Methods and compositions for treating rnfl thinning

Abstract

Provided herein are methods and compositions for treating an eye having a loss of ganglion cell complex (GCC) thickness and / or retinal nerve fiber layer (RNFL) thickness. For example, provided herein are methods of treating a loss in retinal GCC and / or RNFL thickness in an eye of an individual, the method comprising: administering a peptide to the eye, wherein the peptide comprises an amino acid sequence HHIYLGAVNYIY or variant sequence thereof, or a pharmaceutically acceptable salt of the peptide.

Description

METHODS AND COMPOSITIONS FOR TREATING RNFL THINNING CROSS-REFERENCE

[0001] This application claims the benefit of U.S. Provisional Application Number 63 / 497,131 filed on April 19, 2023; U.S. Provisional Application Number 63 / 497,128 filed on April 19, 2023; U.S. Provisional Application Number 63 / 587,386 filed on October 02, 2023; and U.S. Provisional Application Number 63 / 631,378 filed on April 08, 2024 each of which is incorporated by reference herein in its entirety. BACKGROUND

[0002] Vision is generally dependent on maintaining the anatomical and histological integrity of the structures within the eye. Changes in anatomical and histological homeostasis can provide the basis for a decrease and / or loss in vision. Ganglion cell complex (GCC) thinning and retinal nerve fiber layer (RNFL) thinning constitute abnormal changes in the structure of the eye (e.g., retina) that can contribute to a decrease and / or loss in vision. The loss of GCC and / or RNFL thickness generally arises due to age or disease. SUMMARY

[0003] The primary goal of treatments for ocular diseases or disorders associated with GCC thinning or RNFL thinning is typically to prevent further thinning (e.g., rather than to promote thickening). The compositions and methods provided and exemplified herein are useful for treating eyes having GCC thinning and / or RNFL thinning (e.g., reducing or inhibiting thinning). Moreover, the compositions and methods provided and exemplified herein are also useful for increasing GCC thickness and / or RNFL thickness. In both aspects, the compositions and methods are generally useful for treating ocular diseases and disorders characterized by or associated with GCC thinning and / or RNFL thinning.

[0004] In some embodiments, provided herein are methods of treating a loss in retinal nerve fiber layer (RNFL) thickness of an eye of an individual, the method comprising: administering a peptide to the eye, wherein the peptide comprises an amino acid sequence HHIYLGAVNYIY or variant sequence thereof, or a pharmaceutically acceptable salt of the peptide. In certain embodiments, treating the loss in retinal nerve fiber layer thickness comprises inhibiting a reduction in RNFL thickness. In certain embodiments, treating the loss in retinal nerve fiber layer thickness comprises increasing in RNFL thickness. In certain embodiments, treating the loss in retinal nerve fiber layer thickness comprises reducing arate of RNFL thinning compared to an untreated eye. In certain embodiments, treating the loss in retinal nerve fiber layer thickness comprises reducing a decrease in ganglion axons (e.g., by cell death and / or apoptosis) within the RNFL.

[0005] In some embodiments, provided herein are methods of increasing retinal nerve fiber layer (RNFL) thickness of an eye for an individual, the method comprising: administering a peptide to the eye, wherein the peptide comprises an amino acid sequence HHIYLGAVNYIY or variant sequence thereof, or a pharmaceutically acceptable salt of the peptide.

[0006] In certain embodiments, the RNFL thickness (e.g., mean RNFL thickness) is less than 90 um (microns). In certain embodiments, RNFL thickness is measured by optical coherence tomography (e.g., SD-OCT and / or TD-OCT).

[0007] In some embodiments, provided herein are methods of inhibiting a loss of axons within a retinal nerve fiber layer (RNFL) of an eye of an individual, the method comprising: administering a peptide to the eye, wherein the peptide comprises an amino acid sequence HHIYLGAVNYIY or variant sequence thereof, or a pharmaceutically acceptable salt of the peptide.

[0008] In certain embodiments, the loss of axons comprises cell death and / or apoptosis of ganglion cells. In certain embodiments, the eye has a RNFL thickness of less than 90 um (microns). In certain embodiments, the RNFL is the RNFL of an optic nerve.

[0009] In certain embodiments, the method further comprises administering a first dose and a second dose of the peptide or the pharmaceutically acceptable salt of the peptide, and wherein the second composition is administered about 10 weeks or greater after administering the first dose. In certain embodiments, the second dose is administered about 12 weeks after the first dose. In certain embodiments, the peptide or the pharmaceutically acceptable salt thereof has a half-life in the vitreous humor of more than about 30 days (e.g., at least 30 days). In certain embodiments, the method comprises using the vitreous humor as a depot to provide the peptide or the pharmaceutically acceptable salt thereof to retinal tissue in the eye, wherein the peptide or the pharmaceutically acceptable salt thereof is present in the vitreous humor more than about 30 days after administration.

[0010] In certain embodiments, the eye has an ocular disease or disorder. In certain embodiments, the ocular disease or disorder comprises an elevated intraocular pressure. In certain embodiments, the ocular disease or disorder is glaucoma.

[0011] In certain embodiments, the variant sequence comprises an amino acid substitution. In certain embodiments, the variant sequence comprises one amino acid substitution. In certain embodiments, the peptide further comprises a modification.

[0012] In certain embodiments, the modification comprises a modified amino acid. In certain embodiments, the peptide comprises an amidated C-terminus. In certain embodiments, the peptide has the structure of Formula I or a pharmaceutically acceptable salt thereof.

[0013] In certain embodiments, the peptide has the structure of Formula III or a pharmaceutically acceptable salt thereof.

[0014] In certain embodiments, the method comprises administering the pharmaceutically acceptable salt thereof. In certain embodiments, the pharmaceutically acceptable salt is an acetate salt. In certain embodiments, the pharmaceutically acceptable salt is a polyacetate salt. In certain embodiments, the polyacetate salt is a triacetate salt. In certain embodiments, the pharmaceutically acceptable salt is a hydrochloride salt.

[0015] In certain embodiments, the method comprises administering a composition comprising the peptide. In certain embodiments, the composition (e.g., each composition or the first / second composition) further comprises one or more excipients.

[0016] In certain embodiments, the composition (e.g., each composition or the first / second composition) further comprises a surfactant. In certain embodiments, the surfactant is a non-ionic surfactant. In certain embodiments, the surfactant is a polysorbate, a polyethoxylated castor oil derivative, a polyethoxylated fatty acid, a polyethoxylated alcohol, a polyoxyethylene-polyoxypropylene block copolymer, or an oxyethylated tertiary octylphenol formaldehyde polymer. In certain embodiments, the surfactant forms about 0.01% to about 20% weight / weight of the composition. In certain embodiments, the surfactant forms about 0.05% to about 10% weight / weight of the composition. In certain embodiments, the composition (e.g., each composition or the first / second composition) further comprises a tonicity adjusting agent, a buffering agent, or a combination thereof. In certain embodiments, the composition is buffered at a pH of 2.5 to 7.5. In certain embodiments, the composition comprises about 25 micrograms (ug) to about 250 ug of the peptide.

[0017] In some embodiments, provided herein are methods of treating glaucoma in an eye of an individual, the method comprising: (a) measuring retinal nerve fiber layer (RNFL) thickness (e.g., of an optic nerve) of the eye at a first timepoint; (b) administering a first dose of therapeutic agent; (c) measuring RNFL thickness in the eye at a second timepoint; and (d) administering a second dose of the therapeutic agent if the RNFL thickness at the second timepoint is equal to or less than the RNFL thickness at the second timepoint.

[0018] In certain embodiments, (d) further comprises stopping or pausing further treatment if the RNFL thickness at the second timepoint is greater than the RNFL thicknessat the first timepoint. In certain embodiments, the method further comprises (e) measuring RNFL thickness at a third timepoint, and (f) administering an additional dose of the therapeutic agent if the RNFL thickness at the third timepoint is equal to or less than the RNFL thickness at the first timepoint or the second timepoint.

[0019] In some embodiments, provided herein are methods of treating glaucoma in an eye of an individual having a retinal nerve fiber layer (RNFL) thickness less than 90 um (microns), the method comprising: (a) administering a therapeutic agent; and measuring RNFL thickness in the eye; (b) administering a second dose of the therapeutic agent if the RNFL thickness in (b) is less than the RNFL thickness is less than 80 um. In certain embodiments, the (c) further comprises stopping or pausing further treatment if the RNFL thickness in (b) is equal to or greater than the RNFL thickness is less than 80 um. In certain embodiments, the method comprises (d) measuring RNFL thickness at a subsequent timepoint, and (e) administering an additional dose of the therapeutic agent if the RNFL thickness at the subsequent timepoint is less than 80 um or less than the RNFL thickness of a prior measurement (e.g., in (b)).

[0020] In certain embodiments, the therapeutic agent is a Fas inhibitor. In certain embodiments, the therapeutic agent is selected from the group consisting of a Fas inhibitor, a prostaglandin analog, a rho kinase inhibitor, a nitric oxide, a miotic agent, an alpha- adrenergic agonist, a beta blocker, and a carbonic anhydrase inhibitor. In certain embodiments, an increase in RNFL thickness is not a result of an edema.

[0021] In some embodiments, provided herein are methods of treating glaucoma in an eye of an individual, the method comprising: (a) measuring visual field of the eye at a first timepoint; (b) administering a first dose of therapeutic agent; (c) measuring visual field in the eye at a second timepoint; and (d) administering a second dose of the therapeutic agent if the visual field at the second timepoint is equal to or less than the visual field at the first timepoint. In certain embodiments, (d) further comprises stopping or pausing further treatment if the visual field at the second timepoint is greater than the visual field at the first timepoint. In some embodiments, the method further comprises (e) measuring visual field at a third timepoint, and (f) administering an additional dose of the therapeutic agent if the visual field at the third timepoint is equal to or less than the visual field at the first timepoint or the second timepoint.

[0022] In some embodiments, provided herein are methods of treating a loss in ganglion cell complex (GCC) thickness in an eye of an individual, comprising: administering a Fas inhibitor to the eye. In some embodiments, provided herein are methods of treating a loss in ganglion cell complex (GCC) thickness in an eye of an individual, comprising: administeringa peptide to the eye, wherein the peptide comprises an amino acid sequence HHIYLGAVNYIY or a variant sequence thereof, or a pharmaceutically acceptable salt of the peptide. In some embodiments, provided are methods of treating a loss in ganglion cell complex (GCC) thickness in an eye of an individual, comprising: administering a peptide to the eye of the individual, the peptide having the structure of Formula I or a pharmaceutically acceptable salt thereof. In some embodiments, provided are methods of treating a loss in ganglion cell complex (GCC) thickness in an eye of an individual, comprising: administering a peptide to the eye of the individual, the peptide having the structure of Formula III or a pharmaceutically acceptable salt thereof. In certain embodiments, treating the loss in ganglion cell complex thickness comprises inhibiting a reduction in GCC thickness. In certain embodiments, inhibiting the reduction in GCC thickness comprises inhibiting a decrease in GCC thickness. In certain embodiments, inhibiting the reduction in GCC thickness comprises inhibiting a rate of a decrease in GCC thickness compared to an untreated eye or the rate of a decrease in GCC thickness compares to a rate prior to treatment. In certain embodiments, treating the loss in ganglion cell complex thickness comprises increasing in GCC thickness. In certain embodiments, treating the loss of GCC thickness comprises reducing a decrease of ganglion axons (e.g., cell death and / or apoptosis) in nerves within the GCC.

[0023] In some embodiments, provided herein are methods of increasing ganglion cell complex (GCC) thickness of an eye of an individual, comprising: administering a Fas inhibitor to the eye. In some embodiments, provided herein are methods of increasing ganglion cell complex (GCC) thickness of an eye of an individual, comprising: administering a peptide to the eye, wherein the peptide comprises an amino acid sequence HHIYLGAVNYIY or a variant sequence thereof, or a pharmaceutically acceptable salt of the peptide. In some embodiments, provided herein are methods of increasing ganglion cell complex (GCC) thickness of an eye of an individual, comprising: administering a peptide to the eye of the individual, the peptide having the structure of Formula I or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein are methods of increasing ganglion cell complex (GCC) thickness of an eye of an individual, comprising: administering a peptide to the eye of the individual, the peptide having the structure of Formula III or a pharmaceutically acceptable salt thereof.

[0024] In some embodiments, provided herein are methods of inhibiting a loss of axons (e.g., retinal ganglion cell axons) in an eye of an individual, comprising: administering a Fas inhibitor to the eye. In some embodiments, provided herein are methods of inhibiting a loss of axons (e.g., retinal ganglion cell axons) in an eye of an individual, comprising: administering a peptide to the eye of the individual, wherein the peptide comprises an aminoacid sequence HHIYLGAVNYIY or a variant sequence thereof, or a pharmaceutically acceptable salt of the peptide. In some embodiments, provided herein are methods of inhibiting a loss of axons (e.g., retinal ganglion cell axons) in an eye of an individual, comprising: administering a peptide to the eye of the individual, the peptide having the structure of Formula I or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein are methods of inhibiting a loss of axons (e.g., retinal ganglion cell axons) in an eye of an individual, comprising: administering a peptide to the eye, the peptide having the structure of Formula III or a pharmaceutically acceptable salt thereof. In certain embodiments, the loss in cells that innervate the GCC in an eye of an individual comprises cell death of neurons that innervate the GCC. In certain embodiments, cell death comprises apoptosis. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] The novel features of the disclosure are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present disclosure will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the disclosure are utilized, and the accompanying drawings of which:

[0026] FIGs. 1A-1F show data demonstrating the sustained loss of retinal nerve fiber (RNFL) thickness in control patients with glaucoma having undergone sham injections (patients who did not receive a Fas inhibitor). FIG. 1A shows sustained RNFL thinning in patients who do not receive a Fas inhibitor. FIG. 1B-1F show representative RNFL optical coherence tomography (OCT) images from data in FIG.1A.

[0027] FIGs. 2A-2E provide data demonstrating an increase of RNFL thickness in patients having RNFL thinning (e.g., a decrease in RNFL thickness) receiving a 50ug dose of a Fas inhibitor. FIG.2A shows an increase in RNFL thickness in patients receiving a 50ug dose Fas inhibitor in the Study Eye (solid line). FIG.2A also shows RNFL thickness for the untreated Fellow Eye (dotted line, no substantial increase). FIG.2B-2E show representative RNFL OCT images from data in FIG.2A.

[0028] FIG. 3A-3F provide data demonstrating an increase of RNFL thickness in glaucoma patients receiving a 50ug dose of a Fas inhibitor. FIG. 3A shows an increase in RNFL thickness in patients receiving a 50ug dose Fas inhibitor in the Study Eye (solid line). FIG.3A also shows RNFL thickness for the untreated Fellow Eye (dotted line, no substantial increase). FIG. 3B-3E show representative RNFL OCT images from data in FIG.3A.

[0029] FIG.4 shows data demonstrating an increase of RNFL thickness in eyes receiving 50ug and 100ug dose injections of a Fas inhibitor (solid lines labeled 50ug ONL1204 Study Eye and 100ug ONL1204 Study Eye), as compared to eyes that received sham injections and no Fas inhibitor (solid line labeled Sham Study Eye) and untreated eyes (dashed lines labeled Fellow Eye). Arrows indicate administration events of the Fas inhibitor.

[0030] FIG. 5 shows mean data for visual field outcomes in glaucoma patients receiving no Fas inhibitor.

[0031] FIG. 6 shows mean data demonstrating improved visual field outcomes in glaucoma patients receiving multiple 50 microgram doses of a Fas inhibitor.

[0032] FIG. 7 shows mean data demonstrating improved visual field outcomes in glaucoma patients receiving multiple 100 microgram doses of a Fas inhibitor.

