WO2014017927A1 - Method of treating optic nerve damage, ophthalmic ischemia or ophthalmic reperfusion injury - Google Patents
Method of treating optic nerve damage, ophthalmic ischemia or ophthalmic reperfusion injury Download PDFInfo
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- WO2014017927A1 WO2014017927A1 PCT/NZ2013/000132 NZ2013000132W WO2014017927A1 WO 2014017927 A1 WO2014017927 A1 WO 2014017927A1 NZ 2013000132 W NZ2013000132 W NZ 2013000132W WO 2014017927 A1 WO2014017927 A1 WO 2014017927A1
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- Prior art keywords
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- eye
- peptide
- glyargargalaalaproglyargaibglygly
- seq
- Prior art date
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/08—Peptides having 5 to 11 amino acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0048—Eye, e.g. artificial tears
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Definitions
- the invention relates to a method of treating optic nerve damage, ophthalmic ischemia or ophthalmic reperfusion injury.
- Brimonidine an alpha-2A-adrenergic receptor agonist has been shown to be neuroprotective in formulations either topically or intraperitoneal (IP) applied within various ischemia-related optic nerve injury animal models (Weber et al., 2007; Yoles et al., 1999; Levkovitch-Verbin et al., 2000 and Loengren et al., 2006). It is known that Brimonidine is only active when administered in prophylactic fashion within in vivo rodent models of optic nerve ischemia but loses its effect dramatically in regard to promotion of retinal ganglion cell (RGC) survival even when applied minutes after ex vivo performed injuries of retinal tissue (Prokosch et al., 2010). So far, Brimodine has shown promising neuroprotective activities in rodent models of optic nerve damage but failed to do so when used in comparable human ophthalmic diseases.
- IP intraperitoneal
- GlyArgArgAlaAlaProGlyArgAibGlyGly (SEQ ID NO:1) to an eye of a subject in need thereof.
- the peptide consists of the 11 amino acid residue sequence:
- GlyArgArgAlaAlaProGlyArgAibGlyGly and ophthalmologically acceptable derivatives thereof include the sequence wherein the C-terminus of the peptide is amidated to give.
- GlyArgArgAlaAlaProGlyArgAibGlyGly-NH 2 SEQ ID NO:2).
- the administration step to the subject is by way of one or more topically applied eye drops.
- the administration step to the subject's eye may be by way of administration of a cream pr an ointment.
- the administration step to the subject's eye is by way of a liquid drop preparation applied to the conjunctival sac of the eye of the subject.
- the administration step to the subject's eye is by way of an intravitreal injection.
- the method includes the step of administering an effective amount of a peptide comprising the sequence:
- the method includes the step of administering an effective amount of a peptide comprising the sequence:
- GlyArgArgAlaAlaProGlyArgAibGlyGly (SEQ ID NO: 1 ) to an eye of the subject in need thereof on an at least once a day basis.
- the methods defined above include the step of administering the peptide on an at least twice a day basis.
- the subject is selected from the group consisting of: humans and companion animals.
- GlyArgArgAlaAlaProGlyArgAibGlyGly (SEQ ID NO: 1 ) to an eye of a subject in need thereof.
- the peptide consists of the 1 1 amino acid residue sequence:
- GlyArgArgAlaAlaProGlyArgAibGlyGly and ophthalmologically acceptable derivatives thereof include the sequence wherein the C-terminus of the peptide is amidated to give: GlyArgArgAlaAlaProGlyArgAibGlyGly-NH 2 (SEQ ID NO:2).
- the administration step to the subject is by way of one or more topically applied eye drops.
- the administration step to the subject's eye may be by way of administration of a cream or an ointment.
- the administration step to the subject's eye is by way of a liquid drop preparation applied to the conjunctival sac of the eye of the subject.
- the administration step to the subject's eye is by way of an intravitreal injection.
- the method includes the step of administering an effective amount of a peptide comprising the sequence:
- the method includes the step of administering an effective amount of a peptide comprising the sequence:
- GlyArgArgAlaAlaProGlyArgAibGlyGly (SEQ ID NO:1) to an eye of a subject in need thereof on an at least once a day basis.
- the methods defined above include the step of administering the peptide on an at least twice a day basis.
- the subject is selected from the group consisting of: humans and companion animals.
- GlyArgArgAlaAlaProGlyArgAibGlyGly (SEQ ID NO:1) to an eye of a subject in need thereof.
