WO2012105854A2 - Compositions pour administration oculaire - Google Patents

Compositions pour administration oculaire Download PDF

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Publication number
WO2012105854A2
WO2012105854A2 PCT/NZ2012/000004 NZ2012000004W WO2012105854A2 WO 2012105854 A2 WO2012105854 A2 WO 2012105854A2 NZ 2012000004 W NZ2012000004 W NZ 2012000004W WO 2012105854 A2 WO2012105854 A2 WO 2012105854A2
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WO
WIPO (PCT)
Prior art keywords
seq
glyargargalaalaproglyargaibglygly
effective amount
administration
subject
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/NZ2012/000004
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English (en)
Other versions
WO2012105854A3 (fr
Inventor
Frank Sieg
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Curonz Holdings Co Ltd
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Curonz Holdings Co Ltd
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Filing date
Publication date
Application filed by Curonz Holdings Co Ltd filed Critical Curonz Holdings Co Ltd
Publication of WO2012105854A2 publication Critical patent/WO2012105854A2/fr
Publication of WO2012105854A3 publication Critical patent/WO2012105854A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • 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
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics

Definitions

  • the invention relates to the treatment of retinopathies.
  • the invention relates to methods and compositions for use in the treatment of retinal hypoxia and intraocular pressure associated retinopathy.
  • Neuronal Regeneration Peptides are oligopeptides that exhibit neuroprotective, neurogenic, neuro-migratory and neuronal differentiating promoting-activity to neural progenitors, neuroblasts and differentiated neurons.
  • the first published NRP sequence to be located in the human genome was part of the N-terminal length (NRP-derived position 38-50) of a protein, named CAPS-2 (calcium-dependent activator protein of secretion-2, which has been linked to the regulation of Brain Derived Neurotrophic Factor (BDNF) and Neurotrophin-3 (NT-3) (Sadakata et al (2004); Sieg and Antonic (2007) ) .
  • CAPS-2 calcium-dependent activator protein of secretion-2, which has been linked to the regulation of Brain Derived Neurotrophic Factor (BDNF) and Neurotrophin-3 (NT-3) (Sadakata et al (2004); Sieg and Antonic (2007) ) .
  • the invention provides a method of
  • preventing, treating or reducing atrophy of a retina in a subject comprising the step of administration to an eye of the subject an effective amount of at least one of the peptides :
  • the atrophy is caused by a hypoxic or ischemic insult.
  • the invention provides a method of preventing, reducing or treating intraocular pressure associated atrophy of a retina in a subject comprising the step of administration to an eye of the subject an effective amount of at least one of the peptides:
  • the invention provides a method of
  • the present invention provides a method to recover or preserve the b-wave of retinal sum potentials by administration to an eye of a subject an effective amount of at least one of the peptides:
  • the step of administration to the eye is by way of an intravitreal administration.
  • the aqueous formulation further comprises saline and, D (+) -trehalose.
  • the aqueous formulation comprises 0.1-lOmM D (+) -trehalose.
  • SEQ ID NO:l and SEQ ID NO: 2 as defined above or ophthalmic formulations as defined above can be used in for the manufacture of a medicament for preventing, reducing or treating a retinal condition as defined above in an affected eye of a subject.
  • Aqueous means consisting largely of water or dissolved in water . 2012/000004
  • Effective amount means an amount administered according to a dosage regimen that is effective to provide the prevention, reduction or treatment outcome.
  • “Insult” means an physiological event or condition that causes or brings about a hypoxic environment in, or ischemia to the eye of a subject.
  • “Intravitreal” means administration into the vitreous humour of a subject's eye.
  • IOP intraocular pressure
  • Prevention means the impeding of development of at least one symptom associated or caused by a state, disorder or disease in a subject, where the subject is not yet exhibiting any symptoms associated or caused by the state, disorder or disease .
  • Reduction means the diminishment of at least one symptom associated or caused by the state, disorder or disease being treated.
  • Subject means mammalian organisms that are capable of suffering from or are afflicted with a disease, disorder or condition associated with retinal atrophy or hypoxia.
  • subjects include humans, dogs, cows, horses, pigs, sheep and the like.
  • Treatment means the alleviation of at least one symptom associated or caused by the state, disorder or disease being treated.
  • “Vitreous humour” means the jelly-like substance filling the posterior chamber of the subject eye between the lens and the retina .
  • 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) .
  • FIG. 1 Shows expression of glial fibrillary protein (GFAP) as an early marker of retinal degeneration following insult (nerve fibre layer (NFL); inner nuclear layer (INL)).
  • GFAP glial fibrillary protein
  • Figure 2 Shows expression of glial fibrillary protein (GFAP) as an early marker of retinal degeneration following insult and administration of 100 fM of the SEQ ID NO: 2 (nerve fibre layer (NFL); inner nuclear layer (INL) ; outer nuclear layer (ONL) ) .
  • GFAP glial fibrillary protein