[0033] FIG.8 shows induvial point data demonstrating improved visual field outcomes in glaucoma patients receiving multiple 50 microgram doses of a Fas inhibitor.

[0034] FIG. 9 shows induvial point demonstrating improved visual field outcomes in glaucoma patients receiving multiple 100 microgram doses of a Fas inhibitor.

[0035] FIG. 10 shows mean data for visual field outcomes in glaucoma patients receiving no Fas inhibitor.

[0036] FIG.11 shows changes in RNFL thickness as a function of HVF change.

[0037] FIGs. 12A-12I show changes in GCC thickness in treated (50 ug and 100 ug), sham treated, and fellow eye (untreated). 12A-12I provide data demonstrating an increase of GCC thickness in patients having GCC thinning (e.g., a decrease in GCC thickness) receiving a 50 ug or 100 ug doses of a Fas inhibitor. DETAILED DESCRIPTION

[0038] Described and provided herein are compositions and methods useful for treating retinal nerve fiber layer (RNFL) thinning (e.g., a decrease in RNFL thickness) in an eye of an individual. In certain instances, the inhibiting and / or reducing RNFL thinning is achieved by utilizing a Fas inhibitor. The Fas-mediated inflammation signaling pathway is generally initiated by an interaction between the membrane-bound Fas ligand (FasL - a type II transmembrane protein of the TNF family) and Fas receptor, thereby leading to the activation of pro-inflammatory signaling (e.g., cytokine signaling, interleukin signaling, caspase action, etc.) and / or cell death signaling (e.g., apoptotic signaling, necrotic signaling, etc.) pathways.Fas Inhibitors

[0039] Provided herein are Fas inhibitors useful for modulating (e.g., inhibiting, preventing, and / or reducing, etc.) Fas-mediated signaling. In certain instances, the Fas inhibitors useful in treating, inhibiting, preventing, and / or reducing Fas-mediated inflammation. In certain instances, inhibiting, preventing, and / or reducing Fas-mediated inflammation allows for the treatment and / or prevention of RNFL thinning.

[0040] In some embodiments, the Fas inhibitors described herein encompass Met-derived peptides and / or fragments thereof. In some embodiments, the Met protein, also called c-Met or hepatocyte growth factor receptor (HGF receptor), is encoded by the Met gene (NCBI Gene ID 4233, Location: NC_000007.14 (116672196..116798386), UniProtKB - P0858). The Met protein is comprised of two major subunits: the α and β subunits, and Met and fragments of Met, including the extracellular domain of Met and its α subunit, have been shown to bind to Fas and prevent cells from undergoing apoptosis. In some embodiments, the Fas inhibitor comprises a Fas-inhibiting peptide.

[0041] Functionality of Fas-inhibitor and / or Fas-inhibiting peptides can be determined by an in vitro assay. For example, in some embodiments, the Fas inhibitor and / or Fas-inhibiting peptide competes for binding to a Fas receptor (FasR) with Fas ligand (FasL). In some embodiments, the Fas inhibitor and / or Fas-inhibiting peptide inhibits, reduces, or prevents caspase 8 activation in cells treated with FasL (e.g., as measured by commercially available luminescent tetrapeptide cleavage assay kit (Promega, Madison, WI)). In some embodiments, the Fas inhibitor and / or Fas-inhibiting peptide inhibits, reduces, or prevents cell death of cells treated with FasL. By way of further example, in some embodiments, the Fas inhibitor and / or Fas-inhibiting peptide competes for binding to a Fas receptor (FasR) with a Fas-activating antibody (e.g., Fas-agonistic Jo2 monoclonal antibody (BD Biosciences, San Jose, CA)). In some embodiments, the Fas inhibitor and / or Fas-inhibiting peptide inhibits, reduces, or prevents caspase 8 activation in cells treated with a Fas-activating antibody (e.g., as measured by commercially available luminescent tetrapeptide cleavage assay kit (Promega, Madison, WI)). In some embodiments, the Fas inhibitor and / or Fas-inhibiting peptide inhibits, reduces, or prevents cell death of cells treated with a Fas-activating antibody.

[0042] In some embodiments, the Fas inhibitors described herein comprises a Met-derived compound comprising the amino acid acids HHIYLGAVNYIY (His-His-lle-Tyr-Leu-Gly- Ala-Val-Asn-Tyr-lle-Tyr) (e.g., SEQ ID NOs: 1-2). In some embodiments, the peptide comprises the amino acid sequence HHIYLGAVNYIY or a variant sequence thereof.

[0043] As used herein, a peptide includes and / or refers to any of various natural or synthetic compounds containing two or more amino acids joined by a peptide bond that linkthe carboxyl group of one amino acid to the amino group of another. As also used herein, amino acid refers to and / or includes naturally occurring amino acids, unnatural amino acids, amino acid analogues and amino acid mimetics that function in a manner similar to a naturally occurring amino acids. Amino acids are generally referred to herein by either their name, the commonly known three letter symbols, or by the one-letter symbols recommended by the IUPAC-IUB Biochemical Nomenclature Commission.

[0044] In some embodiments, the Fas inhibitor peptides (e.g., a peptide comprising the amino acid sequence HHIYLGAVNYIY) comprises one or more naturally occurring amino acids. In some embodiments, the Fas inhibitor peptides (e.g., a peptide comprising the amino acid sequence HHIYLGAVNYIY) consists of naturally occurring amino acids. As used herein, naturally occurring amino acids include and / or refer to amino acids which are generally found in nature and are not manipulated by man. In some embodiments, naturally occurring includes and / or further refers to the 20 conventional amino acids: alanine (A or Ala), cysteine (C or Cys), aspartic acid (D or Asp), glutamic acid (E or Glu), phenylalanine (F or Phe), glycine (G or Gly), histidine (H or His), isoleucine (I or Ile), lysine (K or Lys), leucine (L or Leu), methionine (M or Met), asparagine (N or Asn), proline (P or Pro), glutamine (Q or Gln), arginine (R or Arg), serine (S or Ser), threonine (T or Thr), valine (V or Val), tryptophan (W or Trp), and tyrosine (Y or Tyr).

[0045] In some embodiments, the Fas inhibitor comprises a variant sequence of the peptide (e.g., a peptide comprising the amino acid sequence HHIYLGAVNYIY). In some embodiments, amino acid substitutions can be made in the sequence of any of the polypeptides described herein, without necessarily decreasing or ablating its activity. Accordingly, in some embodiments, the variant sequence comprises one or more amino acid substitutions. In some embodiments, the variant sequence comprises one amino acid substitution. In some embodiments, the variant sequence comprises two amino acid substitutions. In some embodiments, the variant sequence comprises three amino acid substitutions. In some embodiments, substitutions include conservative substitutions (e.g., substitutions with amino acids of comparable chemical characteristics). In some embodiments, a non-polar amino acid can be substituted and replaced with another non-polar amino acid, wherein non-polar amino acids include alanine, leucine, isoleucine, valine, glycine, proline, phenylalanine, tryptophan, and methionine. In some embodiments, a neutrally charged polar amino acids can be substituted and replaced with another neutrally charged polar amino acid, wherein neutrally charged polar amino acids include serine, threonine, cysteine, tyrosine, asparagine, and glutamine. In some embodiments, a positively charged amino acid can be substituted and replaced with another positively charged aminoacid, wherein positively charged amino acids include arginine, lysine, and histidine. In some embodiments, a negatively charged amino acid can be substituted and replaced with another negatively charged amino acid, wherein negatively charged amino acids include aspartic acid and glutamic acid. Examples of amino acid substitutions also include substituting an L-amino acid for its corresponding D-amino acid, substituting cysteine for homocysteine or other non- natural amino acids.

[0046] In some embodiments, the Fas inhibitor peptides (e.g., a peptide comprising the amino acid sequence HHIYLGAVNYIY) comprises one or more non-natural amino acids. In some embodiments, the Fas inhibitor peptides (e.g., a peptide comprising the amino acid sequence HHIYLGAVNYIY) consists of non-natural amino acids. As used herein, non- natural amino acids and / or unnatural amino acids include and / or refer to amino acid structures that cannot be generated biosynthetically in any organism using unmodified or modified genes from any organism. In some embodiments, non-natural amino acids and / or unnatural amino acids further include and / or refer to an amino acid residue that are not present in the naturally occurring (wild-type) Met protein sequence. For example, these include, but are not limited to, modified amino acids and / or amino acid analogues that are not one of the 20 naturally occurring amino acids (e.g., non-natural side chain variant sequence amino acids), D-amino acids, homo amino acids, beta-homo amino acids, N-methyl amino acids, alpha- methyl amino acids, or. By way of further example, non-natural amino acids also include 4- Benzoylphenylalanine (Bpa), Aminobenzoic Acid (Abz), Aminobutyric Acid (Abu), Aminohexanoic Acid (Ahx), Aminoisobutyric Acid (Aib), Citrulline (Cit), Diaminobutyric Acid (Dab), Diaminopropanoic Acid (Dap), Diaminopropionic Acid (Dap), Gamma- Carboxyglutamic Acid (Gla), Homoalanine (Hala), Homoarginine (Harg), Homoasparagine (Hasn), Homoaspartic Acid (Hasp), Homocysteine (Hcys), Homoglutamic Acid (Hglu), Homoglutamine (Hgln), Homoisoleucine (Hile), Homoleucine (Hleu), Homomethionine (Hmet), Homophenylalanine (Hphe), Homoserine (Hser), Homotyrosine (Htyr), Homovaline (Hval), Hydroxyproline (Hyp), Isonipecotic Acid (Inp), N aphthylalanine (Nal), Nipecotic Acid (Nip), Norleucine (Nle), Norvaline (Nva), Octahydroindole-2-carboxylic Acid (Oic), Penicillamine (Pen), Phenylglycine (Phg), Pyroglutamic Acid (Pyr), Sarcosine (Sar), tButylglycine (Tle), and Tetrahydro-isoquinoline-3-carboxylic Acid (Tic). Such non-natural amino acid residues can be introduced by substitution of naturally occurring amino acids, and / or by insertion of non-natural amino acids into the naturally occurring (wild-type) Met protein sequence. A non-natural amino acid residue also can be incorporated such that a desired functionality is imparted to the apelin molecule, for example, the ability to link a functional moiety (e.g., PEG).

[0047] In some embodiments, a variant sequence comprises one or more amino acid deletions. In some embodiments, the variant sequence comprises one amino acid deletion. In some embodiments, the variant sequence comprises two amino acid deletions. In some embodiments, the variant sequence comprises three amino acid deletions. In some embodiments, the variant sequence comprises four amino acid deletions. In some embodiments, the variant sequence comprises one or more additional amino acids. In some embodiments, the additional amino acids are additional amino acids from the Met sequence. In some embodiments, the variant sequence comprises a substitution and a deletion. In some embodiments, the variant sequence comprises a substitution and one or more additional amino acids. In some embodiments, the substitution comprises a natural amino acid or a non- natural amino acid. In some embodiments, the variant sequence is a retro inverso amino acid sequence. In some embodiments, a variant sequence comprises one or more additional amino acid residues (e.g., one, two, or three additions) to the N or C terminus. In some embodiments, a variant sequence comprises one or more deletions (e.g., one, two, or three deletions) to amino acid residues at the N or C terminus.

[0048] Functionality of variant sequences of the peptide (e.g., a variant sequence of the amino acid sequence HHIYLGAVNYIY) can be determined by an in vitro assay. For example, in some embodiments, the variant sequence competes for binding to a Fas receptor (FasR) with Fas ligand (FasL). In some embodiments, the variant sequence inhibits, reduces, or prevents caspase 8 activation in cells treated with FasL (e.g., as measured by commercially available luminescent tetrapeptide cleavage assay kit (Promega, Madison, WI)). In some embodiments, the variant sequence inhibits, reduces, or prevents cell death of cells treated with FasL. By way of further example, in some embodiments, the variant sequence competes for binding to a Fas receptor (FasR) with a Fas-activating antibody (e.g., Fas-agonistic Jo2 monoclonal antibody (BD Biosciences, San Jose, CA)). In some embodiments, the variant sequence inhibits, reduces, or prevents caspase 8 activation in cells treated with a Fas- activating antibody (e.g., as measured by commercially available luminescent tetrapeptide cleavage assay kit (Promega, Madison, WI)). In some embodiments, the variant sequence inhibits, reduces, or prevents cell death of cells treated with a Fas-activating antibody. Accordingly, in some embodiments, the Fas inhibitor comprises a variant sequence (e.g., any one of the variant sequences described herein) of the peptide (e.g., a peptide comprising the amino acid sequence HHIYLGAVNYIY), wherein the variant sequence competes for binding to a Fas receptor (FasR) with Fas ligand (FasL). In some embodiments, the Fas inhibitor comprises a variant sequence (e.g., any one of the variant sequences described herein) of the peptide (e.g., a peptide comprising the amino acid sequence HHIYLGAVNYIY), wherein thevariant sequence inhibits, reduces, or prevents caspase 8 activation in cells treated with FasL. In some embodiments, the Fas inhibitor comprises a variant sequence (e.g., any one of the variant sequences described herein) of the peptide (e.g., a peptide comprising the amino acid sequence HHIYLGAVNYIY), wherein the variant sequence inhibits, reduces, or prevents cell death of cells treated with FasL. In some embodiments, the Fas inhibitor comprises a variant sequence (e.g., any one of the variant sequences described herein) of the peptide (e.g., a peptide comprising the amino acid sequence HHIYLGAVNYIY), wherein the variant sequence competes for binding to a Fas receptor (FasR) with a Fas-activating antibody. In some embodiments, the Fas inhibitor comprises a variant sequence (e.g., any one of the variant sequences described herein) of the peptide comprising the amino acid sequence HHIYLGAVNYIY, wherein the variant sequence inhibits, reduces, or prevents caspase 8 activation in cells treated with a Fas-activating antibody. In some embodiments, the Fas inhibitor comprises a variant sequence (e.g., any one of the variant sequences described herein) of the peptide comprising the amino acid sequence HHIYLGAVNYIY, wherein the variant sequence inhibits, reduces, or prevents cell death of cells treated with a Fas-activating antibody.

[0049] The peptide or a variant sequence thereof can further comprise one or more modifications. In some embodiments, the peptide (e.g., a comprising the amino acid sequence HHIYLGAVNYIY or a variant sequence thereof) comprises a modification. In some embodiments, the peptide is a modified peptide. As used herein, a modification or a modified peptide includes and / or refers to a modification of one or more amino acids in the peptide. In some embodiments, modifications species of stereoisomers. All stereoisomers of the above compounds are contemplated, either in admixture or in pure or substantially pure form. The compounds can have asymmetric centers at any of the atoms. Consequently, the peptide compounds or components thereof can exist in enantiomeric or diastereomeric forms or in mixtures thereof. The present invention contemplates the use of any racemates (i.e., mixtures containing equal amounts of each enantiomer), enantiomerically enriched mixtures (i.e., mixtures enriched for one enantiomer), pure enantiomers or diastereomers, or any mixtures thereof. The chiral centers can be designated as R or S or R, S or d, D, 1, L or d, 1, D, or L. Compounds comprising amino acid residues include residues of D-amino acids, L-amino acids, or racemic derivatives of amino acids. Compounds comprising sugar residues include residues of D-sugars, L-sugars, or racemic derivatives of sugars. Non-limiting examples of modifications are phosphorylation, glycosylation, ubiquitination, nitrosylation, methylation, acetylation, amidation, or lipidation. Modification can be introduced at the C-terminus of the peptide, the N-terminus of the peptide, or at any place in-between. Thus, a modification or amodified peptide includes and / or refers to modifications of the free amino- and / or carboxyl- terminal (N-terminus and C-terminus, respectively). In some embodiments, N-terminal modifications include but are not limited to acetylation, formylation, pyroglutamylation, carbamide addition, lipidation, sulfonamidation, and alkylamination. In some embodiments, C-terminal modifications include but are not limited to amidation, esterification, and incorporation of an aldehyde group. In some embodiments, the modification comprises amidation. In some embodiments, the amidation is at the c-terminus. In some embodiments, the modification comprises a retro inverso peptide (e.g., YIYNVAGLYIHH). In some embodiments, the modification altering the chirality of one or more amino acid residues of the peptide (e.g., L amino acid to D amino acid).

