WO2018175885A1 - Procédé de sélection d'embryon - Google Patents

Procédé de sélection d'embryon Download PDF

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Publication number
WO2018175885A1
WO2018175885A1 PCT/US2018/024023 US2018024023W WO2018175885A1 WO 2018175885 A1 WO2018175885 A1 WO 2018175885A1 US 2018024023 W US2018024023 W US 2018024023W WO 2018175885 A1 WO2018175885 A1 WO 2018175885A1
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WIPO (PCT)
Prior art keywords
orp
egg
measured
fertilized egg
value
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PCT/US2018/024023
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English (en)
Inventor
David Bar-Or
Raphael Bar-Or
Charles DORSEY
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Aytu Bioscience, Inc.
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Application filed by Aytu Bioscience, Inc. filed Critical Aytu Bioscience, Inc.
Publication of WO2018175885A1 publication Critical patent/WO2018175885A1/fr

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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N27/00—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means
    • G01N27/26—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating electrochemical variables; by using electrolysis or electrophoresis
    • G01N27/416—Systems
    • G01N27/4166—Systems measuring a particular property of an electrolyte
    • G01N27/4168—Oxidation-reduction potential, e.g. for chlorination of water

Definitions

  • the present invention relates to methods using the oxidation-reduction potential (ORP) of a fluid sample containing a fertilized egg to improve the success rate of in vitro fertilization procedures.
  • ORP oxidation-reduction potential
  • IVF in vitro fertilization
  • the fertilized eggs are then typically cultured for another 2 (cleavage stage) to 5 (blastocyst stage) days at which time the most promising zygotes (or blastocysts) are transferred to the recipient's uterus, where they implant and develop.
  • An oxidation-reduction potential (ORP) of an egg and/or the medium in which the egg is cultured is measurement of the oxidation- reduction potential (ORP) of an egg and/or the medium in which the egg is cultured.
  • ORP oxidation- reduction potential
  • An oxidation-reduction system, or redox system involves the transfer of electrons from a reductant to an oxidant according to the following equation:
  • E(ORP) Eo - ⁇ /nF In [reductant]/[oxidant] (2) where R (gas constant), T (temperature in degrees Kelvin) and F (Faraday constant) are constants.
  • E 0 is the standard potential of a redox system measured with respect to a hydrogen electrode, which is arbitrarily assigned an E 0 of 0 volts, and n is the number of electrons transferred. Therefore, ORP is dependent on the total concentrations of reductants and oxidants, and ORP is an integrated measure of the balance between total oxidants and reductants in a particular system.
  • ORP oxidation-reduction potentials
  • Oxidative stress in animals results from an alteration in the relative balance between reductants and oxidants in the animal. Such an alteration in the balance can result from higher production of reactive oxygen and reactive nitrogen species, or a decrease in endogenous protective antioxidative capacity.
  • oxidative stress has been shown to be associated with various diseases and aging, has been found to occur in all types of illnesses, and has been shown to affect numerous biological processes including conception and pregnancy.
  • Oxidative stress in patients has been evaluated by measuring various individual markers. See, e.g., Veglia et al., Biomarkers, 11(6): 562-573 (2006); Roth et al., Current Opinion in Clinical Nutrition and Metabolic Care, 7: 161-168 (2004); U.S. Patent No. 5,290,519 and U.S. Patent Publication No. 2005/0142613.
  • such measurements are often unreliable and provide conflicting and variable measurements of the oxidative status of a patient. See Veglia et al., Biomarkers, 11(6): 562-573 (2006); Roth et al., Current Opinion in Clinical Nutrition and Metabolic Care, 7: 161-168 (2004).
  • One embodiment of the invention is a method of selecting a fertilized egg for implantation in an in vitro fertilization procedure, comprising measuring the oxidation- reduction potential (ORP) of medium in which the fertilized egg is being cultured, at a optimal time after fertilization; comparing the measured ORP to a reference value; and selecting and preparing the egg for implantation in an IVF procedure based on the comparison.
  • ORP oxidation- reduction potential
  • the egg is selected for transfer.
  • the step of measuring is conducted on day 3, 4, 5, or 6, after fertilization.
  • the measured ORP is static ORP (sORP).
  • the measured ORP is capacity ORP (cORP).
  • the method comprises selecting a fertilized egg from among two or more fertilized eggs under consideration, wherein the reference value comprises the measured ORP values of the two or more fertilized eggs under consideration, and wherein the step of selecting comprises selecting the fertilized egg with the lowest ORP value.
  • One embodiment of the invention is a method of determining the quality of a fertilized egg, comprising measuring the oxidation-reduction potential (ORP) of medium in which the fertilized egg is being cultured, at a specific time after fertilization;
  • the measured ORP value is less than, or equal to, a pre-determined reference value, the egg is identified as being of high quality. In certain aspects, if the measured ORP value is greater than a predetermined reference value, the egg is identified as being of low quality.
  • One embodiment of the invention is a method of determining when to transfer a fertilized egg in an in vitro fertilization procedure, comprising measuring the oxidation- reduction potential (ORP) of medium in which the fertilized egg is being cultured, at a specific time after fertilization; comparing the measured ORP to a reference value; and deciding to transfer the egg, or not, based on the comparison.