  • Figure 3 Shows expression of glial fibrillary protein (GFAP) as an early marker of retinal degeneration following insult and administration of 100 pM of the SEQ ID NO: 2 (Nerve fibre layer (NFL); inner nuclear layer (INL); outer nuclear layer (ONL) ) .
  • GFAP glial fibrillary protein
  • FIG. 4 Shows cell death as detected by TUNEL following insult
  • Figure 5 Shows cell death as detected by TUNEL following insult and administration of SEQ ID N0:2 (arrowheads identify photoreceptors) (magnification bar is 50 ⁇ ) .
  • Figure 6 Shows detection of the calcium binding protein parvalbumin in control retina (magnification bar is 50 ⁇ ) .
  • Figure 7. Shows detection of the calcium binding protein parvalbumin in control retina (magnification bar is 50 ⁇ ) .
  • Figure 8 Shows detection of the calcium binding protein parvalbumin in retina following insult by elevation of the intraocular pressure and administration of the SEQ ID NO:2 (magnification bar is 50 ⁇ ) .
  • Figure 9 Shows detection of the calcium binding protein parvalbumin and labelling of glutamine synthetase (GS) in retina following insult by elevation of the intraocular pressure (magnification bar is 50 ⁇ ) .
  • FIG 10 Shows labelling of glutamine synthetase (GS) in control retina (magnification bar is 50 ⁇ ) .
  • FIG 11 Shows labelling of glutamine synthetase (GS) in retina following insult by elevation of the intraocular pressure and
  • FIG 12 Shows double light flash ERGs taken directly after infliction of saline injection injury and at 24 hours after SEQ ID NO: 2 (shown as NNZ-4945 in Figure 12) or saline intravitreal injection (after 48 hours of experimental time line lapse) .
  • Analysis paradigms comprised b-wave amplitude measurement, amplitude difference from a-wave to b-wave (PTP) and summed amplitudes.
  • Figure 13 Shows quantification of the astroglial (Mueller cell) response at 24 hrs after intravitreal injection of SEQ ID NO: 2 (shown as NNZ-4945 in Figure 13) into the cornea that received 25 ⁇ of saline injection prior to the therapeutic intervention. Analysis consists of Glial
  • GFAP Fibrillary Acid Protein
  • Figure 14 Shows quantification of the astroglial (Mueller cell) response after in vitro hypoxia. Rats are prophylactically treated with a daily bolus of 2ng intravitreally injected SEQ ID NO: 2 (shown as NNZ-4945 in
  • FIG. 14 For three subsequent days. Subsequently, retinae are extracted and subjected to 40 min of hypoxia in the presence of two concentrations of SEQ ID NO: 2 (shown as NNZ-4945 in Figure 14) . Analysis consists of Glial Fibrillary Acid Protein (GFAP) density measurements within the retina.
  • GFAP Glial Fibrillary Acid Protein
  • Tissue culture has been determined to be an ideal way to study the actions of NRPs on central nervous tissue. It allows fine control over drug concentration, time course and the analysis of the tissue on a cell-by-cell basis (Kaempf et al (2008) ; Siegel (1999) ) .
  • the specification accompanying international application no. PCT/US2008/011951 discloses, as SEQ ID NO: 5, the neuroprotective activity of the amidated peptide designated SEQ ID NO: 2. These studies did not disclose the intravitreal administration of the amidated peptide .
  • GFAP glial fibrillary protein
  • SEQ I D NO: 2 has been shown in the studies outlined below to have high neuroprotective and astro-glial scar preventing activity in the retina. As such intravitreal administration of SEQ I D NO: 2 is a therapeutic option for use in the treatment of injured hypoxic retina and other retinopathies, including high intraocular pressure associated retinopathy.
  • Retinal explants were incubated in a modified brain buffer mimicking hypoxic damage by bubbling it in 95% N 2 /5% C0 2 .
  • modified brain buffer supplemented with 100 fM SEQ I D NO: 2; or
  • modified brain buffer supplemented with 100 pM SEQ I D NO: 2. After 40 min the tissues were fixed by immersion in a solution with 4% paraformadehyde/0.01% glutaraldehyde for 30 minutes and processed for immunocytochemistry .
  • the tissue was blocked with 6% goat serum (containing 1% BSA and 0.5% Triton) and then a rabbit Glial Fibrillary Acidic Protein (GFAP) primary antibody was applied overnight. The secondary antibody was then applied.
  • GFAP Glial Fibrillary Acidic Protein
  • TUNEL Terminal deoxycleotidyl transferase dUTP Nick End Labelling, In situ Cell Death Detection kit, Fluorescein (ROCHE, Penzberg, Germany) was applied to detect cell death in control and treated whole mount retinas.
  • IOP rat intraocular pressure
  • ERG double light flash-induced electroretinogram
  • Control waveforms were recorded by using the Scope software (AD Instruments, NZ) .
  • the left eyes were injected with 2 pmoles of SEQ ID NO: 2 (or alternatively, saline only) diluted in saline so a final vitreous chamber concentration of 50-100n was achieved.
  • ERG recordings were repeated after 24 hrs and subsequently the eyes were removed and processed for immunocytochemistry.
  • Rabbit anti-GFAP was employed to detect retinal stress and TUNEL cell detection kit was employed to detect cell death.
  • the SEQ ID NO: 2 demonstrated protective activity against cell death in this in vitro model of the hypoxic retina ( Figures 4 and 5). Administration of the SEQ ID NO: 2 reduced
  • Quantification of the GFAP retinal expression after performed ischemia revealed a clearly diminished Mueller cell response in the presence of lOOfM of SEQ ID NO: 2 (p ⁇ 0.001, ANOVA) when compared to saline treated control retina (see Figure 14) .
  • the astroglial proliferative response of the retinal Mueller cells was significantly reduced in retinae that have been treated with a single intravitreally injected bolus of 2ng SEQ ID NO: 2 that was applied 24hrs after IOP induction