[0050] Accordingly, in an embodiment, provided herein are peptides comprising the sequence (a)-HHIYLGAVNYIY-(b) (SEQ ID NO: 1) or (a)-YIYNVAGLYIHH-(b) (SEQ ID NO: 2), or a variant sequence thereof, wherein: (a) is -H, -OH, -NH2, G1(CH2)n-, R1CONH-, or R2O-; (b) is -H, -CH2OH, -CH2OR2, -CHO, -CO2R2, -CONH2, -CONHR2, -CON(R3)2, - CONH(CH2)yNR(3)2, -(CH2)n-G1, -COCH2-G1, -CONHCH2-G1, -(CH2)nNH2, - (CH2)nNHR2, -(CH2)nN(R3)2, NH-Glu-His-OH, NH-Glu-His-NH2, -Ala-His-NH2, - Gly-His-NH2, -NH-Glu-His-OH, -NH-Glu-His-NH2, -Ala-His-NH2, -Gly-His- NH2, -NH-[D]Glu-[D]-His-OH, -NH-[D]Glu-[D]-His-NH2, -[D]Ala-[D]-His-NH2, -Gly[D]-His-NH2, or -CONH(CH2)n-G2; G1, at each occurrence, is independently - H, -C(=O)NH2, -C(=O)NHR2, -C(=O)N(R3)2, C(=O)OR2, or -C(=O)R1; G2at each occurrence is a heterocyclic ring of 4-7 members comprising at least one tertiary amine functionality NR2within the ring, or a carbocyclic ring of 3-7 members substituted with -N(R3)2; R1, at each occurrence, is independently H, C1-6alkyl, -(CH2)x(OCH2CH2)mOR5, C1-6-alkoxy or L; R2, at each occurrence, is independently C1-6alkyl, C2-6alkyl substituted with OR5or NR52, -(CH2)x(OCH2CH2)mOR5or L; L, at each occurrence, is a multivalent polyethylene glycol derivative with 2 -4 termini, each of which can be independently capped with H, R5; R3, at each occurrence, is independently C1-6alkyl, C2-6alkyl substituted with OR5or N(R5)2, -(CH2)x(OCH2CH2)mOR5; or two R3s, taken together with the N atom to which they are attached, can form a monocyclic ring of 4-8 members or a fused, bridged or spiro bicyclic ring of 6-10members, which can include up to two groups within the ring chosen independently from –O-, -(C=O)-, NR6, S, SO, or SO2; R4, at each occurrence, is independently C1-6alkyl, C1-6acyl, or –OPO3(R5)2; R5, at each occurrence, is independently H or C1-6alkyl; R6, at each occurrence, is H, C1-6alkyl, C2-6hydroxyalkyl, C1-6alkoxy-, C1-6alkyl, or C1-6acyl; m = 1-100; n = 0-3; x = 0-6; and y = 2-4, wherein at most one of R1and R2is L.

[0051] In certain instances, provided herein are peptides comprising the structure of Formula I or Formula II, or a pharmaceutically acceptable salt thereof.wherein: A is H-, -OH, -NH2, G1(CH2)n-, R1CONH-, or R2O-; B is -H, CH2OH, CH2OR2, -CHO, -CO2R2, -CONH2, -CONHR2, -CON(R3)2, - CONH(CH2)yN(R3)2, -(CH2)n-G1, -COCH2-G1, -CONHCH2-G1, -(CH2)nNH2, - (CH2)nNHR2, -(CH2)nN(R3)2NH-Glu-His-OH, NH-Glu-His-NH2, -Ala-His-NH2, - Gly-His-NH2, NH-Glu--His-OH, NH-Glu-His-NH2, -Ala-His-NH2, -Gly-His-NH2, NH-[D]Glu-[D]-His-OH, NH-[D]Glu-[D]-His-NH2, -[D]Ala-[D]-His-NH2, -Gly- [D]-His-NH2, or CONH(CH2)n-G2;E, at each occurrence, is independently -H, -OH, -OR4, SH, -SR4, or halogen; G1, at each occurrence, is independently -H, -C(=O)NH2, -C(=O)NHR2, - C(=O)N(R3)2, C(=O)OR2, or -C(=O)R1; G2at each occurrence is a heteroalicyclic ring of 4-7 members comprising at least one tertiary amine functionality NR2within the ring, or a carbocyclic ring of 3-7 members substituted with N(R3)2; Q, at each occurrence, is independently, 1-propyl, 2-propyl, 2-methyl-prop-2-yl, C3-6-cycloalkyl, C4-6-cycloalkenyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothienyl-2-yl, tetrahydrothienyl-3-yl, tetrahydropyran-2-yl, tetrahydropyran-3-yl, tetrahydropyran- 4-yltetrahydrothiopyran-2-yl, tetrahydrothiopyran-3-yl, tetrahydrothiopyran-4-yl or 1-CH(OR5)CH3; R1, at each occurrence, is independently H, C1-6alkyl, -(CH2)x(OCH2CH2)mOR5, C1-6alkoxy or L; R2, at each occurrence, is independently C1-6alkyl, C2-6alkyl substituted with OR5or N(R5)2, -(CH2)x(OCH2CH2)mOR5or L; L, at each occurrence, is a multivalent polyethylene glycol derivative with 2-4 termini, each of which can be independently capped with H, R5or another molecule of the peptide of Formula I or II; R3, at each occurrence, is independently C1-6-alkyl, C2-6-alkyl substituted with OR5or N(R5)2, -(CH2)x(OCH2CH2)mOR5; or two R3s, taken together with the N atom to which they are attached, can form a monocyclic ring of 4-8 members or a fused, bridged or spiro bicyclic ring of 6-10 members, which can include up to two groups within the ring chosen independently from –O-, -(C=O)-, NR6, S, SO, or SO2; R4, at each occurrence, is independently C1-6alkyl, C1-6acyl, or –OPO3(R5)2; R5, at each occurrence, is independently H or C1-6alkyl; R6, at each occurrence, is H, C1-6alkyl, C2-6hydroxyalkyl, C1-6alkoxy-, C1-6alkyl, or C1-6acyl; m = 1-100; n = 0-3; x = 0-6; and y = 2-4, wherein at most one of R1and R2is L.

[0052] In some embodiments, provided is a peptide having the structure of Formula III or a pharmaceutically acceptable salt thereof:Formula III

[0053] In some embodiments, provided is a peptide having the structure of Formula IV or a pharmaceutically acceptable salt thereof:Formula IV

[0054] In some embodiments, provided is a peptide having the structure of Formula V or a pharmaceutically acceptable salt thereof:Formula V

[0055] In some embodiments, provided is a peptide having the structure of Formula VI or a pharmaceutically acceptable salt thereof:Formula VI

[0056] In some embodiments, provided is a peptide having the structure of Formula VII or a pharmaceutically acceptable salt thereof:Formula VII

[0057] In some embodiments, provided is a peptide having the structure of Formula VIII or a pharmaceutically acceptable salt thereof:Formula VIII

[0058] In some embodiments, provided is a peptide having the structure of Formula IX or a pharmaceutically acceptable salt thereof:Formula IX Salts of Fas Inhibiting Peptides

[0059] Further provided herein are salts of the peptide for inhibiting Fas-mediated inflammation in the eye and for use in the methods described here. As used herein, salt is generally synonymous with pharmaceutically acceptable salts, and / or includes or refers to pharmaceutically acceptable salts. Examples of pharmaceutically acceptable salts are salts with organic or inorganic acids such as (but not limited to) include acetic acid, aspartic acid, benzenesulfonic acid, benzoic acid, butyric acid, citric acid, fumaric acid, hydrochloric acid, hydrobromic acid, lactic acid, maleic acid, malonic acid, methanesulfonic acid, 4- methylbenzenesulfonic acid, nicotinic acid, phosphoric acid, succinic acid, sulfuric acid, or tartaric acid, prepared using methods well known in the art. In some embodiments, the salt is a hydrochloride salt.

[0060] In addition, these salts can be prepared form addition of an inorganic base or an organic base to the free acid. Salts derived from an inorganic base include, but are not limited to, the sodium, potassium, lithium, ammonium, calcium, magnesium salts. Salts derived from organic bases include, but are not limited to salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, lysine, arginine, N-ethylpiperidine, piperidine, and polyamine resins.

[0061] Salts and pharmaceutically acceptable salts are described in in J. Pharmaceutical Sciences, 66: 1-19 (1977), the contents of which are incorporated by reference herein.

[0062] In some embodiments, the salt is an acetate salt. In some embodiments, the acetate salt is a poly-acetate salt. In some embodiments, the poly-acetate salt is a tri-acetate salt. Pharmaceutical Compositions

[0063] In an embodiment, further provided are pharmaceutical compositions (also referred to as compositions) comprising the Fas inhibiting peptides. In some embodiments, the pharmaceutical compositions described herein comprise the peptide (e.g., a peptide comprising the amino acid sequence HHIYLGAVNYIY) or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical compositions described herein comprise the peptide comprising the amino acid sequence HHIYLGAVNYIY or variant sequence thereof, or a pharmaceutically acceptable salt of the peptide. In some embodiments, the pharmaceutical compositions described herein comprise the peptide having the structure of any one of Formulas I-IX or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical compositions described herein comprise the peptide having the structure of Formula I or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical compositions described herein comprise the peptide having the structure of Formula III or a pharmaceutically acceptable salt thereof.

[0064] The pharmaceutical composition can comprise one or more excipients. As used herein, an excipient includes and / or refers to any pharmaceutically acceptable additive, carrier, diluent, adjuvant, or other ingredient, other than the active pharmaceutical ingredient (API), which is typically included for formulation and / or administration to a patient. A pharmaceutical composition can comprise a single pharmaceutical formulation (e.g., extended release, immediate release, delayed release, nanoparticulate, etc.) or multiple formulations (e.g., immediate release and delayed release, nanoparticulate and nonnanoparticulate, etc.). An excipient further includes and / or refers to an agent that can beadded to a formulation to provide a desired consistency (e.g., altering the bulk properties), to improve stability, and / or to adjust osmolality. Examples of commonly used excipients include, but are not limited to, sugars, polyols, amino acids, surfactants, and polymers. In some embodiments, a non-ionic excipient or a non-ionizable excipient, as used herein, includes and / or refers to an agent having no net charge.

[0065] In some embodiments, the non-ionic excipient has no net charge under certain formulation conditions, such as pH. Examples of non-ionic excipients include, but are not limited to, sugars (e.g., sucrose), sugar alcohols (e.g., mannitol), and non-ionic surfactants (e.g., polysorbate 80).

[0066] In some embodiments, the compositions comprise excipients that are suitable for ocular application. Suitable excipients and include, but are not limited to, tonicity agents, preservatives, chelating agents, buffering agents, surfactants, cosolvents and antioxidants. Suitable tonicity-adjusting agents include mannitol, sodium chloride, glycerin, sorbitol, and the like. Suitable preservatives include p-hydroxybenzoic acid ester, benzalkonium chloride, benzododecinium bromide, polyquaternium- 1, and the like. Suitable chelating agents include sodium edetate and the like. Suitable buffering agents include phosphates, borates, citrates, acetates, tromethamine, and the like. Suitable surfactants include ionic and nonionic surfactants. In some embodiments, the one or more excipients comprises nonionic surfactants, such as polysorbates, polyethoxylated castor oil derivatives, polyethoxylated fatty acids, polyethoxylated alcohols, polyoxyethylene-polyoxypropylene block copolymers (Poloxamer), and oxyethylated tertiary octylphenol formaldehyde polymer (Tyloxapol). Other suitable surfactants can also be included. Suitable antioxidants include sulfites, thiosulfate, ascorbates, BHA, BHT, tocopherols, and the like.

[0067] In some embodiments, the composition comprises a non-ionic surfactant. In some embodiments, the composition comprises a polysorbate, a polyethoxylated castor oil derivative, a polyethoxylated fatty acid, a polyethoxylated alcohol, a polyoxyethylene- polyoxypropylene block copolymer (Poloxamer), or an oxyethylated tertiary octylphenol formaldehyde polymer (Tyloxapol). In some embodiments, the composition comprises a polysorbate. In some embodiments, the composition comprises a polyethoxylated castor oil derivative. In some embodiments, the composition comprises a polyethoxylated fatty acid. In some embodiments, the composition comprises a polyethoxylated alcohol. In some embodiments, the composition comprises a polyoxyethylene-polyoxypropylene block copolymer (Poloxamer). In some embodiments, the composition comprises an oxyethylated tertiary octylphenol formaldehyde polymer (Tyloxapol).

[0068] In some embodiments, the surfactant makes up 0.01% - 20% weight per weight (w / w) of the composition. In some embodiments, the non-ionic surfactant is about 0.01% w / w of the composition to about 20% w / w of the composition. In some embodiments, the non-ionic surfactant is at least about 0.01% w / w of the composition. In some embodiments, the non-ionic surfactant is at most about 20% w / w of the composition. In some embodiments, the non-ionic surfactant is about 0.05% w / w of the composition to about 0.1% w / w of the composition, about 0.05% w / w of the composition to about 0.1% w / w of the composition, about 0.05% w / w of the composition to about 0.5% w / w of the composition, about 0.05% w / w of the composition to about 1% w / w of the composition, about 0.05% w / w of the composition to about 2% w / w of the composition, about 0.05% w / w of the composition to about 5% w / w of the composition, about 0.05% w / w of the composition to about 10% w / w of the composition, about 0.05% w / w of the composition to about 20% w / w of the composition, about 0.1% w / w of the composition to about 0.5% w / w of the composition, about 0.1% w / w of the composition to about 1% w / w of the composition, about 0.1% w / w of the composition to about 2% w / w of the composition, about 0.1% w / w of the composition to about 5% w / w of the composition, about 0.1% w / w of the composition to about 10% w / w of the composition, about 0.1% w / w of the composition to about 20% w / w of the composition, about 0.5% w / w of the composition to about 1% w / w of the composition, about 0.5% w / w of the composition to about 2% w / w of the composition, about 0.5% w / w of the composition to about 5% w / w of the composition, about 0.5% w / w of the composition to about 10% w / w of the composition, about 0.5% w / w of the composition to about 20% w / w of the composition, about 1% w / w of the composition to about 2% w / w of the composition, about 1% w / w of the composition to about 5% w / w of the composition, about 1% w / w of the composition to about 10% w / w of the composition, about 1% w / w of the composition to about 20% w / w of the composition, about 2% w / w of the composition to about 5% w / w of the composition, about 2% w / w of the composition to about 10% w / w of the composition, about 2% w / w of the composition to about 20% w / w of the composition, about 5% w / w of the composition to about 10% w / w of the composition, about 5% w / w of the composition to about 20% w / w of the composition, or about 10% w / w of the composition to about 20% w / w of the composition. In some embodiments, the non-ionic surfactant is about 0.05% w / w of the composition, about 0.1% w / w of the composition, about 0.5% w / w of the composition, about 1% w / w of the composition, about 2% w / w of the composition, about 5% w / w of the composition, about 10% w / w of the composition, or about 20% w / w of the composition.