  • ORP oxidation- reduction potential
  • the measured ORP value is greater than, or equal to, a pre-determined reference value
  • the egg is transferred.
  • the measured ORP value is less than a pre-determined reference value, the egg is not transferred, and may be incubated for an additional amount of time.
  • One embodiment of the invention is a method of improving the likelihood that a fertilized egg will establish and maintain a successful pregnancy in an IVF procedure, comprising measuring the oxidation-reduction potential (ORP) of medium in which the fertilized egg is being cultured, at a specific time after fertilization; comparing the measured ORP to a reference value; and, based on the comparison, treating the fertilized egg, or the medium in which it is incubated, to improve the ORF characteristics of the egg.
  • ORP oxidation-reduction potential
  • the medium being tested can come from a fertilized egg that was cryogenically stored, thawed and cultured. Such samples are well known in the field of reproductive biology. Moreover, it is appreciated that cryogenic storage involves the use of cryoprotectant agents, such as glycerol and dimethyl sulfoxide. Recent evidence suggests that certain cryoprotectants may affect stored cells. Thus, methods of the present invention can also be used to determine the effect of storage on fertilized egg competence and to identify useful methods and compositions for such storage. In one embodiment, the ORP characteristics are used to measure the effect of various storage conditions on fertilized egg competence. In certain embodiments, the storage conditions are varied by the addition of antioxidants, such as for example, ascorbic acid and a-tocopherol.
  • Fig. 1 Shows the correlation between sORP and embryo score (ES) for all embryos in group.
  • Fig. 2 shows the correlation between sORP and ES at 48 hours.
  • Fig. 3 shows the correlation between sORP and ES at 72 hours.
  • Fig. 4 shows the correlation between sORP and ES at 96 hours.
  • the present invention relates to a method of selecting one or more fertilized eggs for transfer in an IVF procedure. It also relates to the timing of embryo transfer, and a method of improving the likelihood that a fertilized egg will implant and develop normally in an in vitro fertilization procedure. Specifically, the present invention is based on using the ORP value of medium in which a fertilized egg has been cultured, to determine which fertilized egg(s) is/are most likely to successfully implant in the uterus, and to proceed through normal, in utero, development. The inventor has unexpectedly discovered that, not only can the ORP measurement be used to select fertilized eggs for transfer, but that the timing of such measurement is important for selecting those fertilized eggs having the highest potential for successful implantation and normal development.
  • the present invention can generally be practice by measuring the oxidation-reduction potential (ORP) of medium in which a fertilized egg has been cultured, at an optimal time after fertilization, comparing the measured ORP value to a reference value, and selecting fertilized eggs to be transferred based on the comparison.
  • the reference value can be an ORP value that is known to be associated with eggs that implant successfully, develop normally, and result in successful delivery of a baby.
  • the ORP is measured at 3, 4, 5 or 6 days post-fertilization.
  • the measured ORP is static ORP (sORP).
  • the measured ORP is capacity ORP (cORP).
  • nucleic acid molecule refers to one or more nucleic acid molecules.
  • the terms “a”, “an”, “one or more” and “at least one” can be used interchangeably.
  • the terms “comprising”, “including” and “having” can be used interchangeably.
  • the claims may be drafted to exclude any optional element. As such, this statement is intended to serve as antecedent basis for use of such exclusive terminology as “solely,” “only” and the like in connection with the recitation of claim elements, or use of a “negative” limitation.
  • the terms, egg, oocyte, ovum, and the like can be used interchangeably to refer to a female reproductive cell that has not yet been fertilized.
  • the terms sperm and spermatozoa can be used interchangeably to refer to a male reproductive cell.
  • fertilized egg and zygote can be used interchangeably, and refer to a cell that has been produced by the union of an egg and a sperm cell.
  • the phrase "egg quality", and the like refers to the ability of a fertilized egg to establish and maintain a viable pregnancy.
  • a fertilized egg having a high quality is more likely than not to divide appropriately, maintain a diploid state, successfully implant in the endometrium of the uterus, and proceed to at least the fetal stage of development.
  • a fertilized egg that is determined to have a high quality rating is also more likely than not to develop normally.
  • a fertilized egg that is determined to be of low quality is more likely than not to be unable to complete at least one of the above-listed steps. Transfer of low quality eggs often results in spontaneous termination of a pregnancy prior to the fetal stage of development.
  • ORP characteristics generally refers to the ORP value of a sample, such as the egg or medium in which the egg is cultured.
  • ORP characteristics can include the change in an ORP value over time.
  • the ORP can be cORP, sORP, or a combination of both.
  • static ORP refers to a measure of the balance between total oxidants and reductants in a biological system.
  • capacity ORP refers to the amount of antioxidant reserves present in a system. sORP and cORP are described in U.S. patent NO. 9,360,446, which is incorporated herein by reference.
  • ORP ORP value that differs from another ORP value by at least greater than 5%, and preferably at least 10%.
  • approximately refers to a difference in ORP values of 5% or less.