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Ophthalmology & Optometry (AREA)
  • Epidemiology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Immunology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicinal Preparation (AREA)

Abstract

La présente invention concerne des procédés et des compositions destinés à être utilisés dans la prévention, le traitement ou la réduction de l'hypoxie rétinienne et de la rétinopathie associée à la pression intraoculaire chez des sujets, au moyen d'une quantité efficace de l'un des peptides suivants : GlyArgArgAlaAlaProGlyArgAibGlyGly (SEQ ID No :1) ou GlyArgArgAlaAlaProGlyArgAibGlyGly-NH2 (SEQ ID No :2).
PCT/NZ2012/000004 2011-01-31 2012-01-27 Compositions pour administration oculaire Ceased WO2012105854A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
NZ59081511 2011-01-31
NZ590815 2011-01-31

Publications (2)

Publication Number Publication Date
WO2012105854A2 true WO2012105854A2 (fr) 2012-08-09
WO2012105854A3 WO2012105854A3 (fr) 2012-11-01

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2877195A4 (fr) * 2012-07-27 2015-12-02 Curonz Holdings Company Ltd Procédé de traitement d'une lésion du nerf optique, d'une ischémie ophtalmique ou d'une lésion de reperfusion ophtalmique
JP2020508652A (ja) * 2017-02-10 2020-03-26 ザ ロックフェラー ユニバーシティー 薬物標的を特定するための細胞型特異的プロファイリング方法

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5919813C1 (en) * 1998-03-13 2002-01-29 Univ Johns Hopkins Med Use of a protein tyrosine kinase pathway inhibitor in the treatment of diabetic retinopathy
US7563862B2 (en) * 2001-08-24 2009-07-21 Neuren Pharmaceuticals Limited Neural regeneration peptides and methods for their use in treatment of brain damage
WO2009051844A1 (fr) * 2007-10-17 2009-04-23 Neuren Pharmaceuticals Limited Analogues synthétiques de peptides de régénération neurale
US20090148886A1 (en) * 2007-12-07 2009-06-11 The Arizona Board Of Regents On Behalf Of The University Of Arizona Methods of identifying compounds that decrease intraocular pressure

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2877195A4 (fr) * 2012-07-27 2015-12-02 Curonz Holdings Company Ltd Procédé de traitement d'une lésion du nerf optique, d'une ischémie ophtalmique ou d'une lésion de reperfusion ophtalmique
AU2013293645B2 (en) * 2012-07-27 2018-04-12 Curonz Holdings Company Limited Method of treating optic nerve damage, ophthalmic ischemia or ophthalmic reperfusion injury
JP2020508652A (ja) * 2017-02-10 2020-03-26 ザ ロックフェラー ユニバーシティー 薬物標的を特定するための細胞型特異的プロファイリング方法
JP7229538B2 (ja) 2017-02-10 2023-03-01 ザ ロックフェラー ユニバーシティー 薬物標的を特定するための細胞型特異的プロファイリング方法
JP2023058610A (ja) * 2017-02-10 2023-04-25 ザ ロックフェラー ユニバーシティー 薬物標的を特定するための細胞型特異的プロファイリング方法
JP7604014B2 (ja) 2017-02-10 2024-12-23 ザ ロックフェラー ユニバーシティー 薬物標的を特定するための細胞型特異的プロファイリング方法
US12577609B2 (en) 2017-02-10 2026-03-17 The Rockefeller University Methods for cell-type specific profiling to identify drug targets

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Publication number Publication date
WO2012105854A3 (fr) 2012-11-01

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