[0069] In some embodiments, the non-ionic surfactant is about 0.05% w / w of the composition to about 2% w / w of the composition. In some embodiments, the non-ionicsurfactant is at least about 0.05% w / w of the composition. In some embodiments, the non- ionic surfactant is at most about 2% w / w of the composition. In some embodiments, the non- ionic surfactant is about 0.05% w / w of the composition to about 0.1% w / w of the composition, about 0.05% w / w of the composition to about 0.1% w / w of the composition, about 0.05% w / w of the composition to about 0.2% w / w of the composition, about 0.05% w / w of the composition to about 0.3% w / w of the composition, about 0.05% w / w of the composition to about 0.4% w / w of the composition, about 0.05% w / w of the composition to about 0.5% w / w of the composition, about 0.05% w / w of the composition to about 0.6% w / w of the composition, about 0.05% w / w of the composition to about 1% w / w of the composition, about 0.05% w / w of the composition to about 1.5% w / w of the composition, about 0.05% w / w of the composition to about 2% w / w of the composition, about 0.1% w / w of the composition to about 0.1% w / w of the composition, about 0.1% w / w of the composition to about 0.2% w / w of the composition, about 0.1% w / w of the composition to about 0.3% w / w of the composition, about 0.1% w / w of the composition to about 0.4% w / w of the composition, about 0.1% w / w of the composition to about 0.5% w / w of the composition, about 0.1% w / w of the composition to about 0.6% w / w of the composition, about 0.1% w / w of the composition to about 1% w / w of the composition, about 0.1% w / w of the composition to about 1.5% w / w of the composition, about 0.1% w / w of the composition to about 2% w / w of the composition, about 0.1% w / w of the composition to about 0.2% w / w of the composition, about 0.1% w / w of the composition to about 0.3% w / w of the composition, about 0.1% w / w of the composition to about 0.4% w / w of the composition, about 0.1% w / w of the composition to about 0.5% w / w of the composition, about 0.1% w / w of the composition to about 0.6% w / w of the composition, about 0.1% w / w of the composition to about 1% w / w of the composition, about 0.1% w / w of the composition to about 1.5% w / w of the composition, about 0.1% w / w of the composition to about 2% w / w of the composition, about 0.2% w / w of the composition to about 0.3% w / w of the composition, about 0.2% w / w of the composition to about 0.4% w / w of the composition, about 0.2% w / w of the composition to about 0.5% w / w of the composition, about 0.2% w / w of the composition to about 0.6% w / w of the composition, about 0.2% w / w of the composition to about 1% w / w of the composition, about 0.2% w / w of the composition to about 1.5% w / w of the composition, about 0.2% w / w of the composition to about 2% w / w of the composition, about 0.3% w / w of the composition to about 0.4% w / w of the composition, about 0.3% w / w of the composition to about 0.5% w / w of the composition, about 0.3% w / w of the composition to about 0.6% w / w of the composition, about 0.3% w / w of the composition to about 1% w / w of the composition, about 0.3% w / w of the composition to about 1.5% w / w of the composition, about 0.3% w / w of thecomposition to about 2% w / w of the composition, about 0.4% w / w of the composition to about 0.5% w / w of the composition, about 0.4% w / w of the composition to about 0.6% w / w of the composition, about 0.4% w / w of the composition to about 1% w / w of the composition, about 0.4% w / w of the composition to about 1.5% w / w of the composition, about 0.4% w / w of the composition to about 2% w / w of the composition, about 0.5% w / w of the composition to about 0.6% w / w of the composition, about 0.5% w / w of the composition to about 1% w / w of the composition, about 0.5% w / w of the composition to about 1.5% w / w of the composition, about 0.5% w / w of the composition to about 2% w / w of the composition, about 0.6% w / w of the composition to about 1% w / w of the composition, about 0.6% w / w of the composition to about 1.5% w / w of the composition, about 0.6% w / w of the composition to about 2% w / w of the composition, about 1% w / w of the composition to about 1.5% w / w of the composition, about 1% w / w of the composition to about 2% w / w of the composition, or about 1.5% w / w of the composition to about 2% w / w of the composition. In some embodiments, the non-ionic surfactant is about 0.05% w / w of the composition, about 0.1% w / w of the composition, about 0.1% w / w of the composition, about 0.2% w / w of the composition, about 0.3% w / w of the composition, about 0.4% w / w of the composition, about 0.5% w / w of the composition, about 0.6% w / w of the composition, about 1% w / w of the composition, about 1.5% w / w of the composition, or about 2% w / w of the composition

[0070] In some embodiments, the non-ionic surfactant comprises Polysorbate 20, Poloxamer 407, Tyloxapol, or cremophor. In some embodiments, the non-ionic surfactant is Polysorbate 20. In some embodiments, the non-ionic surfactant is Poloxamer 407. In some embodiments, the non-ionic surfactant is Tyloxapol. In some embodiments, the non-ionic surfactant is cremophor. The non-ionic surfactants described herein can be present within any one of the ranges (e.g., percent w / w) described herein, a specific value that falls within the described ranges.

[0071] In some embodiments, the composition further comprises cosolvents (e.g., between 0.5 and 50% w / w), such as N,N- Dimethylacetamide, ethanol, PEG-400, propylene glycol, dimethylsulfoxide (DMSO); oils, or cyclodextrins can be added to a pharmaceutical preparation. In some embodiments, the composition further comprises a tonicity-adjusting agent. In some embodiments, the composition is an isotonic solution. In some embodiments, the tonicity-adjusting agent is mannitol, sorbitol, glucose or trehalose, or an inorganic salt such as sodium chloride. In some embodiments, the composition comprises mannitol. In some embodiments, the composition comprises sorbitol. In some embodiments, the composition comprises glucose or trehalose. In some embodiments, the composition comprises an inorganic salt. In some embodiments, the tonicity-adjusting agent is present at an amountsuitable to bring the tonicity of the composition into the 250-400 mOsm / L range. In some embodiments, the non-ionic surfactant is about 1% w / w of the composition to about 10% w / w of the composition. In some embodiments, the non-ionic surfactant is at least about 1% w / w of the composition. In some embodiments, the non-ionic surfactant is at most about 10% w / w of the composition. In some embodiments, the non-ionic surfactant is about 1% w / w of the composition to about 2% w / w of the composition, about 1% w / w of the composition to about 3% w / w of the composition, about 1% w / w of the composition to about 4% w / w of the composition, about 1% w / w of the composition to about 5% w / w of the composition, about 1% w / w of the composition to about 10% w / w of the composition, about 2% w / w of the composition to about 3% w / w of the composition, about 2% w / w of the composition to about 4% w / w of the composition, about 2% w / w of the composition to about 5% w / w of the composition, about 2% w / w of the composition to about 10% w / w of the composition, about 3% w / w of the composition to about 4% w / w of the composition, about 3% w / w of the composition to about 5% w / w of the composition, about 3% w / w of the composition to about 10% w / w of the composition, about 4% w / w of the composition to about 5% w / w of the composition, about 4% w / w of the composition to about 10% w / w of the composition, or about 5% w / w of the composition to about 10% w / w of the composition. In some embodiments, the non-ionic surfactant is about 1% w / w of the composition, about 2% w / w of the composition, about 3% w / w of the composition, about 4% w / w of the composition, about 5% w / w of the composition, or about 10% w / w of the composition.

[0072] In some embodiments, the composition comprises a buffering agent. In some embodiments, the buffering agent is an acidifying agent. In some embodiments, the acidifying agent is an acetate buffer at pH 4.5. In some embodiments, the concentration acetate buffer pH 4.5 is about 10 millimolar (mM). Generally, the pH can be controlled by an appropriate buffer suitable for injection into the eye, for example the pH of the composition can be in the 2.5-7.5 range or 3.5-4.5 range.

[0073] As described herein, the composition can comprise one or more excipients. Accordingly, in some embodiments, the composition comprises a non-ionic surfactant, a tonicity-adjusting agent, and a buffering agent, in combination with the peptide. Any of the described excipients can be combined within the amounts and / or ranges described. Dosages and Dosing Regimens

[0074] In an embodiment, the compositions described herein comprise an amount of the peptide suitable to inhibit Fas-mediated inflammation and / or treat, inhibit and / or reduce loss in RNFL thickness or the symptoms thereof in an eye. As used herein, a dose or dosageincludes and / or refers to the amount of therapeutic agent, such as the peptides described, in a composition (e.g., a composition for administering to an eye). A dose can refer to either (i) the peptide (parent compound) or the pharmaceutically acceptable salt thereof. In some embodiments, the amount of the peptide in the composition (i.e., pharmaceutical composition) that is suitable for the methods described herein (e.g., treating RNFL thinning) ranges from 5 micrograms (ug) to 10,000 ug. The dosing forms comprising the compositions described herein are generally administered to the vitreous humor of an eye and can be further formulated for injection into the eye (e.g., intravitreal injection). In some embodiments, the amount of the peptide (e.g., a peptide comprising the amino acid sequence HHIYLGAVNYIY) or a pharmaceutically acceptable salt thereof that is suitable for the methods described herein ranges from 5 ug to 10,000 ug. In some embodiments, the amount of the peptide comprising the amino acid sequence HHIYLGAVNYIY or variant sequence thereof, or a pharmaceutically acceptable salt of the peptide that is suitable for the methods described herein ranges from 5 ug to 10,000 ug. In some embodiments, the amount of the peptide having the structure of Formula I or a pharmaceutically acceptable salt thereof that is suitable for the methods described herein ranges from 5 ug to 10,000 ug. In some embodiments, the amount of the peptide having the structure of Formula III or a pharmaceutically acceptable salt thereof that is suitable for the methods described herein ranges from 5 ug to 10,000 ug.

[0075] In some embodiments, a dose comprises about 5-1,000 ug of the peptide (e.g., Formula III) or the variant sequence thereof. In some embodiments, a dose comprises about 25-500 ug of the peptide or the variant sequence thereof. In some embodiments, a dose comprises about 25-250 ug of the peptide or the variant sequence thereof. In some embodiments, a dose comprises about 50-250 ug of the peptide or the variant sequence thereof. In certain embodiments, a dose comprises about 50 ug of the peptide or the variant sequence thereof. In certain embodiments, a dose comprises about 100 ug of the peptide or the variant sequence thereof. In certain embodiments, a dose comprises about 200 ug of the peptide or the variant sequence thereof. In certain embodiments, a dose comprises about 300 ug of the peptide or the variant sequence thereof. In some embodiments, the peptide is present at a concentration 0.1 milligrams per milliliter (mg / mL) to 10 mg / mL. In some embodiments, the peptide is present at a concentration 0.1 milligrams per milliliter (mg / mL) to 5.0 mg / mL.

[0076] In some embodiments, a dose comprises about 5 ug of a pharmaceutically acceptable salt of the peptide to about 300 ug of a pharmaceutically acceptable salt of the peptide. In some embodiments, a dose comprises at least about 5 ug of a pharmaceuticallyacceptable salt of the peptide. In some embodiments, a dose comprises at most about 300 ug of a pharmaceutically acceptable salt of the peptide.

[0077] The concentration of the peptide within the composition can be adjusted in a manner suitable for ocular administration. In some embodiments, the concentration of the peptide within the composition ranges from about 0.1 milligrams per mil liliter (mg / mL) to about 5 mg / mL. In some embodiments, the concentration of the peptide within the composition ranges from about 0.1 milligrams per milliliter (mg / mL) to about 10 mg / mL. In some embodiments, the concentration of the peptide within the composition ranges from about 0.1 milligrams per milliliter (mg / mL) to about 100 mg / mL. In some embodiments, the concentration of the peptide (e.g., a peptide comprising the amino acid sequence HHIYLGAVNYIY) or a pharmaceutically acceptable salt thereof ranges from about 0.1 mg / mL to about 5mg / mL. In some embodiments, the concentration of the peptide comprising the amino acid sequence HHIYLGAVNYIY or variant sequence thereof, or a pharmaceutically acceptable salt of the peptide ranges from about 0.1 milligrams per milliliter (mg / mL) to about 5mg / mL. In some embodiments, the concentration of the peptide having the structure of Formula I or a pharmaceutically acceptable salt thereof ranges from about 0.1 mg / mL to about 5mg / mL. In some embodiments, the concentration of the peptide having the structure of Formula III, or a pharmaceutically acceptable salt thereof ranges from about 0.1 mg / mL to about 5mg / mL. Pharmacokinetics

[0078] In some embodiments, the compositions described herein are administered to an eye of an individual in need thereof. Administration to an eye (i.e., “ocular application” or “ocular administration”) includes subconjunctival, intravitreal, re trobulbar, intracameral administration subretinal, or suprachoroidal. In some embodiments, ocular administration comprises subconjunctival, intravitreal, retrobulbar, or intracameral administration. In some embodiments, ocular administration comprises intravitreal administration. In some embodiments, ocular administration comprises subconjunctival administration. In some embodiments, ocular administration comprises retrobulbar administration. In some embodiments, ocular administration comprises intracameral administration.

[0079] In some embodiments, the dosing forms comprising the compositions described herein are generally administered to the vitreous humor of an eye. In some embodiments, the half-life of the peptide (e.g., a peptide comprising the amino acid sequence HHIYLGAVNYIY) or a pharmaceutically acceptable salt thereof in the vitreous humor is greater than about 30 days to greater than about 275 days. In some embodiments, the peptidecomprising the amino acid sequence HHIYLGAVNYIY or variant sequence thereof, or a pharmaceutically acceptable salt of the peptide has a half-life in the vitreous humor that is greater than about 30 days to greater than about 275 days. In some embodiments, the peptide having the structure of Formula I or a pharmaceutically acceptable salt thereof has a half-life in the vitreous humor that is greater than is greater than about 30 days to greater than about 275 days. In some embodiments, the peptide having the structure of Formula III, or a pharmaceutically acceptable salt thereof has a half-life in the vitreous humor that is greater than is greater than about 30 days to greater than about 275 days. In some embodiments, the peptide comprising the amino acid sequence HHIYLGAVNYIY or variant sequence thereof, or a pharmaceutically acceptable salt of the peptide has a half-life in the vitreous humor that is greater than about 14 days to greater than about 275 days. In some embodiments, the peptide having the structure of Formula I or a pharmaceutically acceptable salt thereof has a half-life in the vitreous humor that is greater than is greater than about 14 days to greater than about 275 days. In some embodiments, the peptide having the structure of Formula III, or a pharmaceutically acceptable salt thereof has a half-life in the vitreous humor that is greater than is greater than about 14 days to greater than about 275 days.

[0080] In some embodiments, the half-life of the peptide is greater than about 14 days in the eye. In some embodiments, the half-life of the peptide is greater than about 30 days in the eye. In some embodiments, the half-life of the peptide is greater than about 60 days in the eye. In some embodiments, the half-life of the peptide is greater than about 90 days in the eye. In some embodiments, the half-life of the peptide is greater than about 120 days in the eye. In some embodiments, the half-life of the peptide is greater than about 150 days in the eye. In some embodiments, the half-life of the peptide is greater than about 180 days in the eye. In some embodiments, the half-life of the peptide is greater than about 210 days in the eye. In some embodiments, the half-life of the peptide is greater than about 240 days in the eye. In some embodiments, the half-life of the peptide is greater than about 270 days in the eye.

[0081] In some embodiments, the half-life of the peptide is greater than about 14 days in the vitreous humor. In some embodiments, the half-life of the peptide is greater than about 30 days in the vitreous humor. In some embodiments, the half-life of the peptide is greater than about 60 days in the vitreous humor. In some embodiments, the half-life of the peptide is greater than about 90 days in the vitreous humor. In some embodiments, the half-life of the peptide is greater than about 120 days in the vitreous humor. In some embodiments, the half- life of the peptide is greater than about 150 days in the vitreous humor. In some embodiments, the half-life of the peptide is greater than about 180 days in the vitreous humor. In someembodiments, the half-life of the peptide is greater than about 210 days in the vitreous humor. In some embodiments, the half-life of the peptide is greater than about 240 days in the vitreous humor. In some embodiments, the half-life of the peptide is greater than about 270 days in the vitreous humor.