- the peptide consists of the 11 amino acid residue sequence:
- GlyArgArgAlaAlaProGlyArgAibGlyGly and ophthalmologically acceptable derivatives thereof include the sequence wherein the C-terminus of the peptide is amidated to give: GlyArgArgAlaAlaProGlyArgAibGlyGly-NH 2 (SEQ ID NO:2).
- the administration step to the subject is by way of one or more topically applied eye drops.
- the administration step to the subject's eye may be by way of administration of a cream or an ointment.
- the administration step to the subject's eye is by way of a liquid drop preparation applied to the conjunctival sac of the eye of the subject.
- the administration step to the subject's eye is by way of an intravitreal injection.
- the method includes the step of administering an effective amount of a peptide comprising the sequence:
- the method includes the step of administering an effective amount of a peptide comprising the sequence:
- GlyArgArgAlaAlaProGlyArgAibGlyGly (SEQ ID NO:1) to an eye of the subject in need thereof on an at least once a day basis.
- the method defined above includes the step of administering the peptide on an at least twice a day basis.
- the subject is selected from the group consisting of: humans and companion animals.
- GlyArgArgAlaAlaProGlyArgAibGlyGly-NH 2 (SEQ ID NO:2) for treating or preventing
- the medicament is adapted for topical ophthalmic administration.
- the medicament is adapted for topical ophthalmic administration in the form of a cream or an ointment.
- the medicament is adapted as a liquid formulation for application to the conjunctival sac of the eye of the subject.
- medicament is adapted as a liquid formulation for application to the subject's eye by way of an intravitreal injection.
- the medicament is adapted for at least once daily administration. In one embodiment the medicament is adapted for at least twice daily administration.
- the subject is selected from the group consisting of: humans and companion animals.
- the effective amount of the peptide of SEQ ID NO:1 or SEQ ID NO: 2 is indicated to be in the range of 2-20 nanogram dose amounts when administered in rodent models of optic nerve injury and in the range of 20- 200 nanogram dose amounts when administered to larger subjects such as dogs or humans.
- Effective amount means an amount effective to treat or prevent optic nerve damage; an ophthalmic reperfusion injury; or ophthalmic ischemia in a given subject.
- “Functionally similar amino acid” means an amino acid with similar properties according to the following groupings:
- Optologically acceptable derivatives means derivatives of the peptide defined in SEQ ID NO:1 obtained by amidation, acylation, alkylation, carboxylation, glycosylation, phosphorylation, prenylation, salification, sulfation, or a combination thereof, that are suitable for inclusion in a composition for administration to the eye.
- Optologically acceptable excipients means excipients selected from stabilizing agents, surfactants, buffering agents, chelating agents, viscosity agents, tonicity agents and preservative agents that are suitable for inclusion in a composition for administration to the eye.
- stabilizing agents selected from stabilizing agents, surfactants, buffering agents, chelating agents, viscosity agents, tonicity agents and preservative agents that are suitable for inclusion in a composition for administration to the eye.
- nucleotides and amino acids of biosequences are identified in accordance with Tables 1 to 4 of Annex C, Appendix 2 of the PCT Administrative Instructions (as in force from January 1 , 2010).
- Figure 1 Shows a plot of a-wave amplitude results wherein SEQ ID NO: 1 also known as NRP2945 was administered as an eye drop (twice daily) in one group of rats starting at 30min after optic nerve ligation / reperfusion injury compared to prophylatically administered Brimonidine to another group of rats.
- Figure 2. Shows a plot of b-wave results where SEQ ID NO: , also known as NRP2945, was administered as an eye drop (twice daily) in one group of rats starting at 30min after optic nerve ligation / reperfusion injury compared to the prophylactically administered Brimonidine to another group of rats.
- Figure 3. Shows a plot of retinal ganglion cells (RCG) survival after SEQ ID NO: 1 also known as NRP2945 was applied 16 x times (twice daily)to a first group of rats starting at 30min after optic nerve ligation/ reperfusion as an eye drop to the cornea of each restrained rat compared to a group of rats rescued by prophylactically applied
- RCG retinal ganglion cells
- Example 1 NRP2945 efficacy in a rat model of optic nerve ligation
- mice Male Long-Evans rats (aged P50) were housed for up to 7 days before the start of experimentation and were monitored for signs of ill health. Animals displaying ocular abnormalities were excluded from the study. Every rat was monitored for body weight daily.
