# US 2021/0330735 A1 · Compositions and methods for the treatment of traumatic optic neuropathy

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- Number: US 2021/0330735 A1
- Document ID: US20210330735A1
- Status: Published application
- Kind: A1
- Application number: 17/260,718
- Filed: 2019-07-15
- Published: 2021-10-28
- Earliest claimed: 2018-07-16
- Assignees: Stealth BioTherapeutics Inc.
- Applicants: Stealth BioTherapeutics Corp
- Inventors: Mark Bamberger; David T. Tse; Daniel Pelaez
- Web page: https://patentgrep.com/patent/US20210330735A1

## CPC

- A61K 38/07: Tetrapeptides
- A61K 31/05: Phenols {(cannabinoids A61K31/658)}
- A61K 31/4178: not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
- A61K 31/4409: only substituted in position 4, e.g. isoniazid, iproniazid
- A61K 38/1793: {for cytokines; for lymphokines; for interferons}
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 27/02: Ophthalmic agents
- C07K 5/1019: {with the first amino acid being basic}
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)

## Abstract

The present disclosure provides novel methods for treating or preventing traumatic optic neuropathy (TON), methods for improving visual function in a subject having TON, methods for promoting retinal ganglion cell (RGC) survival or increasing neurite outgrowth of an RGC, and methods for reducing the risk of having or developing TON in a subject that has experienced a traumatic injury. The methods comprise administering to the subject an effective amount of an aromatic-cationic peptide.

## Claims

### Claim 1

A method for treating or preventing traumatic optic neuropathy (TON) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the peptide D-Arg-2′,6′-Dmt-Lys-Phe-NH2, or a pharmaceutically acceptable salt thereof.

### Claim 2 (depends on 1)

The method of claim 1, wherein the subject has been diagnosed as having TON.

### Claim 3

The method of any one of the previous claims, wherein the TON is caused by direct injury or indirect injury to the subject.

### Claim 4 (depends on 3)

The method of claim 3, wherein the direct or indirect injury is selected from the group consisting of intraorbital injury, intracanalicular injury, intracranial injury, and an injury to the subject's optic nerve.

### Claim 5 (depends on 3, 4)

The method of claim 3 or 4, wherein the peptide is administered prior to injury.

### Claim 6 (depends on 3, 4)

The method of claim 3 or 4, wherein the peptide is administered immediately following injury.

### Claim 7 (depends on 3, 4)

The method of claim 3 or 4, wherein the peptide is administered about 2 hours or less, about 6 hours or less, about 12 hours or less, or about 24 hours or less following the injury.

### Claim 8

The method of any one of the previous claims, wherein the peptide is administered daily for 2 weeks or more.

### Claim 9

The method of any one of the previous claims, wherein the peptide is administered daily for 12 weeks or more.

### Claim 10

The method of any one of the previous claims, wherein the treating or preventing comprises the treatment or prevention of one or more signs or symptoms of TON comprising one or more of vision loss, blurred vision, scotoma, decreased color sensation, uveitis, optic neuritis, eye pain, optic nerve avulsion, optic nerve transection, optic nerve sheath hemorrhage, orbital hemorrhage, choroidal rupture, and commotio retinae.

### Claim 11

The method of any one of the previous claims, wherein the subject is a mammal.

### Claim 12 (depends on 11)

The method of claim 11, wherein the mammalian subject is a human.

### Claim 13

The method of any one of the previous claims, wherein the peptide is administered orally, topically, intranasally, systemically, intravenously, subcutaneously, intraperitoneally, intradermally, intraocularly, ophthalmically, iontophoretically, transmucosally, intravitreally, or intramuscularly.

### Claim 14

The method of any one of the previous claims, further comprising separately, sequentially, or simultaneously administering an additional treatment to the subject.

### Claim 15 (depends on 14)

The method of claim 14, wherein the additional treatment comprises administration of a therapeutic agent.

### Claim 16 (depends on 15)

The method of claim 15, wherein the therapeutic agent is selected from the group consisting of: TNFα inhibitor, corticosteroid, IL-1R antagonist, resveratrol, potassium channel blocker, and necrostatin-1.

### Claim 17 (depends on 15)

The method of claim 15, wherein the TNFα inhibitor is etanercept.

### Claim 18 (depends on 14)

The method of claim 14, wherein the additional treatment comprises reducing the core temperature of the subject.

### Claim 19 (depends on 18)

The method of claim 18, the core temperature of the subject is reduced by about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, or about 50%.

### Claim 20 (depends on 18, 19)

The method of claim 18 or 19, wherein hypothermia is induced in the subject.

### Claim 21 (depends on 14, 15, 16, 17, 18, 19, 20)

The method of any one of claims 14-20, wherein the combination of peptide and an additional therapeutic treatment has a synergistic effect in the prevention or treatment of TON.

### Claim 22

The method of any one of the previous claims, wherein the pharmaceutically acceptable salt comprises a mono-acetate salt, a bis-acetate salt, a tri-acetate salt, a tartrate salt, a mono-trifluoroacetate salt, a bis-trifluoroacetate salt, a tri-trifluoroacetate salt, a mono-hydrochloride (“mono-HCl”) salt, a bis-hydrochloride (“bis-HCl”) salt, a tri-hydrochloride (“tri-HCl”) salt, a mono-tosylate salt, a bis-tosylate salt, or a tri-tosylate salt.