[0082] Determining the amount of the peptide in the vitreous humor generally requires collecting all of the vitreous fluid or a substantial portion thereof from an eye or sacrificing the eye in order to sample the vitreous humor. In some embodiments, collecting all of the vitreous fluid or a substantial portion thereof in a human eye, or sacrificing an eye is not feasible for maintaining the health of an eye in a human. Accordingly, in some embodiments, the half-life of the peptide in a human eye is determined by measuring and / or extrapolating from a half-life of the peptide in the eye of a mammal. In some embodiments, the mammal is a rabbit. In some embodiments, the mammal is a pig (e.g., minipig). In some embodiments, the mammal is a monkey. Various methods of detecting the presence of a drug are also suitable for detecting the peptide. For example, methods suitable for detecting the peptide include performing mass spectrometry (e.g., liquid chromatography-mass spectrometry (LC- MS) or high-performance LC-MS (HPLC-MS)) on a sample from the vitreous humor. Methods Methods of Treating RNFL Thinning

[0083] Provided herein are methods advantageous for treating retinal nerve fiber layer (RNFL) thinning (e.g., a decrease in RNFL thickness of an optic nerve) by inhibiting Fas inflammation. Further provided are methods advantageous for increasing retinal nerve fiber layer (RNFL) thinning (e.g., a decrease in RNFL thickness of an optic nerve). In certain embodiments, an eye comprising a loss in retinal nerve fiber layer (RNFL) thickness has an ocular disease or disorder.

[0084] In some embodiments, provided herein are methods of treating a loss in retinal nerve fiber layer (RNFL) thickness in an eye of an individual, comprising: administering a Fas inhibitor to the eye. In some embodiments, provided herein are methods of treating a loss in retinal nerve fiber layer (RNFL) thickness in an eye of an individual, comprising: administering a peptide to the eye, wherein the peptide comprises an amino acid sequence HHIYLGAVNYIY or a variant sequence thereof, or a pharmaceutically acceptable salt of the peptide. In some embodiments, provided are methods of treating a loss in retinal nerve fiber layer (RNFL) thickness in an eye of an individual, comprising: administering a peptide to the eye of the individual, the peptide having the structure of Formula I or a pharmaceutically acceptable salt thereof. In some embodiments, provided are methods of treating a loss inretinal nerve fiber layer (RNFL) thickness in an eye of an individual, comprising: administering a peptide to the eye of the individual, the peptide having the structure of Formula III or a pharmaceutically acceptable salt thereof. In certain embodiments, treating the loss in retinal nerve fiber layer thickness (e.g., of an optic nerve) comprises inhibiting a reduction in RNFL thickness. In certain embodiments, inhibiting the reduction in RNFL thickness comprises inhibiting a decrease in RNFL thickness. In certain embodiments, inhibiting the reduction in RNFL thickness comprises inhibiting a rate of a decrease in RNFL thickness compared to an untreated eye or the rate of a decrease in RNFL thickness compares to a rate prior to treatment. In certain embodiments, treating the loss in retinal nerve fiber layer thickness comprises increasing in RNFL thickness. In certain embodiments, treating the loss of RNFL thickness comprises reducing a decrease of ganglion axons (e.g., cell death and / or apoptosis) in nerves within the RNFL.

[0085] In some embodiments, provided herein are methods of increasing retinal nerve fiber layer (RNFL) thickness of an eye of an individual, comprising: administering a Fas inhibitor to the eye. In some embodiments, provided herein are methods of increasing retinal nerve fiber layer (RNFL) thickness of an eye of an individual, comprising: administering a peptide to the eye, wherein the peptide comprises an amino acid sequence HHIYLGAVNYIY or a variant sequence thereof, or a pharmaceutically acceptable salt of the peptide. In some embodiments, provided herein are methods of increasing retinal nerve fiber layer (RNFL) thickness of an eye of an individual, comprising: administering a peptide to the eye of the individual, the peptide having the structure of Formula I or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein are methods of increasing retinal nerve fiber layer (RNFL) thickness of an eye of an individual, comprising: administering a peptide to the eye of the individual, the peptide having the structure of Formula III or a pharmaceutically acceptable salt thereof.

[0086] In some embodiments, provided herein are methods of inhibiting a loss of axons (e.g., retinal ganglion cell axons) in an eye of an individual, comprising: administering a Fas inhibitor to the eye. In some embodiments, provided herein are methods of inhibiting a loss of axons (e.g., retinal ganglion cell axons) in an eye of an individual, comprising: administering a peptide to the eye of the individual, wherein the peptide comprises an amino acid sequence HHIYLGAVNYIY or a variant sequence thereof, or a pharmaceutically acceptable salt of the peptide. In some embodiments, provided herein are methods of inhibiting a loss of axons (e.g., retinal ganglion cell axons) in an eye of an individual, comprising: administering a peptide to the eye of the individual, the peptide having the structure of Formula I or a pharmaceutically acceptable salt thereof. In some embodiments,provided herein are methods of inhibiting a loss of axons (e.g., retinal ganglion cell axons) in an eye of an individual, comprising: administering a peptide to the eye, the peptide having the structure of Formula III or a pharmaceutically acceptable salt thereof. In certain embodiments, the loss in cells that innervate the RNFL in an eye of an individual comprises cell death of neurons that innervate the RNFL. In certain embodiments, cell death comprises apoptosis. RNFL

[0087] Retinal nerve fiber layer (RNFL) generally refers to and encompasses a structure and / or layer of the optic nerve made up of (e.g., containing) non-myelinated axons of the retinal ganglion cells that form the optic nerve. Generally, Optical Coherence Tomography (OCT), such as Spectral-Domain OCT (SD-OCT), is a validated technique to image and measure RNFL thickness around the optic nerve head (peripapillary RNFL). In certain instances, RNFL thinning reflects the axonal loss (e.g., via cell death of retinal ganglion cells or the loss of retinal ganglion cell axons within the ganglion layer) within the optic nerve from injuries within the retina, the optic nerve, the optic chiasm, or the optic tracts. In certain instances, RNFL thinning is cause by an optic disease or disorder (e.g., glaucoma).

[0088] In certain embodiments, the RNFL thickness (e.g., mean RNFL thickness of the optic nerve) is equal to or less than 100 um (microns). In certain embodiments, the RNFL thickness (e.g., mean RNFL thickness of the optic nerve) is equal to or less than 90 um (microns). In certain embodiments, the RNFL thickness (e.g., mean RNFL thickness of the optic nerve) is equal to or less than 80 um (microns). In certain embodiments, the RNFL thickness (e.g., mean RNFL thickness of the optic nerve) is equal to or less than 70 um (microns). In certain embodiments, the RNFL thickness (e.g., mean RNFL thickness of the optic nerve) is equal to or less than 60 um (microns). In certain embodiments, the RNFL thickness (e.g., mean RNFL thickness of the optic nerve) is between about 60 um and about 100 um.

[0089] In some embodiments, the RNFL thickness is measured by optical coherence tomography (OCT). In some embodiments, the RNFL is measured by Spectral Domain OCT (SD-OCT). In some embodiments, the RNFL is measured by Time Domain OCT (TD-OCT). In some embodiments, the RNFL is measured by both SD-OCT and TD-OCT. Treating RNFL Thinning

[0090] In certain embodiments, treating the loss in retinal nerve fiber layer thickness (e.g., of an optic nerve) comprises inhibiting a reduction in RNFL thickness. In certainembodiments, inhibiting the reduction in RNFL thickness comprises inhibiting a decrease in RNFL thickness. In certain embodiments, inhibiting the reduction in RNFL thickness comprises inhibiting a rate of a decrease in RNFL thickness compared to an untreated eye or the rate of a decrease in RNFL thickness compares to a rate prior to treatment. In certain embodiments, treating the loss in retinal nerve fiber layer thickness comprises increasing in RNFL thickness. In certain embodiments, treating the loss of RNFL thickness comprises reducing a decrease of ganglion axons (e.g., cell death and / or apoptosis) in nerves within the RNFL. In such instances and embodiments, the increase in RNFL thickness or a reduction in RNFL thinning is not a result of an edema.

[0091] In some embodiments, the methods described herein include methods of treating RNFL thinning associated with inflammation (e.g., Fas-mediated inflammation) in an eye. In some embodiments, retinal inflammation can be determined by a biological assay detecting the presence of inflammatory molecules (e.g., inflammatory cytokines) in a sample (e.g ., vitreous humor sample) taken from the eye. Exemplary inflammatory molecules include, but are not limited to, Fas-mediated inflammation-related molecules (e.g. TNFa, IL-1b, IP-10, IL-18, MIP-1a, IL-6, GFAP, MIP2, MCP-1 , or MIP-1b); a Fas-mediated complement-related molecules (complement component 3 (C3) or complement component 1 q (C1q)) Caspase 8; components of the inflammasome (e.g., NLRP3 or NLRP2); C-X-C motif chemokines (e.g., CXCL2 (MIP-2alpha) or CXCL10 (IP-10)); C-X3-C motif chemokines (e.g., CX3CL1 (fractalkine)); C-C motif chemokines (CCL2 (MCP-1), CCL3 (MIP-1a), and CCL4 (MIP- 1b)); toll-like receptor 4 (TLR4); interleukin cytokines (e.g., IL-1b, IL-18, and IL-6); TNF superfamily cytokines (e.g., TNFa); or GFAP.

[0092] In certain embodiments, the eye of the individual has an ocular injury characterized by RNFL thinning. In some embodiments, the eye of the individual has an ocular disease and / or disorder. In certain embodiments, the ocular disease and / or disorder is glaucoma. As used herein, glaucoma generally includes and refers to a group of ocular diseases characterized by the progressive loss of retinal ganglion cells and is associated with progressive damage to the optic nerve and resultant optical field defects, vision loss and, in some cases, blindness. In some embodiments, glaucoma is accompanied by high intraocular pressure and / or inflammation in the eye (e.g., within the retinal tissue). In some embodiments, glaucoma is not accompanied by abnormally high intraocular pressure and / or inflammation in the eye (e.g., within the retinal tissue). In certain embodiments, the intraocular pressure is controlled and / or stable. In certain embodiments, the intraocular pressure is variable.Methods of Treating GCC Thinning

[0093] Provided herein are methods advantageous for treating ganglion cell complex (GCC) thinning (e.g., a decrease in GCC thickness) by inhibiting Fas inflammation. Further provided are methods advantageous for treating ganglion cell complex (GCC) thinning (e.g., a decrease in GCC thickness). In certain embodiments, an eye comprising a loss in ganglion cell complex (GCC) thickness has an ocular disease or disorder.

[0094] In some embodiments, provided herein are methods of treating a loss in ganglion cell complex (GCC) thickness in an eye of an individual, comprising: administering a Fas inhibitor to the eye. In some embodiments, provided herein are methods of treating a loss in ganglion cell complex (GCC) thickness in an eye of an individual, comprising: administering a peptide to the eye, wherein the peptide comprises an amino acid sequence HHIYLGAVNYIY or a variant sequence thereof, or a pharmaceutically acceptable salt o f the peptide. In some embodiments, provided are methods of treating a loss in ganglion cell complex (GCC) thickness in an eye of an individual, comprising: administering a peptide to the eye of the individual, the peptide having the structure of Formula I or a pharmaceutically acceptable salt thereof. In some embodiments, provided are methods of treating a loss in ganglion cell complex (GCC) thickness in an eye of an individual, comprising: administering a peptide to the eye of the individual, the peptide having the structure of Formula III or a pharmaceutically acceptable salt thereof. In certain embodiments, treating the loss in ganglion cell complex thickness comprises inhibiting a reduction in GCC thickness. In certain embodiments, inhibiting the reduction in GCC thickness comprises inhibiting a decrease in GCC thickness. In certain embodiments, inhibiting the reduction in GCC thickness comprises inhibiting a rate of a decrease in GCC thickness compared to an untreated eye or the rate of a decrease in GCC thickness compares to a rate prior to treatment. In certain embodiments, treating the loss in ganglion cell complex thickness comprises increasing in GCC thickness. In certain embodiments, treating the loss of GCC thickness comprises reducing a decrease of ganglion axons (e.g., cell death and / or apoptosis) in nerves within the GCC.

[0095] In some embodiments, provided herein are methods of increasing ganglion cell complex (GCC) thickness of an eye of an individual, comprising: administering a Fas inhibitor to the eye. In some embodiments, provided herein are methods of increasing ganglion cell complex (GCC) thickness of an eye of an individual, comprising: administering a peptide to the eye, wherein the peptide comprises an amino acid sequence HHIYLGAVNYIY or a variant sequence thereof, or a pharmaceutically acceptable salt of the peptide. In some embodiments, provided herein are methods of increasing ganglion cell complex (GCC) thickness of an eye of an individual, comprising: administering a peptide tothe eye of the individual, the peptide having the structure of Formula I or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein are methods of increasing ganglion cell complex (GCC) thickness of an eye of an individual, comprising: administering a peptide to the eye of the individual, the peptide having the structure of Formula III or a pharmaceutically acceptable salt thereof.

[0096] In some embodiments, provided herein are methods of inhibiting a loss of axons (e.g., retinal ganglion cell axons) in an eye of an individual, comprising: administering a Fas inhibitor to the eye. In some embodiments, provided herein are methods of inhibiting a loss of axons (e.g., retinal ganglion cell axons) in an eye of an individual, comprising: administering a peptide to the eye of the individual, wherein the peptide comprises an amino acid sequence HHIYLGAVNYIY or a variant sequence thereof, or a pharmaceutically acceptable salt of the peptide. In some embodiments, provided herein are methods of inhibiting a loss of axons (e.g., retinal ganglion cell axons) in an eye of an individual, comprising: administering a peptide to the eye of the individual, the peptide having the structure of Formula I or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein are methods of inhibiting a loss of axons (e.g., retinal ganglion cell axons) in an eye of an individual, comprising: administering a peptide to the eye, the peptide having the structure of Formula III or a pharmaceutically acceptable salt thereof. In certain embodiments, the loss in cells that innervate the GCC in an eye of an individual comprises cell death of neurons that innervate the GCC. In certain embodiments, cell death comprises apoptosis. GCC

[0097] Ganglion cell complex (GCC) generally refers to and encompasses the three innermost retinal layers: the nerve fiber layer, the ganglion cell layer, and the inner plexiform layer. Generally, Optical Coherence Tomography (OCT), such as commercial Fourier- domain optical coherence tomography, is a validated technique to identify, image, and measure GCC thickness. In certain instances, GCC thinning reflects the retinal ganglion cell loss (e.g., via cell death of retinal ganglion cells or the loss of retinal ganglion cell axons within the ganglion layer) within the optic nerve from injuries within the retina, the optic nerve, the optic chiasm, or the optic tracts. In certain instances, GCC thinning is cause by an optic disease or disorder (e.g., glaucoma).

[0098] In some embodiments, the GCC thickness is measured by optical coherence tomography (OCT). In some embodiments, the RNFL is measured by Spectral Domain OCT (SD-OCT). In some embodiments, the RNFL is measured by Time Domain OCT (TD-OCT).Treating GCC Thinning

[0099] In certain embodiments, treating the loss in GCC thickness comprises inhibiting a reduction in GCC thickness. In certain embodiments, inhibiting the reduction in GCC thickness comprises inhibiting a decrease in GCC thickness. In certain embodiments, inhibiting the reduction in GCC thickness comprises inhibiting a rate of a decrease in GCC thickness compared to an untreated eye or the rate of a decrease in GCC thickness compares to a rate prior to treatment. In certain embodiments, treating the loss in GCC thickness comprises increasing in GCC thickness. In certain embodiments, treating the loss of GCC thickness comprises reducing a decrease of ganglion axons (e.g., cell death and / or apoptosis) in nerves within the GCC. In such instances and embodiments, the increase in GCC thickness or a reduction in GCC thinning is not a result of an edema.