- Group 1 received 5ng of NRP2945 reconstituted in saline twice daily as an eye drop (starting with 30min after surgery-reperfusion). Only one eye per animal received the injury and drug treatment, while the non-injured eye served as control.
- Group 2 received one dose of physiological saline (intra-vitreal route at 30min after surgery-reperfusion);
- Group 3 received the adrenergic a-type 2 agonist brimonidine in prophylactic fashion at a concentration of 1mg/kg (IP-route at 1 hr before injury).
- ERG measurements were recorded before ischemia (baseline) and 7 days after reperfusion on both eyes in dark-adapted animals.
- the latency times (for a- and b-wave) and the a-wave and b-wave amplitudes ( ⁇ ) was measured for each ERG; the a-wave and b-wave amplitudes was expressed as a percentage of the baseline value obtained before ischemia. 15 min before measurement 10 ⁇ Mydriaticum® (0.5% tropicamide) was instilled for pupillary dilatation.
- Impedence Threshold 90 kQ.
- Alexa 594 conjugated anti-BRN3A Brain-specific homeobox/POU domain protein 3A, Chemicon, cat #mAb 585
- SEQ ID NO: 1 also known as NRP2945 was administered as an eye drop (twice daily) starting at 30min after optic nerve ligation / reperfusion injury, which led to a recovery of 75.8% of the initial b-wave on day 7 after injury.
- the prophylacticaliy administered Brimonidine led to 79.1 % recovery, while the vehicle conditions only led to a 58.4% recovery of the initial b-wave amplitude.
- SEQ ID NO: 1 also known as NRP2945 was applied 16 x times (twice daily) starting at 30min after optic nerve ligation/ reperfusion as an eyedrop to the cornea of a restrained rat.
- Animals were sacrificed at day 8 and retinae were analysed for BrN3A (Brain-specific homeobox/POU domain protein 3A) protein expression patterns that are specific for retinal ganglion cells (RGCs). 12 fields per retina were evaluated.
- BrN3A Brain-specific homeobox/POU domain protein 3A
- RGC density decreased to 421.0 ⁇ 25.9 RGCs/mm2 at 8 days after ischemia (19.6% compared to non-ischemic contralateral eyes) in saline treated group).
- Retinal Ganglion Cells down-regulate gene expression and lose their axons within the optic nerve head in a mouse glaucoma model. J Neurosci 28: 548-561.
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- Organic Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Immunology (AREA)
- Gastroenterology & Hepatology (AREA)
- Ophthalmology & Optometry (AREA)
- Vascular Medicine (AREA)
- Cardiology (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Urology & Nephrology (AREA)
- Heart & Thoracic Surgery (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicinal Preparation (AREA)
- Peptides Or Proteins (AREA)
Abstract
Description
Claims
Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US14/416,667 US20160015771A1 (en) | 2012-07-27 | 2013-07-26 | Method of treating optic nerve damage, ophthalmic ischemia or ophthalmic reperfusion injury |
EP13822996.8A EP2877195B1 (en) | 2012-07-27 | 2013-07-26 | Method of treating optic nerve damage, ophthalmic ischemia or ophthalmic reperfusion injury |
AU2013293645A AU2013293645B2 (en) | 2012-07-27 | 2013-07-26 | Method of treating optic nerve damage, ophthalmic ischemia or ophthalmic reperfusion injury |
JP2015524217A JP6370779B2 (en) | 2012-07-27 | 2013-07-26 | Medicine for treating or preventing ocular ischemia or ocular reperfusion injury |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
NZ60151212 | 2012-07-27 | ||
NZ601512 | 2012-07-27 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2014017927A1 true WO2014017927A1 (en) | 2014-01-30 |
Family
ID=49997619
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/NZ2013/000132 WO2014017927A1 (en) | 2012-07-27 | 2013-07-26 | Method of treating optic nerve damage, ophthalmic ischemia or ophthalmic reperfusion injury |
Country Status (5)
Country | Link |
---|---|
US (1) | US20160015771A1 (en) |
EP (1) | EP2877195B1 (en) |
JP (1) | JP6370779B2 (en) |
AU (1) | AU2013293645B2 (en) |