### Claim 23 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21)

The method of any one of claims 1-21, wherein the pharmaceutically acceptable salt of the peptide that is formulated for administering to the subject is as a tri-HCl salt, a bis-HCl salt, or a mono-HCl salt.

### Claim 24

A method for improving visual function in a subject having traumatic optic neuropathy (TON), the method comprising administering to the subject a therapeutically effective amount of the peptide D-Arg-2′,6′-Dmt-Lys-Phe-NH2, or a pharmaceutically acceptable salt thereof.

### Claim 25 (depends on 24)

The method of claim 24, wherein the subject has experienced a direct injury or an indirect injury.

### Claim 26 (depends on 25)

The method of claim 25, wherein the direct or indirect injury is selected from the group consisting of intraorbital injury, intracanalicular injury, intracranial injury, and an injury to the subject's optic nerve.

### Claim 27 (depends on 25, 26)

The method of claim 25 or 26, wherein the peptide is administered immediately following injury.

### Claim 28 (depends on 25, 26)

The method of claim 25 or 26, wherein the peptide is administered about 2 hours or less, about 6 hours or less, about 12 hours or less, or about 24 hours or less following the injury.

### Claim 29 (depends on 24, 25, 26, 27, 28)

The method of any one of claims 24-28, wherein the peptide is administered daily for 2 weeks or more.

### Claim 30 (depends on 24, 25, 26, 27, 28)

The method of any one of claims 24-28, wherein the peptide is administered daily for 12 weeks or more.

### Claim 31 (depends on 24, 25, 26, 27, 28, 29, 30)

The method of any one of claims 24-30, wherein the visual function is assessed by one or more of pattern electroretinography (PERG), detection of best corrected visual acuity (BVCA), electroretinography (ERG), and optical coherence tomography (OCT).

### Claim 32 (depends on 24, 25, 26, 27, 28, 29, 30, 31)

The method of any one of claims 24-31, wherein the improved visual function comprises improvements in any one or more of visual acuity, BVCA, thickness of the retina as detected by OCT, PERG amplitude, ERG amplitude, ERG latency, vision loss, blurred vision, scotoma, decreased color sensation, uveitis, optic neuritis, eye pain, optic nerve avulsion, optic nerve transection, optic nerve sheath hemorrhage, orbital hemorrhage, choroidal rupture, and commotio retinae compared to an untreated control.

### Claim 33 (depends on 24, 25, 26, 27, 28, 29, 30, 31, 32)

The method of any one of claims 24-32, wherein the subject is a mammal.

### Claim 34 (depends on 33)

The method of claim 33, wherein the mammalian subject is a human.

### Claim 35 (depends on 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34)

The method of any one of claims 24-34, wherein the peptide is administered orally, topically, intranasally, systemically, intravenously, subcutaneously, intraperitoneally, intradermally, intraocularly, ophthalmically, iontophoretically, transmucosally, intravitreally, or intramuscularly.

### Claim 36 (depends on 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35)

The method of any one of claims 24-35, further comprising separately, sequentially, or simultaneously administering an additional treatment to the subject.

### Claim 37 (depends on 36)

The method of claim 36, wherein the additional treatment comprises administration of a therapeutic agent.

### Claim 38 (depends on 37)

The method of claim 37, wherein the therapeutic agent is selected from the group consisting of: TNFα inhibitor, corticosteroid, IL-1R antagonist, resveratrol, potassium channel blocker, and necrostatin-1.

### Claim 39 (depends on 38)

The method of claim 38, wherein the TNFα inhibitor is etanercept.

### Claim 40 (depends on 36)

The method of claim 36, wherein the additional treatment comprises reducing the core temperature of the subject.

### Claim 41 (depends on 40)

The method of claim 40, the core temperature of the subject is reduced by about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, or about 50%.

### Claim 42 (depends on 41, 42)

The method of claim 41 or 42, wherein hypothermia is induced in the subject.

### Claim 43 (depends on 36, 37, 38, 39, 40, 41, 42)

The method of any one of claims 36-42, wherein the combination of peptide and an additional treatment has a synergistic effect in improving visual function.

### Claim 44 (depends on 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43)

The method of any one of claims 24-43, wherein the pharmaceutically acceptable salt comprises a mono-acetate salt, a bis-acetate salt, a tri-acetate salt, a tartrate salt, a mono-trifluoroacetate salt, a bis-trifluoroacetate salt, a tri-trifluoroacetate salt, a mono-hydrochloride (“mono-HCl”) salt, a bis-hydrochloride (“bis-HCl”) salt, a tri-hydrochloride (“tri-HCl”) salt, a mono-tosylate salt, a bis-tosylate salt, or a tri-tosylate salt.

### Claim 45 (depends on 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43)

The method of any one of claims 24-43, wherein the pharmaceutically acceptable salt of the peptide that is formulated for administering to the subject is a tri-HCl salt, a bis-HCl salt, or a mono-HCl salt.

### Claim 46

A method of promoting retinal ganglion cell (RGC) survival or increasing neurite outgrowth of an RGC comprising contacting an RGC with an effective amount of the peptide D-Arg-2′,6′-Dmt-Lys-Phe-NH2, or a pharmaceutically acceptable salt thereof.

