WO2010085568A1 - Procédés de diagnostic et de traitement d'une kératoconjonctivite sèche grave - Google Patents

Procédés de diagnostic et de traitement d'une kératoconjonctivite sèche grave Download PDF

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Publication number
WO2010085568A1
WO2010085568A1 PCT/US2010/021667 US2010021667W WO2010085568A1 WO 2010085568 A1 WO2010085568 A1 WO 2010085568A1 US 2010021667 W US2010021667 W US 2010021667W WO 2010085568 A1 WO2010085568 A1 WO 2010085568A1
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Prior art keywords
timp
mmp
levels
dry eye
eye syndrome
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PCT/US2010/021667
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English (en)
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Robert Sack
Sonal Sathe
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The Research Foundation Of State University Of New York
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Publication of WO2010085568A1 publication Critical patent/WO2010085568A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/34—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving hydrolase
    • C12Q1/37—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving hydrolase involving peptidase or proteinase
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/81—Protease inhibitors
    • G01N2333/8107—Endopeptidase (E.C. 3.4.21-99) inhibitors
    • G01N2333/8146—Metalloprotease (E.C. 3.4.24) inhibitors, e.g. tissue inhibitor of metallo proteinase, TIMP
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/90—Enzymes; Proenzymes
    • G01N2333/914—Hydrolases (3)
    • G01N2333/948—Hydrolases (3) acting on peptide bonds (3.4)
    • G01N2333/95—Proteinases, i.e. endopeptidases (3.4.21-3.4.99)
    • G01N2333/964—Proteinases, i.e. endopeptidases (3.4.21-3.4.99) derived from animal tissue
    • G01N2333/96425—Proteinases, i.e. endopeptidases (3.4.21-3.4.99) derived from animal tissue from mammals
    • G01N2333/96427—Proteinases, i.e. endopeptidases (3.4.21-3.4.99) derived from animal tissue from mammals in general
    • G01N2333/9643—Proteinases, i.e. endopeptidases (3.4.21-3.4.99) derived from animal tissue from mammals in general with EC number
    • G01N2333/96486—Metalloendopeptidases (3.4.24)
    • G01N2333/96491—Metalloendopeptidases (3.4.24) with definite EC number
    • G01N2333/96494—Matrix metalloproteases, e. g. 3.4.24.7
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/16—Ophthalmology

Definitions

  • Various embodiments include a method of diagnosing an increased likelihood of developing dry eye syndrome post corneal surgery relative to a normal subject in an individual, comprising obtaining a sample from the individual, assaying the sample to determine the presence or absence of a high ratio of matrix metal loproteinase (MMP) levels to tissue inhibitor of metalloproteinase (TIMP) levels relative to a normal subject, and diagnosing an increased likelihood of developing dry eye syndrome post corneal surgery relative to a normal subject in the individual based on the presence of a high ratio of MMP levels to TIMP levels
  • MMP comprises MMP-I, MMP-2, MMP-3, MMP-8, MMP-9, MMP-10 and/or MMP-13.
  • TIMP comprises TIMP-I and/or TIMP-2.
  • the sample comprises a pre-surgical tear sample.
  • the assay comprises a protein and/or microarray assay.
  • the high ratio of MMP levels to TIMP levels comprise about 0.8 or higher.
  • the high ratio of MMP levels to TIMP levels comprise about 0.7 or higher.
  • the high ratio of MMP levels to TIMP levels comprise about 0.51 or higher.
  • the corneal surgery comprises laser-assisted in situ keratomileusis (Lasik), photorefractive keratectomy (Prk), and/or corneal transplants.
  • Other embodiments include a method of treating an individual for dry eye syndrome post corneal surgery, comprising determining the presence of a depressed level of tissue inhibitor of metalloproteinase (TIMP) relative to a normal subject and/or a high ratio of matrix metalloproteinase (MMP) levels to TIMP levels relative to a normal subject, and administering a treatment to the individual to address the dry eye syndrome post corneal surgery.
  • the treatment comprises a therapeutically effective amount of MMP inhibitor.
  • the treatment is administered prior to corneal surgery,
  • the treatment is administered post corneal surgery.
  • the treatment comprises a therapeutically effective amount of TIMP and/or chelating agent.
  • the high ratio of MMP levels to TIMP levels comprise about 0.8 or higher. In another embodiment, the high ratio of MMP levels to TIMP levels comprise about 0.7 or higher. In another embodiment, the high ratio of MMP levels to TIMP levels comprise about 0.51 or higher.