[0100] In some embodiments, the methods described herein include methods of treating GCC thinning associated with inflammation (e.g., Fas-mediated inflammation) in an eye. In some embodiments, retinal inflammation can be determined by a biological assay detecting the presence of inflammatory molecules (e.g., inflammatory cytokines) in a sample (e.g., vitreous humor sample) taken from the eye. Exemplary inflammatory molecules include, but are not limited to, Fas-mediated inflammation-related molecules (e.g. TNFa, IL-1b, IP-10, IL-18, MIP-1a, IL-6, GFAP, MIP2, MCP-1 , or MIP-1b); a Fas-mediated complement-related molecules (complement component 3 (C3) or complement component 1 q (C1q)) Caspase 8; components of the inflammasome (e.g., NLRP3 or NLRP2); C-X-C motif chemokines (e.g., CXCL2 (MIP-2alpha) or CXCL10 (IP-10)); C-X3-C motif chemokines (e.g., CX3CL1 (fractalkine)); C-C motif chemokines (CCL2 (MCP-1), CCL3 (MIP-1a), and CCL4 (MIP- 1b)); toll-like receptor 4 (TLR4); interleukin cytokines (e.g., IL-1b, IL-18, and IL-6); TNF superfamily cytokines (e.g., TNFa); or GFAP.

[0101] In certain embodiments, the eye of the individual has an ocular injury characterized by GCC thinning. In some embodiments, the eye of the individual has an ocular disease and / or disorder. In certain embodiments, the ocular disease and / or disorder is glaucoma. As used herein, glaucoma generally includes and refers to a group of ocular diseases characterized by the progressive loss of retinal ganglion cells and is associated with progressive damage to the optic nerve and resultant optical field defects, vision loss and, in some cases, blindness. In some embodiments, glaucoma is accompanied by high intraocular pressure and / or inflammation in the eye (e.g., within the retinal tissue). In some embodiments, glaucoma is not accompanied by abnormally high intraocular pressure and / or inflammation in the eye (e.g., within the retinal tissue). In certain embodiments, theintraocular pressure is controlled and / or stable. In certain embodiments, the intraocular pressure is variable. Methods of Treating Glaucoma

[0102] Provided herein are methods advantageous for treating glaucoma. Generally, changes in visual acuity are slow to present in glaucoma patients, thereby increasing the burden of obtaining or efficiently observing therapeutic outcomes in treating glaucoma. In certain instances, the burden is further complicated by lack of reliable biomarkers for assessing disease progression, wherein intraocular pressure is commonly used as surrogate endpoints given that changes in visual acuity are slow to present. In these instances, and others, these burdens impose costly time and financial challenges for treating glaucoma and conducting clinical trials. The methods provided herein utilize changes (e.g., increases) in retinal nerve fiber layer (RNFL) thickness as a biomarker in the treatment of glaucoma. In certain instances, these methods arise from the surprising outcome that RNFL layer thickness can be increased, e.g., by administering a therapeutic agent such as a Fas inhibitor.

[0103] In some embodiments, provided herein are methods of treating glaucoma comprising measuring RNFL thickness (e.g., of an optic nerve) of the eye at two timepoints (e.g., at least two), and administering a therapeutic agent if (1) an RNFL thickness at a second timepoint is less than the RNFL thickness at the first timepoint, and / or (2) the second timepoint is below a threshold value (e.g., about 80 um).

[0104] In some embodiments, provided herein are methods of treating glaucoma in an eye of an individual, the method comprising: (a) measuring retinal nerve fiber layer (RNFL) thickness (e.g., of an optic nerve) of the eye at a first timepoint; (b) administering a first dose of therapeutic agent; (c) measuring RNFL thickness in the eye at a second timepoint; and (d) administering a second dose of the therapeutic agent if the RNFL thickness at the second timepoint is equal to or less than the RNFL thickness at the second timepoint. In certain embodiments, (d) further comprises stopping or pausing further treatment if the RNFL thickness at the second timepoint is greater than the RNFL thickness at the first timepoint. In certain embodiments, (d) further comprises stopping or pausing further treatment if the RNFL thickness at the second timepoint is greater than an RNFL thickness of a target value. In certain embodiments, the target value comprises an RNFL thickness equal to or greater than 70 um. In certain embodiments, the target value comprises an RNFL thickness equal to or greater than 80 um. In certain embodiments, the target value comprises an RNFL thickness equal to or greater than 90 um. In certain embodiments, the target value comprises an RNFL thickness equal to or greater than 100 um. In certain embodiments the target value comprisesa 1 um or greater increase in RNFL thickness. In certain embodiments the target value comprises a 2 um or greater increase in RNFL thickness. In certain embodiments the target value comprises a 3 um or greater increase in RNFL thickness. In certain embodiments the target value comprises a 4 um or greater increase in RNFL thickness. In certain embodiments the target value comprises a 5 um or greater increase in RNFL thickness.

[0105] In some embodiments, the method further comprises (e) measuring RNFL thickness at a third timepoint, and (f) administering an additional dose of the therapeutic agent if the RNFL thickness at the third timepoint is equal to or less than the RNFL thickness at the first timepoint or the second timepoint. In certain embodiments, the methods comprise administering an additional dose if an RNFL measurement from a previous timepoint is greater than a newly measured timepoint.

[0106] In some embodiments, provided herein are methods of treating glaucoma in an eye of an individual having a retinal nerve fiber layer (RNFL) thickness less than (N) um (microns), the method comprising: (a) administering a therapeutic agent; and (b) measuring RNFL thickness in the eye; (c) administering a second dose of the therapeutic agent if the RNFL thickness in (b) is less than the RNFL thickness is less than (Z) um.

[0107] In certain embodiments, (N) is 100 um or less. In certain embodiments, (N) is 90 um or less. In certain embodiments, (N) is 80 um or less. In certain embodiments, (N) is 70 um or less. In certain embodiments, (N) is equal to (Z). In certain embodiments, (Z) is 80 um or greater. In certain embodiments, (Z) is 90 um or greater. In certain embodiments, (Z) is 1 um greater than (N). In certain embodiments, (Z) is 2 um greater than (N). In certain embodiments, (Z) is 3 um greater than (N). In certain embodiments, (Z) is 1 um greater than (N). In some embodiments, (N) is 100 and (Z) is 80. In some embodiments, (N) is 90 and (Z) is 80. In some embodiments, (N) is 80 and (Z) is 80.

[0108] In some embodiments, (c) further comprises stopping or pausing further treatment if the RNFL thickness in (b) is equal to or greater than the RNFL thickness is less than 80 um. In some embodiments, the method comprises (d) measuring RNFL thickness at a subsequent timepoint, and (e) administering an additional dose of the therapeutic agent if the RNFL thickness at the subsequent timepoint is less than 80 um or less than the RNFL thickness of a prior measurement (e.g., in (b)).

[0109] In some embodiments, a second does is any subsequent dose. In certain embodiments, the second dose follows first dose. In certain embodiments, there can be one or more intervening doses between a first dose and a second dose.

[0110] In some embodiments, a second timepoint for measuring RNFL thickness is any subsequent timepoint. In certain embodiments, the second dose follows first dose. In certainembodiments, there can be one or more intervening RNFL measurements between a first timepoint and a second timepoint.

[0111] In some embodiments, provided herein are methods of treating glaucoma in an eye of an individual, the method comprising: (a) measuring visual field of the eye at a first timepoint; (b) administering a first dose of therapeutic agent; (c) measuring visual field in the eye at a second timepoint; and (d) administering a second dose of the therapeutic agent if the visual field at the second timepoint is equal to or less than the visual field at the first timepoint. In certain embodiments, (d) further comprises stopping or pausing further treatment if the visual field at the second timepoint is greater than the visual field at the first timepoint. In some embodiments, the method further comprises (e) measuring visual field at a third timepoint, and (f) administering an additional dose of the therapeutic agent if the visual field at the third timepoint is equal to or less than the visual field at the first timepoint or the second timepoint.

[0112] In some embodiments, provided herein are methods of treating glaucoma in an eye of an individual, the method comprising: (a) measuring visual field and RNFL thickness of the eye at a first timepoint; (b) administering a first dose of therapeutic agent; (c) measuring visual field and RNFL thickness in the eye at a second timepoint; and (d) administering a second dose of the therapeutic agent if the visual field and RNFL thickness at the second timepoint is equal to or less than the visual field and RNFL thickness at the first timepoint. In certain embodiments, (d) further comprises stopping or pausing further treatment if the visual field and RNFL thickness at the second timepoint is greater than the visual field at the first timepoint. In some embodiments, the method further comprises (e) measuring visual field and RNFL thickness at a third timepoint, and (f) administering an additional dose of the therapeutic agent if the visual field and RNFL thickness at the third timepoint is equal to or less than the visual field and RNFL thickness at the first timepoint or the second timepoint.

[0113] In some embodiments, the visual field is a measure of the Humphrey Visual Field (e.g., as measured by a Humphrey field analyzer). In some embodiments, the visual field comprises a sub-global measure of local (e.g., region specific within the eye) visual field measurements. In some embodiments, sub-global measure of local (e.g., region specific within the eye) visual field measurements are averaged within a cluster / specific region within the eye. In some embodiments, measuring the visual field comprises generating local visua l field measurements within the eye, and wherein (d) comprises administering the second dose of the therapeutic agent if a local visual field measurement at the second timepoint is equal to or less than the visual field at the first timepoint. In some embodiments, the visual field ismeasured using a clustering analysis to generate measures of local (e.g., region specific within the eye) visual field measurements. Multiple Dosing and PK

[0114] In some embodiments, the methods provided herein further comprises administering a first dose and a second dose of the peptide of the pharmaceutically acceptable salt of the peptide. In certain embodiments, the second composition is administered about 4 weeks or more after administering the first composition. In certain embodiments, the second composition is administered about 8 weeks or more after administering the first composition. In certain embodiments, the second composition is administered about 10 weeks or more after administering the first composition. In certain embodiments, the second composition is administered about 12 weeks or more after administering the first composition. In so certain me embodiments, the second composition is administered about 16 weeks or more after administering the first composition. In certain embodiments, the second composition is administered about 20 weeks or more after administering the first composition. In certain embodiments, the second composition is administered about 24 weeks or more after administering the first composition. In certain embodiments, the second composition is administered about 26 weeks or more after administering the first composition.

[0115] In certain embodiments, an additional dose is administered between 8 weeks and 26 weeks after an initial dose. In certain embodiments, an additional dose is administered between 10 weeks and 26 weeks after an initial dose. In certain embodiments, an additional dose is administered between 26 weeks and 25 weeks after an initial dose. In certain embodiments, an additional dose is administered between 14 weeks and 26 weeks after an initial dose.

[0116] In some embodiments, the rate of RNFL thinning is reduced after administering a first dose, wherein administering the second composition maintains the reduced rate of RNFL thinning. In some embodiments, the rate of RNFL thinning is reduced after administering the second composition. In some embodiments, the rate of RNFL thinning is reduced after administering the first composition and is further reduced after administering the second composition. In certain embodiments, a reduction in RNFL thinning is compared to the rate of RNFL thinning in an eye that has not been treated with the peptide.

[0117] In some embodiments, the methods comprise administering a plurality of doses to the eye, wherein: each dose of the plurality of doses comprises the peptide (e.g., comprising an amino acid sequence HHIYLGAVNYIY or variant sequence thereof, or apharmaceutically acceptable salt thereof); and no greater than five doses are administered to the eye within a year.

[0118] In some embodiments, no greater than four doses are administered to the eye within a year. In certain embodiments, no greater than three doses are administered to the eye within a year. In certain embodiments, no greater than two doses are administered to the eye within a year. In some embodiments, the plurality of doses comprises 2 doses. In certain embodiments, the plurality of doses comprises 3 doses. In certain embodiments, the plurality of doses comprises 4 doses. In certain embodiments, the plurality of doses comprises 5 doses. In some embodiments, no greater than one dose is administered to the eye within a year.

[0119] In some embodiments, the method comprises administering each dose to the vitreous humor of the eye. In certain embodiments, the peptide has a half-life in the vitreous humor more than about 30 days (e.g., at least 30 days). In certain embodiments, the peptide has a half-life in the vitreous humor more than about 90 days (e.g., at least 90 days). In certain embodiments, the peptide has a half-life in the vitreous humor more than about 180 days (e.g., at least 180 days). In some embodiments, the peptide has a half-life in the vitreous humor m than about 200 days (e.g., at least 200 days).

[0120] In some embodiments, the method comprises using the vitreous humor as a depot to provide the peptide or the pharmaceutically acceptable salt thereof to retinal tissue in the eye. In certain embodiments, the peptide or the pharmaceutically acceptable salt thereof is present in the vitreous humor more than about 30 days after administration. In certain embodiments, the peptide or the pharmaceutically acceptable salt thereof is present in the vitreous humor greater than about 10 weeks after administration. In certain embodiments, the peptide or the pharmaceutically acceptable salt thereof is present in the vitreous humor greater than about 12 weeks after administration. In certain embodiments, the peptide or the pharmaceutically acceptable salt thereof is present in the vitreous humor greater than about 16 weeks after administration. In certain embodiments, the peptide or the pharmaceutically acceptable salt thereof is present in the vitreous humor greater than about 20 weeks after administration. In certain embodiments, the peptide or the pharmaceutically acceptable salt thereof is present in the vitreous humor greater than about 24 weeks after administration. In certain embodiments, the peptide or the pharmaceutically acceptable salt thereof is present in the vitreous humor greater than about 30 weeks after administration. In certain embodiments, the peptide or the pharmaceutically acceptable salt thereof is present in the vitreous humor greater than about 40 weeks after administration. In certain embodiments, the peptide or the pharmaceutically acceptable salt thereof is present in the vitreous humor greater than about 50 weeks after administration.Peptides

[0121] In some embodiments, the methods described herein comprise administering a Fas-inhibitor. In some embodiments, the methods described herein comprise administering a Fas-inhibiting peptide. In some embodiments, the methods described herein comprise administering a peptide (e.g., a Fas inhibiting peptide) having a variant sequence of HHIYLGAVNYIY. In some embodiments, the methods described herein comprise administering a peptide having a variant amino acid sequence of Formula I. In some embodiments, the methods described herein comprise administering a peptide having a variant amino acid sequence of Formula III.

[0122] In certain embodiments, the variant sequence comprises an amino acid substitution. In certain embodiments, the variant sequence comprises one amino acid substitution. In some embodiments, the variant sequence comprises two amino acid substitutions. In certain embodiments, the variant sequence comprises three amino acid substitutions. In certain embodiments, the amino acid substitution is a conservative amino acid substitution. In some embodiments, the variant sequence comprises a truncation.

[0123] In some embodiments, the peptide further comprises a modification. In some embodiments, comprises a modified amino acid or a non-natural amino acid. In some embodiments, the peptide comprises an amidated C-terminus. In some embodiments, the peptide has the structure of Formula I, or a pharmaceutically acceptable salt thereof. In some embodiments, the peptide has the structure of Formula III, or a pharmaceut ically acceptable salt thereof.

[0124] In some embodiments, the methods comprise administering a pharmaceutically acceptable salt of the peptide is administered. In certain embodiments, the pharmaceutically acceptable salt is an acetate salt. In certain embodiments, the pharmaceutically acceptable salt is a polyacetate salt. In certain embodiments, the polyacetate salt is a triacetate salt. In certain embodiments, the pharmaceutically acceptable salt is a hydrochloride salt.

[0125] In some embodiments, the peptide, or the variant sequence thereof, or the pharmaceutically acceptable salt of the peptide is formulated in a composition (e.g., the pharmaceutical compositions described herein).