### Claim 47 (depends on 46)

The method of claim 46, wherein the RGC is in vitro.

### Claim 48 (depends on 46)

The method of claim 46, wherein the RGC is in a subject with TON.

### Claim 49 (depends on 48)

The method of claim 48, wherein the subject is a mammal.

### Claim 50 (depends on 49)

The method of claim 49, wherein the mammalian subject is a human.

### Claim 51 (depends on 46, 47, 48, 49, 50)

The method of any one of claims 46-50, further comprising separately, sequentially, or simultaneously administering an additional treatment to the subject.

### Claim 52 (depends on 51)

The method of claim 51, wherein the additional treatment comprises administration of a therapeutic agent.

### Claim 53 (depends on 52)

The method of claim 52, wherein the therapeutic agent is selected from the group consisting of: TNFα inhibitor, corticosteroid, IL-1R antagonist, resveratrol, potassium channel blocker, and necrostatin-1.

### Claim 54 (depends on 53)

The method of claim 53, wherein the TNFα inhibitor is etanercept.

### Claim 55 (depends on 54)

The method of claim 54, wherein the additional treatment comprises reducing the core temperature of the subject.

### Claim 56 (depends on 55)

The method of claim 55, the core temperature of the subject is reduced by about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, or about 50%.

### Claim 57 (depends on 54, 55)

The method of claim 54 or 55, wherein hypothermia is induced in the subject.

### Claim 58 (depends on 51, 52, 53, 54, 55, 56, 57)

The method of any one of claims 51-57, wherein the combination of peptide and an additional treatment has a synergistic effect in in promoting RGC survival or increasing neurite outgrowth of an RGC.

### Claim 59 (depends on 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58)

The method of any one of claims 46-58, wherein the pharmaceutically acceptable salt comprises a mono-acetate salt, a bis-acetate salt, a tri-acetate salt, a tartrate salt, a mono-trifluoroacetate salt, a bis-trifluoroacetate salt, a tri-trifluoroacetate salt, a mono-hydrochloride (“mono-HCl”) salt, a bis-hydrochloride (“bis-HCl”) salt, a tri-hydrochloride (“tri-HCl”) salt, a mono-tosylate salt, a bis-tosylate salt, or a tri-tosylate salt.

### Claim 60 (depends on 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58)

The method of any one of claims 46-58, wherein the pharmaceutically acceptable salt of the peptide that is formulated for administering to the subject is a tri-HCl salt, a bis-HCl salt, or a mono-HCl salt.

### Claim 61

Use of a composition in the preparation of a medicament for treating or preventing traumatic optic neuropathy (TON) in a subject in need thereof, wherein the composition comprises a therapeutically effective amount of the peptide D-Arg-2′,6′-Dmt-Lys-Phe-NH2, or a pharmaceutically acceptable salt thereof.

### Claim 62 (depends on 61)

The use of claim 61, wherein the subject has been diagnosed as having TON.

### Claim 63 (depends on 61, 62)

The use of claim 61 or 62, wherein the TON is caused by direct injury or indirect injury to the subject.

### Claim 64 (depends on 63)

The use of claim 63, wherein the direct or indirect injury is selected from the group consisting of intraorbital injury, intracanalicular injury, intracranial injury, and an injury to the subject's optic nerve.

### Claim 65 (depends on 63, 64)

The use of claim 63 or 64, wherein the peptide is intended to be administered prior to injury.

### Claim 66 (depends on 63, 64)

The use of claim 63 or 64, wherein the peptide is intended to be administered immediately following injury.

### Claim 67 (depends on 63, 64)

The use of claim 63 or 64, wherein the peptide is intended to be administered about 2 hours or less, about 6 hours or less, about 12 hours or less, or about 24 hours or less following the injury.

### Claim 68 (depends on 61, 62, 63, 64, 65, 66, 67)

The use of any one of claims 61-67, wherein the peptide is intended to be administered daily for 2 weeks or more.

### Claim 69 (depends on 61, 62, 63, 64, 65, 66, 67)

The use of any one of claims 61-67, wherein the peptide is intended to be administered daily for 12 weeks or more.

### Claim 70 (depends on 61, 62, 63, 64, 65, 66, 67, 68, 69)

The use of any one of claims 61-69, wherein the treating or preventing comprises the treatment or prevention of one or more signs or symptoms of TON comprising one or more of vision loss, blurred vision, scotoma, decreased color sensation, uveitis, optic neuritis, eye pain, optic nerve avulsion, optic nerve transection, optic nerve sheath hemorrhage, orbital hemorrhage, choroidal rupture, and commotio retinae.

### Claim 71 (depends on 61, 62, 63, 64, 65, 66, 67, 68, 69, 70)

The use of any one of claims 61-70, wherein the subject is a mammal.

### Claim 72 (depends on 71)

The use of claim 71, wherein the mammalian subject is a human.

### Claim 73 (depends on 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72)

The use of any one of claims 61-72, wherein the peptide is formulated for administration orally, topically, intranasally, systemically, intravenously, subcutaneously, intraperitoneally, intradermally, intraocularly, ophthalmically, iontophoretically, transmucosally, intravitreally, or intramuscularly.

### Claim 74 (depends on 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73)

The use of any one of claims 61-73, wherein the peptide is intended to be separately, sequentially, or simultaneously used with an additional treatment.