  • TIMP tissue inhibitor of metalloproteinase
  • Figure I depicts, in accordance with an embodiment described herein, the basic steps involved in a protein array assay.
  • the arrays consist of a three by three set of nine capture antibodies for MMP-I, MMP-2, MMP-3, MMP-8, MMP-9, MMP-IO, MMP- 13 and TlMPs 1 and 2 as shown in figure 3 herein. Copies of these arrays are imprinted in individual wells of a 96 micro well plate. Tears are added to the array and a series of steps similar to classical sandwich ELISA assays are carried out including a streptavidin-biotin amplification step. Quantification is based upon a peroxidase reporter enzyme with parallel wells containing known amounts of each of the 9 proteins with detection based upon chemo luminescence.
  • Figure 2 depicts, in accordance with an embodiment described herein, the volume of tears collected on Schirmer strips (length in mm from the bulb) in an atypical lasik surgical subject (lasik-4) before and after (at set periods of time) surgery.
  • the rapid onset of a dry eye syndrome is apparent one day after surgery and is still present 3 months after surgery.
  • Data includes Lasik-4 atypical subject who developed post surgical dry eye syndrome.
  • FIG. 3 depicts, in accordance with an embodiment described herein, the results of MMP protein array assays of identical size extracts from Schirmer strips recovered from patient lasik-4 with sampling carried out before and after surgery. Note that in samples recovered from the left and right eyes immediately before surgery, the signal for TIMP-I was virtually absent. Tear samples 2 of 5 of the patients who developed post-surgical dry eye syndrome contained negligible levels of TIMP-I in the pre-surgical tear samples. 3/5 exhibited negligible levels of TIMPl in 1 or more samples.
  • Figure 4 depicts, in accordance with an embodiment described herein, the results of MMP and TIMP assays from similar sets of Schirmer strip extracts from individuals who did not develop post surgical dry eye syndrome with high levels of TIMP-I present in all of the extracts.
  • Normals Pre and Post Surgical Samples (none of these patents developed post surgical dry eye syndrome). None of these samples exhibited low levels of TIMPs.
  • FIG. 5 depicts, in accordance with an embodiment described herein, the results of the assays of typical groups of normal and pathological tear samples using the MMP array. High levels of TIMP-I were common to all of these samples. Dozens of other tear samples have been assayed from normals and individuals with a wide range of pathologies. None of these samples had a low level of TIMP-I or 2.
  • Figure 6 depicts, in accordance with an embodiment described herein, the results of the assays of typical groups of normal and pathological tear samples using the MMP array. High levels of TIMP-I and a high MMP-9/TIMP-1 ratio were common to all of these samples. Typical Results Assay Chronic and Acute Allergic Reactions. Note that all samples exhibit strong signals for TIMP-I and TIMP-2.
  • Figure 7 depicts, in accordance with an embodiment described herein, the results of array assays of the pre surgical tear samples from the single patient who developed a post surgical epitheliopathy and dry eye. Note that TIMPs 1 and 2 were absent in these samples. Pre surgical tear samples from subjects who developed dry eye or epithelial opathy.
  • Figure 8 depicts, in accordance with an embodiment described herein, results depicting a clear association between MMP-I O/TIMP-1 ratio of the pre-surgicai tear samples and a likelihood of developing clinical defined post-surgical dry eye syndrome. Measured unit is in pg/ml. The first four columns indicate the sex (male or female) of the test subject, (OD/OS-eye) and the type of refractive surgery employed upon each of the patients, as well as their respective age.
  • the next three additional columns indicate the concentrations of MMP-10, TIMP-I , and the MMP-IO to TIMP-I ratio, respectively, as obtained on the assay of the pre-surgical tear sample, as determined by an MMP and TlMP array of the Schirmer extract with the ratio presented in descending order.
  • the last few columns indicate with a "#1 " those eyes which have been diagnosed with dry eye syndrome at least once. The columns indicate the exact times when the diagnosis was made. " ⁇ 9" is indicative of no data obtained. Diagnosis is based upon clinical examination encompassing a variety of measurements.
  • the inventors are able to conclude that for at least a MMP-10 to TIMP-I ratio of 0.8 or higher, one could significantly reduce the incidence of surgically induced dry eye syndrome.
  • the overall quality of surgery would be improved and a significant fraction of patients who are at risk for an adverse reaction would be identified.