[0126] In some embodiments, about 5-1,000 ug of the peptide or the variant sequence thereof, or the pharmaceutically acceptable salt of the peptide is administered. In some embodiments, about 25-500 ug of the peptide or the variant sequence thereof, or the pharmaceutically acceptable salt of the peptide is administered. In some embodiments, about 25-250 ug of the peptide or the variant sequence thereof, or the pharmaceutically acceptable salt of the peptide is administered. In some embodiments, about 50-250 ug of the peptide orthe variant sequence thereof, or the pharmaceutically acceptable salt of the peptide is administered. In certain embodiments, about 50 ug of the peptide or the variant sequence thereof, or the pharmaceutically acceptable salt of the peptide is administered. In certain embodiments, about 100 ug of the peptide or the variant sequence thereof, or the pharmaceutically acceptable salt of the peptide is administered. In certain embodiments, about 200 ug of the peptide or the variant sequence thereof, or the pharmaceutically acceptable salt of the peptide is administered. In some embodiments, the peptide is present at a concentration 0.1 milligrams per milliliter (mg / mL) to 10 mg / mL. In some embodiments, the peptide is present at a concentration 0.1 milligrams per milliliter (mg / mL) to 5.0 mg / mL. Therapeutic Agents

[0127] In some embodiments, the therapeutic agent comprises a Fas inhibitor. In certain embodiments, the Fas inhibitor comprises a Fas-inhibiting peptide. In certain embodiments, the Fas-inhibiting peptide comprises an amino acid sequence HHIYLGAVNYIY or a variant sequence thereof, or a pharmaceutically acceptable salt of the peptide. In certain embodiments, the Fas-inhibiting peptide comprises a peptide having the structure of Formula I or a pharmaceutically acceptable salt thereof. In certain embodiments, the Fas-inhibiting peptide comprises a peptide having the structure of Formula III or a pharmaceutically acceptable salt thereof.

[0128] In some embodiments, the therapeutic agent is selected from the group consisting of a Fas inhibitor, a prostaglandin analog, a rho kinase inhibitor, a nitric oxide, a miotic agent, an alpha-adrenergic agonist, a beta blocker, and a carbonic anhydrase inhibitor. In some embodiments, the therapeutic agent is selected from the group consisting of a peptide comprising an amino acid sequence HHIYLGAVNYIY or a variant sequence thereof, or a pharmaceutically acceptable salt of the peptide, a peptide comprising a peptide having the structure of Formula I or a pharmaceutically acceptable salt thereof, a peptide comprising a peptide having the structure of Formula III or a pharmaceutically acceptable salt thereof, Xalatan (latanoprost), Travatan Z (travoprost), Zioptan (tafluprost), Lumigan (bimatoprost), Rhopressa (netarsudil), Vyzulta (latanoprostene bunod), Isopto Carpine (pilocarpine), Iopidine (apraclonidine), Alphagan P or Qoliana (brimonidine), Betoptic (betaxolol) and Betimol, Istalol, Timoptic (timolol), Trusopt (dorzolamide), and Azopt (brinzolamide).

[0129] As used herein, inhibition or inhibiting or reducing includes and / or refers to the reduction or suppression of a given condition, symptom, disorder, or disease, and / or a decrease in the baseline activity of a biological activity or process.

[0130] As used herein, individual is synonymous with patient and / or subject and includes and / or refers to a human and can be a human that has been diagnosed as needing to treat a disease or condition as disclosed herein. However, examples are not limited to humans and include, chimpanzees, marmosets, cows, horses, sheep, goats, pigs, rabbits, dogs, cats, rats, mice, guinea pigs, and the like. The individual is typically a human and can be a human that has been diagnosed as needing to treat a disease or condition as disclosed herein.

[0131] As used herein, treating or treatment of includes and / or refers to ameliorating the disease or disorder or symptoms thereof (e.g., slowing or arresting or reducing the development of the disease or at least one of the clinical symptoms thereof). In certain embodiments, treating or treatment also includes and / or refers to alleviating or ameliorating at least one physical and / or biological parameters including those which may not be discernible by the patient. In certain embodiments, treating or treatment includes and / or refers to modulating a disease, disorder, or biological process either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical and / or biological parameter), or both. In certain embodiments, treating or treatment includes and / or refers to preventing or delaying the onset or development or progression of the disease or disorder. In certain embodiments, treating or treatment includes and / or refers to preventing or delaying or inhibiting the deterioration of (i) a healthy physiological state or (ii) a baseline physiological state (e.g., the progression of a disease or disorder).

[0132] As used herein, “a” or “an” when used in conjunction with the term “comprising” in the claims and / or the specification includes and / or refers to “one” and also consistent with the meaning of “one or more”, “at least one”, and “one or more than one”. Similarly, the word “another” may mean at least a second or more.

[0133] As used herein, the words “comprising” (and any form of comprising, such as “comprise” and “comprises”), “having” (and any form of having, such as “have” and “has”), “including” (and any form of including, such as “include” and “includes”) or “containing” (and any form of containing, such as “contain” and “contains”), are inclusive or open -ended and do not exclude additional, unrecited elements or process steps. As used herein, in any instance or embodiment described herein, “comprising” may be replaced with “consisting essentially of” and / or “consisting of”. used herein, in any instance or embodiment described herein, “comprises” may be replaced with “consists essentially of” and / or “consists of”.

[0134] As used herein, the term “about” in the context of a given value or range includes and / or refers to a value or range that is within 20%, within 10%, and / or within 5% of the given value or range.

[0135] As used herein, the term “and / or” is to be taken as specific disclosure of each of the two specified features or components with or without the other. For example, “A and / or B” is to be taken as specific disclosure of each of (i) A, (ii) B and (iii) A and B, just as if each were set out individually herein.

[0136] As used herein, a “sample” includes and / or refers to any fluid or liquid sample which is being analyzed in order to detect and / or quantify an analyte. In some embodiments, a sample is a biological sample. Examples of samples include without limitation a bodily fluid, an extract, a solution containing proteins and / or DNA, a cell extract, a cell lysate, or a tissue lysate. Non-limiting examples of bodily fluids include urine, saliva, blood, serum, plasma, cerebrospinal fluid, tears, semen, sweat, pleural effusion, liquified fecal matter, and lacrimal gland secretion. EXAMPLES Example 1 – Reducing Loss of GCC Thickness and Retinal Nerve Fiber Layer Thickness in Patients Objective

[0137] The primary objective was to determine the efficacy and select doses of a peptide having the structure of Formula III (ONL1204) in patients having a retinal nerve fiber layer (RNFL) thinning. The primary endpoints of the study were clinical evaluations including RNFL thickness. Study design

[0138] Glaucoma patients showing a loss of RNFL thickness received two intravitreal injections of a Fas-inhibiting peptide having an acetate salt of the structure of Formula III (ONL1204). Injections were delivered at Day 0 and Day 90. Baseline RNFL thickness (thickness in microns (um)) was measured prior to treatment with ONL1204. RNFL thickness was then measured at the following time points: Day 90, Day 135, Day 177, Day 267. 50 ug per injection and 100 ug per injection doses were evaluated. A control group received sham injections. Outcomes

[0139] All glaucoma patients receiving doses comprising 50 micrograms (ug) and all but one patient receiving 100 ug of ONL1204 showed an increase in RNFL thickness in the StudyEye (e.g., compared to Baseline RNFL thickness). There was no similar increase in RNFL thickness in eyes that received sham injections or in untreated Fellow Eyes.

[0140] FIG.1A shows study data for glaucoma patients who received sham injections in the Study Eye. No increase in RNFL thickness from the Baseline measurement was observed for patients receiving sham injections in the Study eye (FIG. 1A, solid line). FIG. 1B-1F show representative RNFL optical coherence tomography (OCT) images from data in FIG. 1A . Table 1 shows sustained RNFL thickness associated with Study eyes receiving sham injections and in untreated Fellow eyes. Table 1: Sham Injections, RNFL Thickness (um)

[0141] FIG. 2A shows study data for glaucoma patients who received 50ug injections of ONL1204 in the Study Eye. An increase in RNFL thickness from the Baseline measurement was observed for patients receiving ONL1204 in the Study eye (FIG. 2A, solid line). FIG. 2B-2F show representative RNFL optical coherence tomography (OCT) images from data in FIG. 2A. Table 2 shows increased RNFL thickness associated with Study Eyes receiving 50ug injections of ONL1204. No similar increase in RNFL thickness was seen in untreated Fellow eyes.Table 2: 50 ug Fas inhibitor, RNFL Thickness (um)

[0142] FIG. 3A shows study data for glaucoma patients who received 100ug injections of ONL1204 in the Study Eye. An increase in RNFL thickness from the Baseline measurement was observed for patients receiving ONL1204 in the Study eye (FIG.3A, solid line). FIG. 3B-3F show representative RNFL optical coherence tomography (OCT) images from data in FIG. 3A. Table 3 shows increased RNFL thickness associated with Study eyes receiving 100ug injections of ONL1204. No similar increase in RNFL thickness was seen in untreated Fellow eyes. Table 3100 ug Fas inhibitor, RNFL Thickness (um)*patient and data under review (e.g., non-drug-related AE)

[0143] FIG.4 shows data demonstrating an increase of RNFL thickness in eyes receiving 50ug and 100ug dose intravitreal injections of a Fas inhibitor (solid lines labeled 50ug ONL 1204 Study Eye and 100ug ONL 1204 Study Eye), as compared to eyes that received sham injections and no Fas inhibitor (solid line labeled Sham Study Eye) and untreated eyes (dashed lines labeled Fellow Eye). Arrows indicate administration times of the Fas inhibitor at Day 0 and Day 90. Example 2 – Reducing Loss of GCC Thickness in Patients Objective

[0144] The primary objective was to determine the efficacy and select doses of a peptide having the structure of Formula III (ONL1204) in patients having GCC thinning. The primary endpoints of the study were clinical evaluations including GCC thickness. Study design

[0145] Glaucoma patients showing a loss of GCC thickness received two intravitreal injections of a Fas-inhibiting peptide having an acetate salt of the structure of Formula III (ONL1204). Injections were delivered at Day 0 and Day 90. Baseline GCC thickness (thickness in microns (um)) was measured prior to treatment with ONL1204. GCC thickness was then measured at the following time points: Day 90, Day 135, Day 177, Day 267.50 ug per injection, and 100 ug per injection doses were evaluated. A control group received sham injections. Outcomes

[0146] Glaucoma patients receiving doses comprising 50 micrograms (ug) and 100 ug of Fas inhibitor ONL1204 showed an increase in GCC thickness in the Study Eye. There wasno general increase in GCC thickness in eyes that received sham injections or in untreated Fellow Eyes.

[0147] FIG. 12A-I show changes in GCC thickness in treated (50 ug and 100 ug), sham treated, and fellow eye (untreated). 12A-I each show different regions or subregions of the GCC. The data demonstrated that treatment with Fas inhibitor ONL1204 resulted in an increase of GCC thickness in patients having GCC thinning (e.g., a decrease in GCC thickness) and a 50 ug or 100 ug doses of a Fas inhibitor. Example 3 – Improving Visual Outcomes in Open Angle Glaucoma Patients Objective

[0148] The primary objective was to determine multi-dose safety of a peptide having the structure of Formula III (ONL1204) and select doses in patients having open-angle glaucoma. The primary endpoints were the safety profile demonstrated in this study, including: adverse event reporting, clinical evaluations including visual function (e.g., visual field), and clinical evaluation. Study design

[0149] Patients showing open-angle glaucoma were enrolled in ascending dose groups and received a two intravitreal injections (day 0, day 90) of a peptide having an aceta te salt of the structure of Formula III (ONL1204). Visual function metrics were measured at over two screening time points, a baseline, and at about days 90, 177, 180, and 270. Measures for visual function included visual field analysis pre- and post-treatment with ONL1204.

[0150] This single-masked, randomized, sham-controlled study of 25 patients was designed to demonstrate the safety of ONL1204 Ophthalmic Solution in patients with progressing open angle glaucoma. Eligible patients were randomized (2:2:1) into 1 of 3 groups (Treatment Groups: ONL1204 Ophthalmic Solution 50 μg dose injection; ONL1204 Ophthalmic Solution 100 μg dose injection; or Sham Group: sham injection) and treated with 2 intravitreal (IVT) injections of 1 of 2 doses of ONL1204 Ophthalmic Solution or 2 sham injections. Patients were part of the study for approximately 39 weeks (270 days). Randomization was be stratified by HVF mean deviation (-5.00 dB to >-10.00 dB and ≤-10.00 dB to -15.00 dB).Outcomes

[0151] Patients receiving multiple doses comprising 50 ug and 100 ug of ONL1204 showed an improvement in visual field outcomes as measured by Humphrey Visual Field (HVF) analysis that included cluster trend analysis (e.g., measuring changes in local predefined regions / clusters) (see Gardiner et al. Detection of Functional Change Using Cluster Trend Analysis in Glaucoma. Invest Ophthalmol Vis Sci. 2017 May 1 ). FIGs. 5-7 show study and fellow eye data for the changes in mean visual field analysis of clusters in sham, 50 ug, and 100 ug patients. The data represents mean data for each cluster (10 clusters per patient). X axis (baseline sensitivity) shows the deviation from age -matched normal at baseline, averaged across locations in the cluster. Y Axis (annual change) shows the rate of change total deviation (i.e., change in sensitivity adjusted for normal aging), averaged across locations in the cluster. Each cluster is denoted by a rate of change in sensitivity, in dB / yr. The Baseline sensitivity of each cluster is denoted in dB. Positive values indicate an improvement in visual field and / or improving rate of visual field change. FIGs. 8-10 show study and fellow eye data for the changes in mean visual field analysis (unclustered, point specific, pointwise) in sham, 50 ug, and 100 ug patients.

[0152] An improvement in visual field was generally observed for patients receiving ONL1204 as compared to sham. Additionally, the benefits of ONL1204 treatment were also observed in patients having lower baseline sensitivities (e.g., equal to or less than - 5). A general association was observed between RNFL change and the change in HVF (clustered analysis). FIG. 11 shows changes in RNFL thickness as a function of HVF change. Patients treated with ONL1204 generally show increased RNFL thickness and an improvement in HVF measures (indicated by a shift upward and the right on the graph in FIG. 11) as compared to sham treatment and the fellow eyeSEQUENCES

Claims

CLAIMS 1. A method of treating a loss in retinal nerve fiber layer (RNFL) thickness of an eye of an individual, the method comprising: administering a peptide to the eye, wherein the peptide comprises an amino acid sequence HHIYLGAVNYIY or variant sequence thereof, or a pharmaceutically acceptable salt of the peptide.

2. The method of claim 1, wherein treating the loss in retinal nerve fiber layer thickness comprises inhibiting a reduction in RNFL thickness.

3. The method of any one of claims 1-2, wherein treating the loss in retinal nerve fiber layer thickness comprises increasing in RNFL thickness.

4. The method of any one of claims 1-3, wherein treating the loss in retinal nerve fiber layer thickness comprises reducing a rate of RNFL thinning compared to an untreated eye.

5. The method of any one of claims 1-4, wherein treating the loss in retinal nerve fiber layer thickness comprises reducing a decrease in ganglion axons (e.g., by cell death and / or apoptosis) within the RNFL.

6. A method of increasing retinal nerve fiber layer (RNFL) thickness of an eye for an individual, the method comprising: administering a peptide to the eye, wherein the peptide comprises an amino acid sequence HHIYLGAVNYIY or variant sequence thereof, or a pharmaceutically acceptable salt of the peptide.

7. The method of any one of claims 1-6, wherein the RNFL thickness (e.g., mean RNFL thickness) is less than 90 um (microns).