### Claim 75 (depends on 74)

The use of claim 74, wherein the additional treatment comprises use of a therapeutic agent.

### Claim 76 (depends on 75)

The use of claim 75, wherein the therapeutic agent is selected from the group consisting of: TNFα inhibitor, corticosteroid, IL-1R antagonist, resveratrol, potassium channel blocker, and necrostatin-1.

### Claim 77 (depends on 76)

The use of claim 76, wherein the TNFα inhibitor is etanercept.

### Claim 78 (depends on 74)

The use of claim 74, wherein the additional treatment comprises reducing the core temperature of the subject.

### Claim 79 (depends on 78)

The use of claim 78, the core temperature of the subject is reduced by about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, or about 50%.

### Claim 80 (depends on 78, 79)

The use of claim 78 or 79, wherein hypothermia is induced in the subject.

### Claim 81 (depends on 74, 75, 76, 77, 78, 79, 80)

The use of any one of claims 74-80, wherein the combination of peptide and an additional treatment has a synergistic effect in the prevention or treatment of TON.

### Claim 82 (depends on 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81)

The use of any one of claims 61-81, wherein the pharmaceutically acceptable salt comprises a mono-acetate salt, a bis-acetate salt, a tri-acetate salt, a tartrate salt, a mono-trifluoroacetate salt, a bis-trifluoroacetate salt, a tri-trifluoroacetate salt, a mono-hydrochloride (“mono-HCl”) salt, a bis-hydrochloride (“bis-HCl”) salt, a tri-hydrochloride (“tri-HCl”) salt, a mono-tosylate salt, a bis-tosylate salt, or a tri-tosylate salt.

### Claim 83 (depends on 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81)

The use of any one of claims 61-81, wherein the pharmaceutically acceptable salt of the peptide that is formulated for administering to the subject is a tri-HCl salt, a bis-HCl salt, or a mono-HCl salt.

### Claim 84

Use of a composition in the preparation of a medicament for improving visual function in a subject having traumatic optic neuropathy (TON), wherein the composition comprises a therapeutically effective amount of the peptide D-Arg-2′,6′-Dmt-Lys-Phe-NH2, or a pharmaceutically acceptable salt thereof.

### Claim 85 (depends on 84)

The use of claim 84, wherein the subject has experienced a direct injury or an indirect injury.

### Claim 86 (depends on 85)

The use of claim 85, wherein the direct or indirect injury is selected from the group consisting of intraorbital injury, intracanalicular injury, intracranial injury, and an injury to the subject's optic nerve.

### Claim 87 (depends on 85, 86)

The use of claim 85 or 86, wherein the peptide is intended to be administered immediately following injury.

### Claim 88 (depends on 85, 86)

The use of claim 85 or 86, wherein the peptide is intended to be administered about 2 hours or less, about 6 hours or less, about 12 hours or less, or about 24 hours or less following the injury.

### Claim 89 (depends on 84, 85, 86, 87, 88)

The use of any one of claims 84-88, wherein the peptide is intended to be administered daily for 2 weeks or more.

### Claim 90 (depends on 84, 85, 86, 87, 88)

The use of any one of claims 84-88, wherein the peptide is intended to be administered daily for 12 weeks or more.

### Claim 91 (depends on 84, 85, 86, 87, 88, 89, 90)

The use of any one of claims 84-90, wherein the visual function is assessed by one or more of pattern electroretinography (PERG), detection of best corrected visual acuity (BVCA), electroretinography (ERG), and optical coherence tomography (OCT).

### Claim 92 (depends on 84, 85, 86, 87, 88, 89, 90, 91)

The use of any one of claims 84-91, wherein the improved visual function comprises improvements in any one or more of visual acuity, BVCA, thickness of the retina as detected by OCT, PERG amplitude, ERG amplitude, ERG latency, vision loss, blurred vision, scotoma, decreased color sensation, uveitis, optic neuritis, eye pain, optic nerve avulsion, optic nerve transection, optic nerve sheath hemorrhage, orbital hemorrhage, choroidal rupture, and commotio retinae compared to an untreated control.

### Claim 93 (depends on 84, 85, 86, 87, 88, 89, 90, 91, 92)

The use of any one of claims 84-92, wherein the subject is a mammal.

### Claim 94 (depends on 93)

The use of claim 93, wherein the mammalian subject is a human.

### Claim 95 (depends on 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94)

The use of any one of claims 84-94, wherein the peptide is intended to be administered orally, topically, intranasally, systemically, intravenously, subcutaneously, intraperitoneally, intradermally, intraocularly, ophthalmically, iontophoretically, transmucosally, intravitreally, or intramuscularly.

### Claim 96 (depends on 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95)

The use of any one of claims 84-95, wherein the peptide is intended to be separately, sequentially, or simultaneously used with an additional treatment.

### Claim 97 (depends on 96)

The use of claim 96, wherein the additional treatment comprises use of a therapeutic agent.

### Claim 98 (depends on 97)

The use of claim 97, wherein the therapeutic agent is selected from the group consisting of: TNFα inhibitor, corticosteroid, IL-1R antagonist, resveratrol, potassium channel blocker, and necrostatin-1.

### Claim 99 (depends on 98)

The use of claim 98, wherein the TNFα inhibitor is etanercept.