  • One embodiment of the present invention is a method for assessing the quality of a fertilized egg, the method comprising measuring the ORP characteristics of a sample of the medium in which the fertilized egg is cultured, at a particular time, and evaluating if the ORP characteristics are significantly different from the ORP characteristics of a reference ORP value. The quality of the fertilized egg is then determined from this evaluation.
  • a measured ORP value greater than a pre-determined reference ORP (threshold ORP) value, or cut-off value indicates the egg is of low quality.
  • a measured ORP value less than a pre-determined reference ORP (threshold ORP) value, or cut-off value indicates the egg is of high quality.
  • a measured ORP value less than, but approximately equal to a pre-determined reference ORP value indicates the egg is of optimal quality.
  • the threshold ORP value represents an ORP value above which, the chance of establishing and maintaining a successful pregnancy, is significantly reduced compared to the chance of establishing and maintaining a successful pregnancy observed at the threshold, or lower, ORP values.
  • the threshold ORP value represents an ORP value below which, the egg being measured is likely to establish and maintain a successful pregnancy.
  • the threshold ORP can be determined, for example, from historical ORP data obtained from previous successes or failures in transferring fertilized eggs.
  • the measured ORP is greater than the reference ORP, the egg is identified being of low quality.
  • the measured ORP is less than, or equal to, the reference ORP, the egg is identified being of high quality.
  • the egg is selected, prepared and transferred into a uterus.
  • the inventors have unexpected found that the timing of measuring the medium
  • the fertilized egg being tested is a zygote. In certain aspects, the fertilized egg being tested has reached the cleavage stage. In certain aspects, the fertilized egg is a blastocyst. In certain aspects, the fertilized egg is a morula. In certain aspects, the fertilized egg is a blastula. In certain aspects, the fertilized egg is a blastocyst.
  • the ORP value of the medium is determined at least two days post-fertilization. In certain aspects, the ORP value of the medium is determined at least three days post-fertilization. In certain aspects, the ORP value of the medium is determined at least four days post-fertilization. In certain aspects, the ORP value of the medium is determined at least five days post-fertilization. In certain aspects, the ORP value of the medium is determined at least six days post-fertilization.
  • the ORP characteristics of the culture medium may be checked at suitable intervals.
  • the ORP characteristics of the medium in which the egg has been cultured can be checked every 30 minutes, hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 12 hours or 18 hours.
  • the change and/or the rate of change in ORP over time is determined.
  • One embodiment of the invention is a method of selecting a fertilized egg for implantation in an in vitro fertilization procedure, the method comprising measuring the oxidation-reduction potential (ORP) characteristics of medium in which a fertilized egg is cultured, at a particular time; comparing the measured ORP to a reference value; and selecting and preparing the egg for transfer in an IVF procedure based on the comparison.
  • ORP oxidation-reduction potential
  • a measured ORP value greater than a pre-determined reference ORP (threshold ORP) value, or cut-off value indicates the egg is of low quality.
  • the threshold ORP value represents an ORP value above which, the chance of establishing and maintaining a successful pregnancy, is significantly reduced compared to the chance of establishing and maintaining a successful pregnancy observed at the threshold, or lower, ORP values.
  • the threshold ORP value represents an ORP value below which, the egg being measured is likely to establish and maintain a successful pregnancy.
  • the threshold ORP can be determined, for example, from historical ORP data obtained from previous successes or failures in transferring fertilized eggs.
  • the measured ORP is significantly lower than, or equal to, the reference ORP, the egg being measured is selected for transfer.
  • the measured ORP is significantly higher than the reference ORP, the egg is not selected for transfer.
  • the egg is transferred into a uterus.
  • the method comprises selecting a fertilized egg from among two or more fertilized eggs under consideration, wherein the reference value comprise the measured ORPs of the two or more fertilized eggs under consideration, and wherein the step of selecting comprises selecting the fertilized egg with the lowest ORP value.
  • the fertilized egg being tested is a zygote. In certain aspects, the fertilized egg being tested has reached the cleavage stage. In certain aspects, the fertilized egg is a blastocyst. In certain aspects, the fertilized egg is a morula. In certain aspects, the fertilized egg is a blastula. In certain aspects, the fertilized egg is a blastocyst.
  • the ORP value of the medium is determined at least two days post-fertilization. In certain aspects, the ORP value of the medium is determined at least three days post-fertilization. In certain aspects, the ORP value of the medium is determined at least four days post-fertilization. In certain aspects, the ORP value of the medium is determined at least five days post-fertilization. In certain aspects, the ORP value of the medium is determined at least six days post-fertilization.
  • the ORP characteristics of the culture medium may be checked at suitable intervals.
  • the ORP characteristics of the medium in which the egg has been cultured can be checked every 30 minutes, hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 12 hours or 18 hours.
  • ORP characteristics can include the change in an ORP value over time.