WO (1) | WO2014017927A1 (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2015194970A3 (en) * | 2014-06-20 | 2016-07-28 | Curonz Holdings Company Limited | Method of treating or preventing multiple sclerosis using one or more neural regeneration peptides |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US10531655B2 (en) | 2011-12-02 | 2020-01-14 | The Regents Of The University Of California | Reperfusion protection solution and uses thereof |
US20150031712A1 (en) | 2013-03-12 | 2015-01-29 | Moshe Rogosnitzky | Therapeutic Compositions Containing Dipyridamole and Treatment Packs Including Such Compositions and Methods for Producing Same |
DE102014116665A1 (en) * | 2014-09-22 | 2016-03-24 | Carl Zeiss Ag | Method and device for determining eye refraction |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2006121926A2 (en) * | 2005-05-06 | 2006-11-16 | Neuren Pharmaceuticals Limited | Neural regeneration peptides and methods for their use |
WO2009051844A1 (en) | 2007-10-17 | 2009-04-23 | Neuren Pharmaceuticals Limited | Synthetic analogues of neural regeneration peptides |
Family Cites Families (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2004168697A (en) * | 2002-11-19 | 2004-06-17 | Senju Pharmaceut Co Ltd | Therapeutic agent for retinal disease |
JP5026083B2 (en) * | 2003-10-31 | 2012-09-12 | クロンズ ホールディングズ カンパニー リミテッド | Nerve regeneration peptides and their use in the treatment of brain injury |
CA2581126A1 (en) * | 2004-09-24 | 2006-04-06 | Rfe Pharma Llc | Carboxy-amido-triazoles for the localized treatment of ocular diseases |
WO2007011595A2 (en) * | 2005-07-15 | 2007-01-25 | Neuren Pharmaceuticals Limited | Neural regeneration peptides and antioxidants protect neurons from degeneration |
US20070014760A1 (en) * | 2005-07-18 | 2007-01-18 | Peyman Gholam A | Enhanced recovery following ocular surgery |
CA2724199C (en) * | 2008-06-06 | 2016-07-26 | Children's Medical Center Corporation | Promoting axon regeneration in the adult cns through control of protein translation |
WO2012102625A2 (en) * | 2011-01-28 | 2012-08-02 | Curonz Holdings Company Limited | Therapeutic composition |
WO2012105854A2 (en) * | 2011-01-31 | 2012-08-09 | Curonz Holdings Company Limited | Compositions for administration to the eye |
-
2013
- 2013-07-26 US US14/416,667 patent/US20160015771A1/en not_active Abandoned
- 2013-07-26 EP EP13822996.8A patent/EP2877195B1/en not_active Not-in-force
- 2013-07-26 JP JP2015524217A patent/JP6370779B2/en not_active Expired - Fee Related
- 2013-07-26 WO PCT/NZ2013/000132 patent/WO2014017927A1/en active Application Filing
- 2013-07-26 AU AU2013293645A patent/AU2013293645B2/en not_active Ceased
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WO2006121926A2 (en) * | 2005-05-06 | 2006-11-16 | Neuren Pharmaceuticals Limited | Neural regeneration peptides and methods for their use |
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LEVKOVITCH-VERBIN, H.; HARRIS-CERRUTI, C.; GRONER, Y.; WHEELER, L.A.; SCHWARTZ, M.; YOLES, E.: "RGC death in mice after optic nerve crush injury: oxidative stress and neuroprotection", INVEST OPHTHALMOL VIS SCI, vol. 41, 2000, pages 4169 - 4174, XP002980855 |
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See also references of EP2877195A4 |
SOTO, I.; OGLESBY, E.; BUCKINGHAM, B.P.; SON, J.L.; ROBERSON, E.D.O.; STEELE, M.R.; INMAN, D.M.; VETTER, M.L.; HORNER, P.J.; MARSH: "Retinal Ganglion Cells down-regulate gene expression and lose their axons within the optic nerve head in a mouse glaucoma model", J NEUROSCI, vol. 28, 2008, pages 548 - 561 |
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Cited By (1)
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WO2015194970A3 (en) * | 2014-06-20 | 2016-07-28 | Curonz Holdings Company Limited | Method of treating or preventing multiple sclerosis using one or more neural regeneration peptides |
Also Published As
Publication number | Publication date |
---|---|
EP2877195A4 (en) | 2015-12-02 |
EP2877195B1 (en) | 2018-03-21 |
AU2013293645B2 (en) | 2018-04-12 |
JP6370779B2 (en) | 2018-08-08 |
EP2877195A1 (en) | 2015-06-03 |
US20160015771A1 (en) | 2016-01-21 |
JP2015524431A (en) | 2015-08-24 |
AU2013293645A1 (en) | 2015-03-05 |
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