  • MMP matrix metal loproteinase
  • TlMP tissue inhibitor of metalloproteinase
  • Laser means laser-assisted in situ keratomileusis and is a type of refractive laser eye surgery that may be performed for correcting a condition such as myopia, hyperopia or astigmatism.
  • PRK photorefractive keratectomy
  • advanced surface ablation is a type of laser eye surgery that may be used to correct an individual's vision.
  • ''MMP inhibitor means a compound or molecule capable of inhibiting the activity or signaling capacity of matrix metalloproteases.
  • dry eye syndrome is a condition in which the eyes do not produce enough tears, causing them to become dry and irritated and is frequently associated with inflammation.
  • normal subject refers to a population when taken as a whole or average, with the average amount of incidence.
  • inhibitors and the corresponding MMPs that are down regulated by these inhibitors are well known factors critical to wound healing and tissue remodeling. These factors as shown herein can be readily assayed using a microwell based array using minute tear samples and other forms of assay of TIMP-I and 2 and/or the corresponding affected MMPs should have wide spread applicability as a pre-screening agent identifying those subjects who are poor candidates for a positive outcome from this elective form of surgery. The general nature of this apparent biochemical defect in this small population is also a diagnostic indicator of individuals who might be at risk of serious consequences of other forms of corneal surgery in which wound healing is a critical factor, which includes corneal transplants where -10% of the transplants are rejected.
  • results demonstrate that the prophylactic treatment or pre-treatment prior to and after surgery of individuals who might be at risk with TIMP-I and or mixtures of TIMPl and TIMP2 as well as other MMP inhibitors (such as chelating agents) could reduce the risk and severity of developing these complications.
  • the overall quality of surgery would be improved and a significant fraction of patients who are at risk for an adverse reaction would be identified. These patients could be counseled to considering avoiding surgery or more closely followed after surgery with earlier intervention.
  • the present invention provides a method of diagnosing susceptibility to post surgical dry eye syndrome in an individual by determining the presence or absence of a low level of TIMP and/or a high MMP/TIMP ratio, where the presence of the low level of TIMP and/or high MMP/TIMP ratio is indicative of susceptibility to post surgical dry eye syndrome in the individual.
  • TIMP is TIMP-I and/or T1MP-2.
  • MMP is MMP-2, MMP-9, and/or MMP-IO.
  • the TIMP and/or MMP is taken from a tear sample.
  • the tear sample is used in conjunction with a 4-plex assay for TIMP-I, TIMP-2 and MMP-2 and MMP-9 with the ratios of MMPs to associated inhibitors determining risk.
  • post surgical dry eye syndrome includes epitheliopathy.
  • the present invention provides a method of diagnosing dry eye syndrome in an individual by determining the presence or absence of a low level of TIMP and/or a high MMP/TIMP ratio, where the presence of the low level of TIMP and/or high MMP/TIMP ratio is indicative of post surgical dry eye syndrome in the individual.
  • TIMP is TIMP-I and/or TIMP-2.
  • MMP is MMP-2, MMP-9 and/or MMP-IO.
  • the TIMP and/or MMP is taken from a tear sample.
  • post surgical dry eye syndrome includes epitheliopathy.
  • the dry eye syndrome is secondary to surgery.
  • the surgery is Lasik or PRK and variants of refractive surgery.
  • the present invention provides a method of treating post surgical dry eye syndrome and/or epitheliopathy by determining the presence of a low level of TIMP- 1 and/or TIMP-2 and administering a therapeutically effective amount of an MMP inhibitor to the individual.
  • the MMP inhibitor is TIMP-I and/or TIMP-2.
  • the MMP inhibitor is a chelating agent.
  • the present invention is also directed to a kit to prepare an assay for determining the presence or absence of TIMP and/or MMP, as well as the delivery of the MMP inhibitors to an individual, and may include a pipette, pipette solution, tear sample solution, T1MP/MMP assay solution, and combinations thereof.
  • the kit is an assemblage of materials or components, including at least one of the inventive compositions.
  • the kit contains a composition including a therapeutically effective dosage of MMP inhibitor, as described above.
  • kits The exact nature of the components configured in the inventive kit depends on its intended purpose. For example, some embodiments are configured for the purpose of delivering a therapeutically effective dosage of MMP inhibitor to a subject, such as, but not limited to, human subjects, farm animals, domestic animals, and laboratory animals. Other embodiments, for example, are configured for preparing a therapeutically effective dosage of MMP inhibitor to a subject, such as, but not limited to, human subjects, farm animals, domestic animals, and laboratory animals. Instructions for use may be included in the kit.
