presence or absence of one or more genomic variants indicates that the subject has the eye disease, The method according to claim 1, wherein the presence or absence of one or more genomic variants selected from the group including rs4147863, rs2275029, rs1800739, rs4147857, rs4147856, rs1801555, and rs1801574 indicates that the subject has the eye disease.

6. The treatment is, Equation (I) 【Chemistry 1】 A pharmaceutical composition comprising an RBP4 inhibitor having the structure of, or a pharmaceutically acceptable salt thereof, During the ceremony, RA1, RA2, RA3, RA4, and RA5 are each independently H, halogen, CF3, or C1-C4 alkyl. If two or more of R A 1, R A 2, R A 3, R A 4, and R A 5 are not H, R A 6 is H, OH, or halogen. A A is structure 【Chemistry 2】 It has, During the ceremony, α, β, χ, and δ are each independent of whether they exist or not, and if they exist, each is a combination. X is either C or N, Z1 is N, Z2 is N or NR A9, R A 9 is H, C1-C4 alkyl, or oxetane. B A is a substituted or unsubstituted 5, 6, or 7-membered ring structure. The method according to claim 1.

7. The compound has a structure 【Transformation 3】 The method according to claim 6, comprising, or a pharmaceutically acceptable salt thereof.

8. The compound has a structure 【Chemistry 4】 The method according to claim 6, comprising, or a pharmaceutically acceptable salt thereof.

9. The method according to claim 1, wherein at least one of the at least two variables relates to one or more selected from the group including changes in visual acuity, changes in the mean score of a functional vision questionnaire, and changes in measurements obtained from imaging techniques for detecting or quantifying changes in the structure or visual function of the eye.

10. The method according to claim 1, wherein at least one of the at least two variables relates to changes in ocular structure, changes in ocular pathology, changes in retinal atrophy, changes in macular atrophy, changes in macular degeneration, or a combination thereof.

11. The method according to claim 1, wherein the at least two variables include values ​​obtained from a logarithmic minimum separation threshold angle (logMAR) chart, a Snellen chart, a best corrected visual acuity (BCVA) test, an early intervention diabetic retinopathy study (ETDRS) letter test, or a combination thereof.

12. The method according to claim 1, wherein the at least two variables include values ​​obtained from microperimeter (MP), perimeter, or both.

13. The method according to claim 1, wherein the at least two variables include values ​​obtained from one or more selected from the group consisting of fundus photography, fundus angiography (FA), fundus autofluorescence (FAF), spectral domain optical coherence tomography (SD-OCT), quantitative autofluorescence (qAF), infrared (IR) imaging, optical coherence tomography-angiography (OCT-A), and wide-field imaging.

14. The method according to claim 1, wherein the at least two variables include one or more selected from the group including questionable autofluorescence reduction regions (QDAF), clear autofluorescence reduction regions (DDAF), autofluorescence reduction regions (DAF), retinal thickness, ellipsoid zone (EZ) defect width, central subfield retinal thickness (CST), outer subfield retinal thickness (OST), intermediate subfield retinal thickness (MST), and variations thereof.

15. The method according to claim 1, wherein the at least two variables include two or more selected from the group including visual acuity, QDAF, DAF, EZ defect width, or changes thereon.

16. The width of the EZ defect correlates with the visual acuity, or Whether the EZ defect width correlates with the QDAF, Whether the EZ defect width correlates with the DAF, Whether the aforementioned visual acuity correlates with the aforementioned QDAF, Whether the EZ defect width correlates with the visual acuity, the QDAF, and the DAF, or The method according to claim 15, wherein the visual acuity correlates with the EZ defect width and the QDAF.

17. The method according to claim 1, wherein the at least two variables of the target are obtained from both the right eye and the left eye of the target.

18. The method according to claim 1, further comprising the step of predicting whether the prognosis of the treatment will improve based on one or more of the composite biomarkers.

19. The method according to claim 1, wherein if the composite biomarker exceeds the threshold, the treatment is therapeutically effective in treating the subject.

20. The method according to claim 1, wherein if the composite biomarker does not exceed the threshold, the treatment is not therapeutically effective in treating the subject.

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