### Claim 100 (depends on 96)

The use of claim 96, wherein the additional treatment comprises reducing the core temperature of the subject.

### Claim 101 (depends on 100)

The use of claim 100, the core temperature of the subject is reduced by about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, or about 50%.

### Claim 102 (depends on 100, 101)

The use of claim 100 or 101, wherein hypothermia is induced in the subject.

### Claim 103 (depends on 96, 97, 98, 99, 100, 101, 102)

The use of any one of claims 96-102, wherein the combination of peptide and an additional treatment has a synergistic effect in improving visual function.

### Claim 104 (depends on 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103)

The use of any one of claims 84-103, wherein the pharmaceutically acceptable salt comprises a mono-acetate salt, a bis-acetate salt, a tri-acetate salt, a tartrate salt, a mono-trifluoroacetate salt, a bis-trifluoroacetate salt, a tri-trifluoroacetate salt, a mono-hydrochloride (“mono-HCl”) salt, a bis-hydrochloride (“bis-HCl”) salt, a tri-hydrochloride (“tri-HCl”) salt, a mono-tosylate salt, a bis-tosylate salt, or a tri-tosylate salt.

### Claim 105 (depends on 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103)

The use of any one of claims 84-103, wherein the pharmaceutically acceptable salt of the peptide that is formulated for administering to the subject is a tri-HCl salt, a bis-HCl salt, or a mono-HCl salt.

### Claim 106

Use of a composition in the preparation of a medicament for promoting retinal ganglion cell (RGC) survival or increasing neurite outgrowth of an RGC, wherein the composition comprises an effective amount of the peptide D-Arg-2′,6′-Dmt-Lys-Phe-NH2, or a pharmaceutically acceptable salt thereof.

### Claim 107 (depends on 106)

The use of claim 106, wherein the RGC is in vitro.

### Claim 108 (depends on 106)

The use of claim 106, wherein the RGC is in a subject with TON.

### Claim 109 (depends on 108)

The use of claim 108, wherein the subject is a mammal.

### Claim 110 (depends on 109)

The use of claim 109, wherein the mammalian subject is a human.

### Claim 111 (depends on 106, 107, 108, 109, 110)

The use of any one of claims 106-110, wherein the peptide is intended to be separately, sequentially, or simultaneously used an additional treatment.

### Claim 112 (depends on 111)

The use of claim 111, wherein the additional treatment comprises use of a therapeutic agent.

### Claim 113 (depends on 112)

The use of claim 112, wherein the therapeutic agent is selected from the group consisting of: TNFα inhibitor, corticosteroid, IL-1R antagonist, resveratrol, potassium channel blocker, and necrostatin-1.

### Claim 114 (depends on 113)

The use of claim 113, wherein the TNFα inhibitor is etanercept.

### Claim 115 (depends on 114)

The use of claim 114, wherein the additional treatment comprises reducing core temperature.

### Claim 116 (depends on 115)

The use of claim 115, the core temperature is reduced by about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, or about 50%.

### Claim 117 (depends on 114, 115)

The use of claim 114 or 115, wherein hypothermia is induced.

### Claim 118 (depends on 111, 112, 113, 114, 115, 116, 117)

The use of any one of claims 111-117, wherein the combination of peptide and an additional treatment has a synergistic effect in promoting RGC survival or increasing neurite outgrowth of an RGC.

### Claim 119 (depends on 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118)

The use of any one of claims 106-118, wherein the pharmaceutically acceptable salt comprises a mono-acetate salt, a bis-acetate salt, a tri-acetate salt, a tartrate salt, a mono-trifluoroacetate salt, a bis-trifluoroacetate salt, a tri-trifluoroacetate salt, a mono-hydrochloride (“mono-HCl”) salt, a bis-hydrochloride (“bis-HCl”) salt, a tri-hydrochloride (“tri-HCl”) salt, a mono-tosylate salt, a bis-tosylate salt, or a tri-tosylate salt.

### Claim 120 (depends on 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118)

The use of any one of claims 106-118, wherein the pharmaceutically acceptable salt of the peptide that is formulated for administering to the subject is a tri-HCl salt, a bis-HCl salt, or a mono-HCl salt.

### Claim 121

A peptide D-Arg-2′,6′-Dmt-Lys-Phe-NH2, or a pharmaceutically acceptable salt thereof, for use in treating or preventing traumatic optic neuropathy (TON) in a subject in need thereof.

### Claim 122 (depends on 121)

The peptide of claim 121, for use wherein the subject has been diagnosed as having TON.

### Claim 123 (depends on 121, 122)

The peptide of claim 121 or 122, for use wherein the TON is caused by direct injury or indirect injury to the subject.

### Claim 124 (depends on 123)

The peptide of claim 123, for use wherein the direct or indirect injury is selected from the group consisting of intraorbital injury, intracanalicular injury, intracranial injury, and an injury to the subject's optic nerve.

### Claim 125 (depends on 123, 124)

The peptide of claim 123 or 124, for use wherein the peptide is intended to be administered prior to injury.

### Claim 126 (depends on 123, 124)

The peptide of claim 123 or 124, for use wherein the peptide is intended to be administered immediately following injury.