  • kits for use typically include a tangible expression describing the technique to be employed in using the components of the kit to effect a desired outcome, such as to prepare a solution for determining the presence of TIMP or MMP and/or deliver a therapeutically effective dosage of MMP inhibitor either pre or post surgery.
  • the kit also contains other useful components, such as, diluents, buffers, pharmaceutically acceptable carriers, syringes, catheters, applicators, pipetting or measuring tools, bandaging materials or other useful paraphernalia as will be readily recognized by those of skill in the art.
  • the materials or components assembled in the kit can be provided to the practitioner stored in any convenient and suitable ways that preserve their operability and utility.
  • the components can be in dissolved, dehydrated, or lyophilized form; they can be provided at room, refrigerated or frozen temperatures.
  • the components are typically contained in suitable packaging material(s).
  • packaging material ' ' refers to one or more physical structures used to house the contents of the kit, such as inventive compositions and the like.
  • the packaging material is constructed by well known methods, preferably to provide a sterile, contaminant-free environment.
  • the term "package” refers to a suitable solid matrix or material such as glass, plastic, paper, foil, and the like, capable of holding the individual kit components.
  • a package can be a glass vial used to contain suitable quantities of an inventive composition containing a solution of MMP inhibitor or components thereof.
  • the packaging material generally has an external label which indicates the contents and/or purpose of the kit and/or its components.
  • the present invention provides pharmaceutical compositions including a pharmaceutically acceptable excipient along with a therapeutically effective amount of MMP inhibitor.
  • ' Pharmaceutically acceptable excipient
  • excipients may be solid, liquid, semisolid, or, in the case of an aerosol composition, gaseous.
  • the pharmaceutical compositions according to the invention may be formulated for delivery via any route of administration.
  • Ring of administration may refer to any administration pathway known in the art, including but not limited to pipette, intravenous injection, aerosol, nasal, oral, transmucosal, transdermal or parenteral.
  • Parenteral refers to a route of administration that is generally associated with injection, including intraorbital, infusion, intraarterial, intracapsular, intracardiac, intradermal, intramuscular, intraperitoneal, intrapulmonary, intraspinal, intrasternal, intrathecal, intrauterine, intravenous, subarachnoid, subcapsular, subcutaneous, transmucosal, or transtracheal.
  • the compositions may be in the form of solutions or suspensions for infusion or for injection, or as lyophilized powders.
  • the MMP inhibitor according to the invention can also contain any pharmaceutically acceptable carrier.
  • “Pharmaceutically acceptable carrier” as used herein refers to a pharmaceutically acceptable material, composition, or vehicle that is involved in carrying or transporting a compound of interest from one tissue, organ, or portion of the body to another tissue, organ, or portion of the body.
  • the carrier may be a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, or a combination thereof.
  • Each component of the carrier must be “pharmaceutically acceptable” in that it must be compatible with the other ingredients of the formulation. It must also be suitable for use in contact with any tissues or organs with which it may come in contact, meaning that it must not carry a risk of toxicity, irritation, allergic response, immunogenicity, or any other complication that excessively outweighs its therapeutic benefits.
  • the MMP inhibitor according to the invention can also be encapsulated, tableted or prepared in an emulsion or syrup for oral administration.
  • Pharmaceutically acceptable solid or liquid carriers may be added to enhance or stabilize the composition, or to facilitate preparation of the composition.
  • Liquid carriers include syrup, peanut oil, olive oil, glycerin, saline, alcohols and water.
  • Solid carriers include starch, lactose, calcium sulfate, dihydrate, terra alba, magnesium stearate or stearic acid, talc, pectin, acacia, agar or gelatin.
  • the carrier may also include a sustained release material such as glyceryl monostearate or glyceryl distearate, alone or with a wax.
  • the preparations of the MMP inhibitor are made following the conventional techniques of pharmacy involving milling, mixing, granulation, and compressing, when necessary, for tablet forms; or milling, mixing and filling for hard gelatin capsule forms.
  • a liquid carrier When a liquid carrier is used, the preparation will be in the form of a syrup, elixir, emulsion or an aqueous or non-aqueous suspension.
  • Such a liquid formulation may be administered directly p.o. or filled into a soft gelatin capsule.