  • the ORP can be cORP, sORP, or a combination of both.
  • one embodiment of the present invention is a method of improving the likelihood that a fertilized egg will establish and maintain a successful pregnancy, the method comprising measuring the ORP characteristics of a sample of the medium in which the fertilized egg is cultured, evaluating if the ORP characteristics are significantly different from the ORP characteristics of the reference ORP value, and if the ORP characteristics are significantly different from the ORP characteristics of a reference ORP value, treating the culture medium, or the fertilized egg, to improve the ORP characteristics of the fertilized egg.
  • treatment of the cultured fertilized egg can comprise treating the culture medium (e.g., with antioxidants, or other suitable compounds) to improve the ORP characteristics of the medium, or treating the egg with a compound (e.g., a pharmaceutical compound, or a natural compound) to improve the quality of the egg.
  • Treatments can include supplementing or refreshing the medium in which the egg is incubated (i.e., removing the medium and replacing it with fresh medium).
  • One embodiment of the present invention is a method determining when to transfer a fertilized egg in culture, at a particular time, the method comprising measuring the ORP characteristics of a sample from the individual, evaluating if the ORP characteristics are significantly different from the ORP characteristics of a reference ORP value, and using the evaluation to determine the optimal time for transferring the fertilized egg.
  • an increase in the ORP characteristics to a pre-determined ORP threshold value, or cut-off value indicates it is time to transfer the fertilized egg into the uterus.
  • the threshold ORP value represents an ORP value at which the fertilized egg is more likely than not to establish and maintain a successful pregnancy.
  • the threshold ORP can be determined, for example, from historical ORP data obtained from previous successes or failures in transferring fertilized eggs.
  • the egg if the measured ORP is less than the reference ORP, the egg is can, but may not be transferred. Instead, the egg may be incubated for an additional amount of time.
  • the measured ORP if the measured ORP is approximately equal to (i.e., within 5%), the reference ORP, the egg is transferred.
  • the measured ORP is greater than the reference ORP, the egg may be transferred, but such an egg has a lower likelihood of successfully implanting and developing than does an egg having a measured ORP approximately equal to the reference ORP.
  • the measured ORP if the measured ORP is greater than the reference ORP, the egg is not transferred.
  • the fertilized egg being tested is a zygote. In certain aspects, the fertilized egg being tested has reached the cleavage stage. In certain aspects, the fertilized egg is a blastocyst. In certain aspects, the fertilized egg is a morula. In certain aspects, the fertilized egg is a blastula. In certain aspects, the fertilized egg is a blastocyst.
  • the ORP value of the medium is determined at least two days post-fertilization. In certain aspects, the ORP value of the medium is determined at least three days post-fertilization. In certain aspects, the ORP value of the medium is determined at least four days post-fertilization. In certain aspects, the ORP value of the medium is determined at least five days post-fertilization. In certain aspects, the ORP value of the medium is determined at least six days post-fertilization.
  • the ORP characteristics of the culture medium may be checked at suitable intervals.
  • the ORP characteristics of the medium in which the egg has been cultured can be checked every 30 minutes, hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 12 hours or 18 hours.
  • the medium being tested can come from a fertilized egg that was cryogenically stored, thawed and cultured. Such samples are well known in the field of reproductive biology. Moreover, it is appreciated that cryogenic storage involves the use of cryoprotectant agents, such as glycerol and dimethyl sulfoxide. Recent evidence suggests that certain cryoprotectants may affect stored cells. Thus, methods of the present invention can also be used to determine the effect of storage on fertilized egg competence and to identify useful methods and compositions for such storage. In one embodiment, the ORP characteristics are used to measure the effect of various storage conditions on fertilized egg competence.
  • the storage conditions are varied by the addition of antioxidants, such as for example, ascorbic acid and a-tocopherol.
  • antioxidants such as for example, ascorbic acid and a-tocopherol.
  • This example demonstrates the use of measuring sORP levels for embryo selection in patients undergoing intracytoplasmic sperm injection (ICS!) by comparing it to the morphological assessment of the embryos.
  • ICS intracytoplasmic sperm injection
  • the morphology scoring column refers to the cleavage state. Higher numbers are indicative of higher cell cleavage. Combined with morphology grading, this guides which and how many embryos will be implanted. In the Veeck grading criteria the morphology (grade) is as follows: Grade I: blastomeres of equal size and no cytoplasmic fragments
  • Grade III blastomeres of distinctly unequal size with few to no cytoplasmic fragments
  • Grade IV blastomeres of equal or unequal size with significant cytoplasmic fragmentation
  • Grade V few blastomeres of any size and severe or complete fragmentation
  • the three-letter codes in the first column are sample identifiers.
  • oxidative stress specifically the sORP
  • the measurement of oxidative stress, specifically the sORP, in the spent culture medium using this simplified methodology is a useful method for embryo selection in patients treated with ICSI. Correlation between the ORP and the embryo score is good at 72 hours and much better at 96 hours after insemination.