### Claim 127 (depends on 123, 124)

The peptide of claim 123 or 124, for use wherein the peptide is intended to be administered about 2 hours or less, about 6 hours or less, about 12 hours or less, or about 24 hours or less following the injury.

### Claim 128 (depends on 121, 122, 123, 124, 125, 126, 127)

The peptide of any one of claims 121-127, for use wherein the peptide is intended to be administered daily for 2 weeks or more.

### Claim 129 (depends on 121, 122, 123, 124, 125, 126, 127)

The peptide of any one of claims 121-127, for use wherein the peptide is intended to be administered daily for 12 weeks or more.

### Claim 130 (depends on 121, 122, 123, 124, 125, 126, 127, 128, 129)

The peptide of any one of claims 121-129, for use wherein the treating or preventing comprises the treatment or prevention of one or more signs or symptoms of TON comprising one or more of vision loss, blurred vision, scotoma, decreased color sensation, uveitis, optic neuritis, eye pain, optic nerve avulsion, optic nerve transection, optic nerve sheath hemorrhage, orbital hemorrhage, choroidal rupture, and commotio retinae.

### Claim 131 (depends on 121, 122, 123, 124, 125, 126, 127, 128, 129, 130)

The peptide of any one of claims 121-130, for use wherein the subject is a mammal.

### Claim 132 (depends on 131)

The peptide of claim 131, for use wherein the mammalian subject is a human.

### Claim 133 (depends on 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132)

The peptide of any one of claims 121-132, for use wherein the peptide is formulated for administration orally, topically, intranasally, systemically, intravenously, subcutaneously, intraperitoneally, intradermally, intraocularly, ophthalmically, iontophoretically, transmucosally, intravitreally, or intramuscularly.

### Claim 134 (depends on 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133)

The peptide of any one of claims 121-133, for use wherein the peptide is intended to be separately, sequentially, or simultaneously used with an additional treatment.

### Claim 135 (depends on 134)

The peptide of claim 134, for use wherein the additional treatment comprises use of a therapeutic agent.

### Claim 136 (depends on 135)

The peptide of claim 135, for use wherein the therapeutic agent is selected from the group consisting of: TNFα inhibitor, corticosteroid, IL-1R antagonist, resveratrol, potassium channel blocker, and necrostatin-1.

### Claim 137 (depends on 136)

The peptide of claim 136, for use wherein the TNFα inhibitor is etanercept.

### Claim 138 (depends on 134)

The peptide of claim 134, for use wherein the additional treatment comprises reducing the core temperature of the subject.

### Claim 139 (depends on 138)

The peptide of claim 138, for use wherein the core temperature of the subject is reduced by about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, or about 50%.

### Claim 140 (depends on 138, 139)

The peptide of claim 138 or 139, for use wherein hypothermia is induced in the subject.

### Claim 141 (depends on 134, 135, 136, 137, 138, 139, 140)

The peptide of any one of claims 134-140, for use wherein the combination of peptide and an additional treatment has a synergistic effect in the prevention or treatment of TON.

### Claim 142 (depends on 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141)

The peptide of any one of claims 121-141, for use wherein the pharmaceutically acceptable salt comprises a mono-acetate salt, a bis-acetate salt, a tri-acetate salt, a tartrate salt, a mono-trifluoroacetate salt, a bis-trifluoroacetate salt, a tri-trifluoroacetate salt, a mono-hydrochloride (“mono-HCl”) salt, a bis-hydrochloride (“bis-HCl”) salt, a tri-hydrochloride (“tri-HCl”) salt, a mono-tosylate salt, a bis-tosylate salt, or a tri-tosylate salt.

### Claim 143 (depends on 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141)

The peptide of any one of claims 121-141, for use wherein the pharmaceutically acceptable salt of the peptide that is formulated for administering to the subject is a tri-HCl salt, a bis-HCl salt, or a mono-HCl salt.

### Claim 144

A peptide D-Arg-2′,6′-Dmt-Lys-Phe-NH2, or a pharmaceutically acceptable salt thereof, for use in improving visual function in a subject having traumatic optic neuropathy (TON).

### Claim 145 (depends on 144)

The peptide of claim 144, for use wherein the subject has experienced a direct injury or an indirect injury.

### Claim 146 (depends on 145)

The peptide of claim 145, for use wherein the direct or indirect injury is selected from the group consisting of intraorbital injury, intracanalicular injury, intracranial injury, and an injury to the subject's optic nerve.

### Claim 147 (depends on 145, 146)

The peptide of claim 145 or 146, for use wherein the peptide is intended to be administered immediately following injury.

### Claim 148 (depends on 145, 146)

The peptide of claim 145 or 146, for use wherein the peptide is intended to be administered about 2 hours or less, about 6 hours or less, about 12 hours or less, or about 24 hours or less following the injury.

### Claim 149 (depends on 144, 145, 146, 147, 148)

The peptide of any one of claims 144-148, for use wherein the peptide is intended to be administered daily for 2 weeks or more.

### Claim 150 (depends on 144, 145, 146, 147, 148)

The peptide of any one of claims 144-148, for use wherein the peptide is intended to be administered daily for 12 weeks or more.

### Claim 151 (depends on 144, 145, 146, 147, 148, 149, 150)

The peptide of any one of claims 144-150, for use wherein the visual function is assessed by one or more of pattern electroretinography (PERG), detection of best corrected visual acuity (BVCA), electroretinography (ERG), and optical coherence tomography (OCT).