  • the MMP inhibitor according to the invention may be delivered in a therapeutically effective amount.
  • the precise therapeutically effective amount is that amount of the composition that will yield the most effective results in terms of efficacy of treatment in a given subject. This amount will vary depending upon a variety of factors, including but not limited to the characteristics of the therapeutic compound (including activity, pharmacokinetics, pharmacodynamics, and bioavailability), the physiological condition of the subject (including age, sex, disease type and stage, general physical condition, responsiveness to a given dosage, and type of medication), the nature of the pharmaceutically acceptable carrier or carriers in the formulation, and the route of administration.
  • MMP inhibitors can be in the ranges recommended by the manufacturer where known therapeutic compounds are used, and also as indicated to the skilled artisan by the in vitro responses or responses in animal models. Such dosages typically can be reduced by up to about one order of magnitude in concentration or amount without losing the relevant biological activity.
  • the actual dosage will depend upon the judgment of the physician, the condition of the patient, and the effectiveness of the therapeutic method based, for example, on the in vitro responsiveness of the relevant primary cultured cells or histocultured tissue sample, such as the responses observed in the appropriate animal model.
  • the detection paradigms that can be employed to this end include optical methods, electrochemical methods (voltametry and amperometry techniques), atomic force microscopy, and radio frequency methods, e.g., multipolar resonance spectroscopy.
  • Illustrative of optical methods in addition to microscopy, both confocal and non-confocal, are detection of fluorescence, luminescence, chemiluminescence, absorbance, reflectance, transmittance, and birefringence or refractive index (e.g., surface plasmon resonance, ellipsometry, a resonant mirror method, a grating coupler waveguide method or interferometry).
  • detection of fluorescence, luminescence, chemiluminescence, absorbance, reflectance, transmittance, and birefringence or refractive index e.g., surface plasmon resonance, ellipsometry, a resonant mirror method, a grating coupler waveguide method or interferometry.
  • a MMP and TIMP biomarkers may be captured using biospecific capture reagents, such as antibodies, aptamers or antibodies that recognize the biomarker and modified forms of it. This method could also result in the capture of protein interactors that are bound to the proteins or that are otherwise recognized by antibodies and that, themselves, can be biomarkers.
  • biospecific capture reagents may also be bound to a solid phase.
  • the captured proteins can be detected by SELDI mass spectrometry or by eluting the proteins from the capture reagent and detecting the eluted proteins by traditional MALD ⁇ or by SELDL
  • SELDI affinity capture mass spectrometry
  • SEAC Surface-Enhanced Affinity Capture
  • Some examples of mass spectrometers are time-of- flight, magnetic sector, quadrupole filter, ion trap, ion cyclotron resonance, electrostatic sector analyzer and hybrids of these.
  • the presence of biomarkers such as polypeptides maybe detected using traditional immunoassay techniques.
  • Immunoassay requires biospecific capture reagents, such as antibodies, to capture the analytes.
  • the assay may also be designed to specifically distinguish protein and modified forms of protein, which can be done by employing a sandwich assay in which one antibody captures more than one form and second, distinctly labeled antibodies, specifically bind, and provide distinct detection of, the various forms.
  • Antibodies can be produced by immunizing animals with the biomolecules.
  • Traditional immunoassays may also include sandwich immunoassays including ELISA or fluorescence -based immunoassays, as well as other enzyme immunoassays.
  • MMP and TIMP biomarkers Prior to detection, MMP and TIMP biomarkers may also be fractionated to isolate them from other components in a solution or of blood that may interfere with detection. Fractionation may include platelet isolation from other blood components, sub-cellular fractionation of platelet components and/or fractionation of the desired biomarkers from other biomolecules found in platelets using techniques such as chromatography, affinity purification, 1 D and 2D mapping, and other methodologies for purification known to those of skill in the art.
  • a sample is analyzed by means of a biochip.
  • Biochips generally comprise solid substrates and have a generally planar surface, to which a capture reagent (also called an adsorbent or affinity reagent) is attached. Frequently, the surface of a biochip comprises a plurality of addressable locations, each of which has the capture reagent bound there.
  • any number of assays and mediums may be used in conjunction with various embodiments described herein.
  • methods of determining the presence or absence of levels of TIMP, MMP, and lheir respective ratio levels may include the use of a strip for rapid diagnosis, a chip, "lab on a chip," a micro fluidic device, a protein array, or any other number of assays or mediums readily available and known in the art.