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Abstract

L'invention concerne des procédés et des systèmes permettant de mesurer et d'utiliser le potentiel d'oxydoréduction (ORP) d'un échantillon biologique. Les mesures d'ORP sont utilisées afin de déterminer la qualité d'un ovocyte ou d'un œuf fertilisé. La connaissance de la qualité d'un œuf fertilisé permet la sélection des œufs les plus susceptibles de conduire à une grossesse réussie. Une telle connaissance peut également être utilisée afin de déterminer le temps optimal de transfert d'un œuf fertilisé dans l'utérus, ce qui permet d'augmenter la probabilité d'une grossesse réussie.
PCT/US2018/024023 2017-03-23 2018-03-23 Procédé de sélection d'embryon WO2018175885A1 (fr)

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US62/475,622 2017-03-23

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016009416A1 (fr) * 2014-07-18 2016-01-21 Pécsi Tudományegyetem Évaluation de viabilité d'embryons humains cultivés <i> in vitro </i> à partir du milieu de culture
WO2016085997A2 (fr) * 2014-11-25 2016-06-02 Aytu Bioscience, Inc. Détermination de potentiel de fécondité à partir du potentiel d'oxydoréduction d'un échantillon biologique

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016009416A1 (fr) * 2014-07-18 2016-01-21 Pécsi Tudományegyetem Évaluation de viabilité d'embryons humains cultivés <i> in vitro </i> à partir du milieu de culture
WO2016085997A2 (fr) * 2014-11-25 2016-06-02 Aytu Bioscience, Inc. Détermination de potentiel de fécondité à partir du potentiel d'oxydoréduction d'un échantillon biologique

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
AGARWAL ET AL.: "MiOXSYS: A Novel Method of Measuring Oxidation Reduction Potential in Semen and Seminal Plasma", FERTILITY AND STERILITY, vol. 106, no. 3, 31 May 2016 (2016-05-31), pages 566 - 573, XP055473604 *
OPUWARI ET AL.: "An Update on Oxidative Damage to Spermatozoa and Oocytes", BIOMED RESEARCH INTERNATIONAL, vol. 2016, 28 January 2016 (2016-01-28), pages 1 - 11, XP055543525 *
SALLAM ET AL.: "P-67: Measurement of Oxidative Stress in the Spent Culture Medium of Individual Embryos - A Possible Method for Embryo Selection", FERTILITY AND STERILITY, vol. 107, no. 3, 24 March 2017 (2017-03-24), pages e44, XP029952410 *

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