### Claim 152 (depends on 144, 145, 146, 147, 148, 149, 150, 151)

The peptide of any one of claims 144-151, for use wherein the improved visual function comprises improvements in any one or more of visual acuity, BVCA, thickness of the retina as detected by OCT, PERG amplitude, ERG amplitude, ERG latency, vision loss, blurred vision, scotoma, decreased color sensation, uveitis, optic neuritis, eye pain, optic nerve avulsion, optic nerve transection, optic nerve sheath hemorrhage, orbital hemorrhage, choroidal rupture, and commotio retinae compared to an untreated control.

### Claim 153 (depends on 144, 145, 146, 147, 148, 149, 150, 151, 152)

The peptide of any one of claims 144-152, for use wherein the subject is a mammal.

### Claim 154 (depends on 153)

The peptide of claim 153, wherein the mammalian subject is a human.

### Claim 155 (depends on 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154)

The peptide of any one of claims 144-154, for use wherein the peptide is intended to be administered orally, topically, intranasally, systemically, intravenously, subcutaneously, intraperitoneally, intradermally, intraocularly, ophthalmically, iontophoretically, transmucosally, intravitreally, or intramuscularly.

### Claim 156 (depends on 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155)

The peptide of any one of claims 144-155, for use wherein the peptide is intended to be separately, sequentially, or simultaneously used with an additional treatment.

### Claim 157 (depends on 156)

The peptide of claim 156, for use wherein the additional treatment comprises use of a therapeutic agent.

### Claim 158 (depends on 157)

The peptide of claim 157, for use wherein the therapeutic agent is selected from the group consisting of: TNFα inhibitor, corticosteroid, IL-1R antagonist, resveratrol, potassium channel blocker, and necrostatin-1.

### Claim 159 (depends on 158)

The peptide of claim 158, for use wherein the TNFα inhibitor is etanercept.

### Claim 160 (depends on 156)

The peptide of claim 156, for use wherein the additional treatment comprises reducing the core temperature of the subject.

### Claim 161 (depends on 160)

The peptide of claim 160, for use wherein the core temperature of the subject is reduced by about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, or about 50%.

### Claim 162 (depends on 160, 161)

The peptide of claim 160 or 161, for use wherein hypothermia is induced in the subject.

### Claim 163 (depends on 156, 157, 158, 159, 160, 161, 162)

The peptide of any one of claims 156 to 162, for use wherein the combination of peptide and an additional treatment has a synergistic effect in improving visual function.

### Claim 164 (depends on 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163)

The peptide of any one of claims 144-163, for use wherein the pharmaceutically acceptable salt comprises a mono-acetate salt, a bis-acetate salt, a tri-acetate salt, a tartrate salt, a mono-trifluoroacetate salt, a bis-trifluoroacetate salt, a tri-trifluoroacetate salt, a mono-hydrochloride (“mono-HCl”) salt, a bis-hydrochloride (“bis-HCl”) salt, a tri-hydrochloride (“tri-HCl”) salt, a mono-tosylate salt, a bis-tosylate salt, or a tri-tosylate salt.

### Claim 165 (depends on 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163)

The peptide of any one of claims 144-163, for use wherein the pharmaceutically acceptable salt of the peptide that is formulated for administering to the subject is a tri-HCl salt, a bis-HCl salt, or a mono-HCl salt.

### Claim 166

A peptide D-Arg-2′,6′-Dmt-Lys-Phe-NH2, or a pharmaceutically acceptable salt thereof, for use in promoting retinal ganglion cell (RGC) survival or increasing neurite outgrowth of an RGC.

### Claim 167 (depends on 166)

The peptide of claim 166, for use wherein the RGC is in vitro.

### Claim 168 (depends on 166)

The peptide of claim 166, for use wherein the RGC is in a subject with TON.

### Claim 169 (depends on 168)

The peptide of claim 168, for use wherein the subject is a mammal.

### Claim 170 (depends on 169)

The peptide of claim 169, for use wherein the mammalian subject is a human.

### Claim 171 (depends on 166, 167, 168, 169, 170)

The peptide of any one of claims 166-170, for use wherein the peptide is intended to be separately, sequentially, or simultaneously used an additional treatment.

### Claim 172 (depends on 171)

The peptide of claim 171, for use wherein the additional treatment comprises use of a therapeutic agent.

### Claim 173 (depends on 172)

The peptide of claim 172, for use wherein the therapeutic agent is selected from the group consisting of: TNFα inhibitor, corticosteroid, IL-1R antagonist, resveratrol, potassium channel blocker, and necrostatin-1.

### Claim 174 (depends on 173)

The peptide of claim 173, for use wherein the TNFα inhibitor is etanercept.

### Claim 175 (depends on 174)

The peptide of claim 174, for use wherein the additional treatment comprises reducing core temperature.

### Claim 176 (depends on 175)

The peptide of claim 175, the core temperature is reduced by about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, or about 50%.

### Claim 177 (depends on 175, 176)

The peptide of claim 175 or 176, for use wherein hypothermia is induced.

### Claim 178 (depends on 171, 172, 173, 174, 175, 176, 177)

The peptide of any one of claims 171-177, for use wherein the combination of peptide and an additional treatment has a synergistic effect in in promoting RGC survival or increasing neurite outgrowth of an RGC.