  • the invention is not limited to only be used in conjunction with Lasik or PRK surgery.
  • TIMP- 1 and -2 TIMP- 1 and -2 and the corresponding MMPs that are down regulated by these inhibitors are well known factors critical to wound healing and tissue remodeling. These factors as shown here can be readily assayed using a microwell based array using minute tear samples. That and other forms of assay of TIMP-I and -2 and/or also the corresponding affected MMPs should have wide spread applicability as a pre-screening agent identifying those subjects who are poor candidates for a positive outcome from this elective form of surgery.
  • Another possible use could be in the form of a 4-plex assay for TIMP-I, TIMP-2 and MMP-2 and MMP-9 with the ratios of MMPs to associated inhibitors determining the risk. Additionally, a protein array for differential diagnosis of ocular diseases, or an assay on a chip or strip for rapid diagnosis could also be used.
  • Example 3 Generally MMPs are known to be proteases involved in wound healing and tissue remodeling that are inhibited by TIMPs, with TIMP-I inhibiting MMP-9 and TIMP-2 inhibiting MMP-2.
  • proteases are involved in the control of apoptosis and tissue remodeling.
  • LASIK and PRK surgeries involve destruction of regions of the corneal epithelium and removal of some stroma.
  • TIMP-2 results in excess inflammation and tissue destruction immediately after lasik or PRK surgery. All subjects described herein who had depressed levels of TIMPl developed serious aqueous deficiency dry eye syndrome. This deficiency was observed in about 50% of the subjects who developed aqueous deficiency dry eye syndrome secondary to surgery.
  • Example 4 MMP to TIMP ratios
  • the inventors examined clinical data of subjects who had undergone refractive surgery and compared it to data of MMP and TIMP levels of pre- surgical samples taken from those same subjects. The result is that a clear relationship is shown between MMP and TIMP ratios of pre -surgical tear samples and the likelihood of developing clinical defined postsurgical dry eye syndrome.
  • the first four columns indicate the sex (male or female) of the test subject, and the type of refractive surgery employed upon each of the patients, as well as their respective age.
  • the next three additional columns indicate the concentrations of MMP-IO, TIMP-I, and the MMP-10 to TIMP-I ratio, respectively, as obtained on the assay of the pre-surgical tear sample, as determined by an MMP and TlMP array of the Schirmer extract with the ratio presented in descending order.
  • the last few columns indicate with a "#1" those eyes which have been diagnosed with dry eye syndrome at least once. The columns indicate the exact times when the diagnosis was made. Based on the data depicted in Figure 8 and herein, the inventors are able to conclude that for at least a MMP-10 to TIMP-I ratio of 0.8 or higher, one could significantly reduce the incidence of surgically induced dry eye syndrome. Thus, for example, the overall quality of surgery would be improved and a significant fraction of patients who are at risk for an adverse reaction would be identified.

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Abstract

La présente invention porte sur des procédés de diagnostic d'un risque de développer une kératoconjonctivite sèche après avoir subi une chirurgie. Dans un mode de réalisation, la présente invention porte sur un procédé de diagnostic d'une susceptibilité à une kératoconjonctivite sèche post-chirurgicale chez un individu par la détermination de la présence ou de l'absence d'un faible taux de TIMP et/ou d'un rapport MMP/TIMP élevé, la présence du faible taux de TIMP et/ou du rapport MMP/TIMP élevé étant indicative d'une susceptibilité à une kératoconjonctivite sèche post-chirurgicale chez l'individu.
PCT/US2010/021667 2009-01-21 2010-01-21 Procédés de diagnostic et de traitement d'une kératoconjonctivite sèche grave WO2010085568A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3547898A4 (fr) * 2016-12-02 2020-07-08 Oculeve, Inc. Appareil et méthode de prévision de sécheresse oculaire et recommandation de traitement
US10967173B2 (en) 2013-04-19 2021-04-06 Oculeve, Inc. Nasal stimulation devices and methods for treating dry eye
RU2801475C1 (ru) * 2022-12-09 2023-08-09 федеральное государственное автономное учреждение "Национальный медицинский исследовательский центр "Межотраслевой научно-технический комплекс "Микрохирургия глаза" имени академика С.Н. Федорова" Министерства здравоохранения Российской Федерации Способ определения показаний к проведению кераторефракционной хирургии с учетом состояния глазной поверхности

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