8. The method of any one of claims 1-7, wherein RNFL thickness is measured by optical coherence tomography (e.g., SD-OCT and / or TD-OCT).

9. A method of inhibiting a loss of axons within a retinal nerve fiber layer (RNFL) of an eye of an individual, the method comprising: administering a peptide to the eye, wherein the peptide comprises an amino acid sequence HHIYLGAVNYIY or variant sequence thereof, or a pharmaceutically acceptable salt of the peptide.

10. The method of claim 9, wherein the loss of axons comprises cell death and / or apoptosis of ganglion cells.

11. The method of any one of claims 9-10, wherein the eye has a RNFL thickness of less than 90 um (microns).

12. The method of any one of claims 1-11, wherein the RNFL is the RNFL of an optic nerve.

13. The method of any one of claims 1-12, wherein the method further comprises administering a first dose and a second dose of the peptide or the pharmaceutically acceptable salt of the peptide, and wherein the second composition is administered about 10 weeks or greater after administering the first dose.

14. The method of claim 13, wherein the second dose is administered about 12 weeks after the first dose.

15. The method of any one of claims 1-14, wherein the peptide or the pharmaceutically acceptable salt thereof has a half-life in the vitreous humor of more than about 30 days (e.g., at least 30 days).

16. The method of any one of claims 1-15, wherein the method comprises using the vitreous humor as a depot to provide the peptide or the pharmaceutically acceptable salt thereof to retinal tissue in the eye, wherein the peptide or the pharmaceutically acceptable salt thereof is present in the vitreous humor more than about 30 days after administration.

17. The method of any one of claims 1-14, wherein the eye has an ocular disease or disorder.

18. The method of claim 15, wherein the ocular disease or disorder comprises an elevated intraocular pressure.

19. The method of any one of claims 14-16, wherein the ocular disease or disorder is glaucoma.

20. The method of any one of claims 1-19, wherein the variant sequence comprises an amino acid substitution.

21. The method of claim 20, wherein the variant sequence comprises one amino acid substitution.

22. The method of any one of claims 1-21, wherein the peptide further comprises a modification.

23. The method of claim 22, wherein the modification comprises a modified amino acid.

24. The method of any one of claims 1-23, wherein the peptide comprises an amidated C- terminus.

25. The method of any one of claims 1-24, wherein the peptide has the structure of Formula I or a pharmaceutically acceptable salt thereof.

26. The method of any one of claims 1-25, wherein the peptide has the structure of Formula III:(Formula III) or a pharmaceutically acceptable salt thereof.

27. The method of any one of claims 1-26, wherein the method comprises administering the pharmaceutically acceptable salt thereof.

28. The method of claim 27, wherein the pharmaceutically acceptable salt is an acetate salt.

29. The method of claim 28, wherein the pharmaceutically acceptable salt is a polyacetate salt.

30. The method of claim 29, wherein the polyacetate salt is a triacetate salt.

31. The method of claim 27, wherein the pharmaceutically acceptable salt is a hydrochloride salt.

32. The method of any one of claims 1-31, wherein the method comprises administering a composition comprising the peptide.

33. The method of claim 32, wherein the composition (e.g., each composition or the first / second composition) further comprises one or more excipients.

34. The method of any one of claims 32-33, wherein the composition (e.g., each composition or the first / second composition) further comprises a surfactant.

35. The method of claim 34, wherein the surfactant is a non-ionic surfactant.

36. The method of claim 35, wherein the surfactant is a polysorbate, a polyethoxylated castor oil derivative, a polyethoxylated fatty acid, a polyethoxylated alcohol, a polyoxyethylene- polyoxypropylene block copolymer, or an oxyethylated tertiary octylphenol formaldehyde polymer.

37. The method any one of claims 34-36, wherein the surfactant forms about 0.01% to about 20% weight / weight of the composition.

38. The method of claim 37, wherein the surfactant forms about 0.05% to about 10% weight / weight of the composition.

39. The method of any one of claims 32-38, wherein the composition (e.g., each composition or the first / second composition) further comprises a tonicity adjusting agent, a buffering agent, or a combination thereof.

40. The method of any one of claims 32-39, wherein the composition is buffered at a pH of 2.5 to 7.5.

41. The method of any one of claims 32-40, wherein the composition comprises about 25 micrograms (ug) to about 250 ug of the peptide.

42. A method of treating glaucoma in an eye of an individual, the method comprising: (a) measuring retinal nerve fiber layer (RNFL) thickness (e.g., of an optic nerve) of the eye at a first timepoint; (b) administering a first dose of therapeutic agent; (c) measuring RNFL thickness in the eye at a second timepoint; and (d) administering a second dose of the therapeutic agent if the RNFL thickness at the second timepoint is equal to or less than the RNFL thickness at the first timepoint.

43. The method of claim 42, wherein (d) further comprises stopping or pausing further treatment if the RNFL thickness at the second timepoint is greater than the RNFL thickness at the first timepoint.

44. The method of any one of claims 42-43, wherein the method further comprises (e) measuring RNFL thickness at a third timepoint, and (f) administering an additional dose of the therapeutic agent if the RNFL thickness at the third timepoint is equal to or less than the RNFL thickness at the first timepoint or the second timepoint.

45. A method of treating glaucoma in an eye of an individual having a retinal nerve fiber layer (RNFL) thickness less than 90 um (microns), the method comprising: (a) administering a therapeutic agent; and (b) measuring RNFL thickness in the eye; (c) administering a second dose of the therapeutic agent if the RNFL thickness in (b) is less than the RNFL thickness is less than 80 um.

46. The method of claim 45, wherein the (c) further comprises stopping or pausing further treatment if the RNFL thickness in (b) is equal to or greater than the RNFL thickness is less than 80 um.

47. The method of any one of claims 45-46, wherein the method comprises (d) measuring RNFL thickness at a subsequent timepoint, and (e) administering an additional dose of the therapeutic agent if the RNFL thickness at the subsequent timepoint is less than 80 um or less than the RNFL thickness of a prior measurement (e.g., in (b)).

48. The method of any one of claims 42-47, wherein the therapeutic agent is a Fas inhibitor.

49. The method of any one of claims 42-47, wherein the therapeutic agent is selected from the group consisting of a Fas inhibitor, a prostaglandin analog, a rho kinase inhibitor, a nitric oxide, a miotic agent, an alpha-adrenergic agonist, a beta blocker, and a carbonic anhydrase inhibitor.

50. The method of any one of claims 42-49, wherein a decrease in RNFL thickness comprises a decrease in ganglion axons (e.g., cell death and / or apoptosis) in nerves within the RNFL 51. The method of any one of claims 42-50, wherein treating the loss of RNFL thickness comprises reducing a decrease of ganglion axons (e.g., cell death and / or apoptosis) in nerves within the RNFL 52. The method of any one of claims 42-51, wherein an increase in RNFL thickness is not a result of an edema.

53. A method of treating glaucoma in an eye of an individual, the method comprising: (a) measuring visual field of the eye at a first timepoint; (b) administering a first dose of therapeutic agent; (c) measuring visual field in the eye at a second timepoint; and (d) administering a second dose of the therapeutic agent if the visual field at the second timepoint is equal to or less than the visual field at the first timepoint.

54. The method of claim 53, wherein (d) further comprises stopping or pausing further treatment if the visual field at the second timepoint is greater than the visual field at the first timepoint.

55. The method of any one of claims 53-54, wherein the method further comprises (e) measuring visual field at a third timepoint, and (f) administering an additional dose of the therapeutic agent if the visual field at the third timepoint is equal to or less than the visual field at the first timepoint or the second timepoint.

56. The method of any one of claims 53-55, wherein the therapeutic agent is a Fas inhibitor.

57. The method of any one of claims 53-56, wherein the therapeutic agent is selected from the group consisting of a Fas inhibitor, a prostaglandin analog, a rho kinase inhibitor, a nitric oxide, a miotic agent, an alpha-adrenergic agonist, a beta blocker, and a carbonic anhydrase inhibitor.

58. The method of any one of claims 53-57, wherein the visual field is Humphrey Visual Field.

59. The method of any one of claims 53-58, wherein the visual field comprises a sub-global measure of local (e.g., region specific within the eye) visual field measurements.

60. The method of claim 59, wherein measuring the visual field comprises generating local visual field measurements within the eye, and wherein (d) comprises administering the second dose of the therapeutic agent if a local visual field measurement at the second timepoint is equal to or less than the visual field at the first timepoint.

61. The method of any one of claims 53-60, wherein the visual field is measured using a clustering analysis to generate measures of local (e.g., region specific within the eye) visual field measurements.

62. A method of treating glaucoma in an eye of an individual, the method comprising: (a) measuring retinal nerve fiber layer (RNFL) thickness (e.g., of an optic nerve) and visual field of the eye at a first timepoint; (b) administering a first dose of therapeutic agent; (c) measuring visual field and retinal nerve fiber layer (RNFL) thickness (e.g., of an optic nerve) in the eye at a second timepoint; and (d) administering a second dose of the therapeutic agent if the visual field and / or retinal nerve fiber layer (RNFL) thickness (e.g., of an optic nerve) at the second timepoint is equal to or less than the visual field and / or retinal nerve fiber layer (RNFL) thickness (e.g., of an optic nerve) at the first timepoint.

63. The method of claim 62, wherein (d) further comprises stopping or pausing further treatment if the visual field and / or retinal nerve fiber layer (RNFL) thickness (e.g., of an optic nerve) at the second timepoint is greater than the visual field at the first timepoint.

64. The method of any one of claims 62-63, wherein the method further comprises (e) measuring visual field and retinal nerve fiber layer (RNFL) thickness (e.g., of an optic nerve) at a third timepoint, and (f) administering an additional dose of the therapeutic agent if the visual field and / or retinal nerve fiber layer (RNFL) thickness (e.g., of an optic nerve) at the third timepoint is equal to or less than the visual field and / or retinal nerve fiber layer (RNFL) thickness (e.g., of an optic nerve) at the first timepoint and / or retinal nerve fiber layer (RNFL) thickness (e.g., of an optic nerve) at the second timepoint.

65. The method of any one of claims 62-64, wherein the therapeutic agent is a Fas inhibitor.

66. The method of any one of claims 62-65, wherein the therapeutic agent is selected from the group consisting of a Fas inhibitor, a prostaglandin analog, a rho kinase inhibitor, a nitric oxide, a miotic agent, an alpha-adrenergic agonist, a beta blocker, and a carbonic anhydrase inhibitor.

67. The method of any one of claims 62-66, wherein the visual field is Humphrey Visual Field.

68. The method of any one of claims 62-67, wherein the visual field comprises a sub-global measure of local (e.g., region specific within the eye) visual field measurements.

69. The method of claim 68, wherein measuring the visual field comprises generating local visual field measurements within the eye, and wherein (d) comprises administering the second dose of the therapeutic agent if a local visual field measurement at the second timepoint is equal to or less than the visual field at the first timepoint.

70. The method of any one of claims 62-69, wherein the visual field is measured using a clustering analysis to generate measures of local (e.g., region specific within the eye) visual field measurements.

71. A method of treating a loss in ganglion cell complex (GCC) thickness in an eye of an individual, the method comprising: administering a peptide to the eye, wherein the peptide comprises an amino acid sequence HHIYLGAVNYIY or variant sequence thereof, or a pharmaceutically acceptable salt of the peptide.

72. The method of claim 71, wherein treating the loss in GCC thickness comprises inhibiting a reduction in GCC thickness (e.g., compared to an untreated eye).

73. The method of any one of claims 71-72, wherein treating the loss in GCC thickness comprises increasing in GCC thickness (e.g., compared to an untreated eye).

74. The method of any one of claims 71-73, wherein treating the loss in GCC thickness comprises reducing a rate of GCC thinning (e.g., compared to an untreated eye).

75. The method of any one of claims 71-74, wherein treating the loss in (e.g., compared to an untreated eye) thickness comprises reducing a decrease in ganglion cells (e.g., by cell death and / or apoptosis) within the GCC.

76. A method of increasing ganglion cell complex (GCC) thickness in an eye of an individual, the method comprising: administering a peptide to the eye, wherein the peptide comprises an amino acid sequence HHIYLGAVNYIY or variant sequence thereof, or a pharmaceutically acceptable salt of the peptide.

77. The method of any one of claims 71-76, wherein RNFL thickness is measured by optical coherence tomography (e.g., SD-OCT and / or TD-OCT).

78. The method of any one of claims 71-77, wherein the method further comprises administering a first dose and a second dose of the peptide or the pharmaceutically acceptable salt of the peptide, and wherein the second composition is administered about 10 weeks or greater after administering the first dose.

79. The method of claim 78, wherein the second dose is administered about 12 weeks after the first dose.

80. The method of any one of claims 77-79, wherein the peptide or the pharmaceutically acceptable salt thereof has a half-life in the vitreous humor of more than about 30 days (e.g., at least 30 days).

81. The method of any one of claims 71-80, wherein the method comprises using the vitreous humor as a depot to provide the peptide or the pharmaceutically acceptable salt thereof to retinal tissue in the eye, wherein the peptide or the pharmaceutically acceptable salt thereof is present in the vitreous humor more than about 30 days after administration.

82. The method of any one of claims 71-81, wherein the eye has an ocular disease or disorder.

83. The method of claim 82, wherein the ocular disease or disorder comprises an elevated intraocular pressure.

84. The method of any one of claims 82-83, wherein the ocular disease or disorder is glaucoma.

85. The method of any one of claims 71-84, wherein the variant sequence comprises an amino acid substitution.

86. The method of claim 85, wherein the variant sequence comprises one amino acid substitution.

87. The method of any one of claims 71-86, wherein the peptide further comprises a modification.

88. The method of claim 87, wherein the modification comprises a modified amino acid.

89. The method of any one of claims 71-88, wherein the peptide comprises an amidated C- terminus.

90. The method of any one of claims 71-89, wherein the peptide has the structure of Formula I or a pharmaceutically acceptable salt thereof.

91. The method of any one of claims 71-90, wherein the peptide has the structure of Formula III:(Formula III) or a pharmaceutically acceptable salt thereof.

92. The method of any one of claims 71-91, wherein the method comprises administering the pharmaceutically acceptable salt thereof.

93. The method of claim 92, wherein the pharmaceutically acceptable salt is an acetate salt.

94. The method of claim 93, wherein the pharmaceutically acceptable salt is a polyacetate salt.

95. The method of claim 94, wherein the polyacetate salt is a triacetate salt.

96. The method of claim 92, wherein the pharmaceutically acceptable salt is a hydrochloride salt.

97. The method of any one of claims 71-96, wherein the method comprises administering a composition comprising the peptide.

98. The method of claim 97, wherein the composition (e.g., each composition or the first / second composition) further comprises one or more excipients.

99. The method of any one of claims 97-98, wherein the composition (e.g., each composition or the first / second composition) further comprises a surfactant.

100. The method of claim 99, wherein the surfactant is a non-ionic surfactant.

101. The method of claim 100, wherein the surfactant is a polysorbate, a polyethoxylated castor oil derivative, a polyethoxylated fatty acid, a polyethoxylated alcohol, a polyoxyethylene- polyoxypropylene block copolymer, or an oxyethylated tertiary octylphenol formaldehyde polymer.

102. The method any one of claims 100-101, wherein the surfactant forms about 0.01% to about 20% weight / weight of the composition.

103. The method of claim 102, wherein the surfactant forms about 0.05% to about 10% weight / weight of the composition.

104. The method of any one of claims 97-103, wherein the composition (e.g., each composition or the first / second composition) further comprises a tonicity adjusting agent, a buffering agent, or a combination thereof.

105. The method of any one of claims 97-104, wherein the composition is buffered at a pH of 2.5 to 7.

5.

106. The method of any one of claims 97-105, wherein the composition comprises about 25 micrograms (ug) to about 250 ug of the peptide.

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