### Claim 179 (depends on 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178)

The peptide of any one of claims 166-178, for use wherein the pharmaceutically acceptable salt comprises a mono-acetate salt, a bis-acetate salt, a tri-acetate salt, a tartrate salt, a mono-trifluoroacetate salt, a bis-trifluoroacetate salt, a tri-trifluoroacetate salt, a mono-hydrochloride (“mono-HCl”) salt, a bis-hydrochloride (“bis-HCl”) salt, a tri-hydrochloride (“tri-HCl”) salt, a mono-tosylate salt, a bis-tosylate salt, or a tri-tosylate salt.

### Claim 180 (depends on 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178)

The peptide of any one of claims 166-178, for use wherein the pharmaceutically acceptable salt of the peptide that is formulated for administering to the subject is a tri-HCl salt, a bis-HCl salt, or a mono-HCl salt.

### Claim 181

A method for reducing the risk of TON in a subject that has experienced a traumatic injury, the method comprising administering to the subject a therapeutically effective amount of the peptide D-Arg-2′,6′-Dmt-Lys-Phe-NH2, or a pharmaceutically acceptable salt thereof.

### Claim 182 (depends on 181)

The method of claim 181, wherein the traumatic injury is a direct injury or an indirect injury.

### Claim 183 (depends on 182)

The method of claim 182, wherein the direct or indirect injury is selected from the group consisting of intraorbital injury, intracanalicular injury, intracranial injury, and an injury to the subject's optic nerve.

### Claim 184 (depends on 181, 182, 183)

The method of any one of claims 181-183, wherein the peptide is administered immediately following the traumatic injury.

### Claim 185 (depends on 181, 182, 183)

The method of any one of claims 181-183, wherein the peptide is administered about 2 hours or less, about 6 hours or less, about 12 hours or less, or about 24 hours or less following the traumatic injury.

### Claim 186 (depends on 181, 182, 183, 184, 185)

The method of any one of claims 181-185, wherein the peptide is administered daily for 2 weeks or more.

### Claim 187 (depends on 181, 182, 183, 184, 185)

The method of any one of claims 181-185, wherein the peptide is administered daily for 12 weeks or more.

### Claim 188 (depends on 181, 182, 183, 184, 185, 186, 187)

The method of any one of claims 181-187, wherein the subject is a mammal.

### Claim 189 (depends on 188)

The method of claim 188, wherein the mammalian subject is a human.

### Claim 190 (depends on 181, 182, 183, 184, 185, 186, 187, 188, 189)

The method of any one of claims 181-189, wherein the peptide is administered orally, topically, intranasally, systemically, intravenously, subcutaneously, intraperitoneally, intradermally, intraocularly, ophthalmically, iontophoretically, transmucosally, intravitreally, or intramuscularly.

### Claim 191 (depends on 181, 182, 183, 184, 185, 186, 187, 188, 189, 190)

The method of any one of claims 181-190, further comprising separately, sequentially, or simultaneously administering an additional treatment to the subject.

### Claim 192 (depends on 191)

The method of claim 191, wherein the additional treatment comprises administration of a therapeutic agent.

### Claim 193 (depends on 192)

The method of claim 192, wherein the therapeutic agent is selected from the group consisting of: TNFα inhibitor, corticosteroid, IL-1R antagonist, resveratrol, potassium channel blocker, and necrostatin-1.

### Claim 194 (depends on 193)

The method of claim 193, wherein the TNFα inhibitor is etanercept.

### Claim 195 (depends on 191)

The method of claim 191, wherein the additional treatment comprises reducing the core temperature of the subject.

### Claim 196 (depends on 195)

The method of claim 195, the core temperature of the subject is reduced by about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, or about 50%.

### Claim 197 (depends on 195, 196)

The method of claim 195 or 196, wherein hypothermia is induced in the subject.

### Claim 198 (depends on 191, 192, 193, 194, 195, 196, 197)

The method of any one of claims 191-197, wherein the combination of peptide and an additional treatment has a synergistic effect in the prevention or treatment of TON.

### Claim 199 (depends on 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198)

The method of any one of claims 181-198, wherein the pharmaceutically acceptable salt comprises a mono-acetate salt, a bis-acetate salt, a tri-acetate salt, a tartrate salt, a mono-trifluoroacetate salt, a bis-trifluoroacetate salt, a tri-trifluoroacetate salt, a mono-hydrochloride (“mono-HCl”) salt, a bis-hydrochloride (“bis-HCl”) salt, a tri-hydrochloride (“tri-HCl”) salt, a mono-tosylate salt, a bis-tosylate salt, or a tri-tosylate salt.

### Claim 200 (depends on 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198)

The method of any one of claims 181-198, wherein the pharmaceutically acceptable salt of the peptide that is formulated for administering to the subject is a tri-HCl salt, a bis-HCl salt, or a mono-HCl salt.

### Claim 201 (depends on 16, 38, 53, 76, 98, 136, 158)

The method of any one of claim 16, 38, 53, or 193, or the use of any one of claim 76, 98, or 113, or the peptide of any one of claim 136, 158, or 173, wherein the potassium channel blocker is 4-aminopyridine (4-AP).