WO2018023126A1 - Methods of treating osmidrosis - Google Patents

Methods of treating osmidrosis Download PDF

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Publication number
WO2018023126A1
WO2018023126A1 PCT/US2017/044731 US2017044731W WO2018023126A1 WO 2018023126 A1 WO2018023126 A1 WO 2018023126A1 US 2017044731 W US2017044731 W US 2017044731W WO 2018023126 A1 WO2018023126 A1 WO 2018023126A1
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Prior art keywords
seq
examples
sequence
homologous
targeted
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English (en)
French (fr)
Inventor
Roger L. Kaspar
Thomas V. BARKER
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Individual
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Priority to US16/321,583 priority Critical patent/US20210301289A1/en
Priority to EP17835426.2A priority patent/EP3491129A4/en
Priority to KR1020197005466A priority patent/KR20190123256A/ko
Priority to JP2019526209A priority patent/JP2019523302A/ja
Publication of WO2018023126A1 publication Critical patent/WO2018023126A1/en
Anticipated expiration legal-status Critical
Priority to JP2022127495A priority patent/JP2022169627A/ja
Priority to US18/131,509 priority patent/US20240167028A1/en
Priority to US18/959,170 priority patent/US20250188461A1/en
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
    • C12N15/113—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7088—Compounds having three or more nucleosides or nucleotides
    • A61K31/713—Double-stranded nucleic acids or oligonucleotides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
    • A61K48/0075—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy characterised by an aspect of the delivery route, e.g. oral, subcutaneous
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
    • A61K48/0083—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy characterised by an aspect of the administration regime
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/60—Sugars; Derivatives thereof
    • A61K8/606—Nucleosides; Nucleotides; Nucleic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q15/00—Anti-perspirants or body deodorants
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
    • C12N15/113—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing
    • C12N15/1138—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing against receptors or cell surface proteins
    • 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
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • 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
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • 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
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0021—Intradermal administration, e.g. through microneedle arrays, needleless injectors
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/10—Type of nucleic acid
    • C12N2310/11—Antisense
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
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    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/10—Type of nucleic acid
    • C12N2310/14—Type of nucleic acid interfering nucleic acids [NA]
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
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    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/10—Type of nucleic acid
    • C12N2310/14—Type of nucleic acid interfering nucleic acids [NA]
    • C12N2310/141—MicroRNAs, miRNAs
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/30—Chemical structure
    • C12N2310/31—Chemical structure of the backbone
    • C12N2310/318—Chemical structure of the backbone where the PO2 is completely replaced, e.g. MMI or formacetal
    • C12N2310/3181—Peptide nucleic acid, PNA
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/30—Chemical structure
    • C12N2310/32—Chemical structure of the sugar
    • C12N2310/323—Chemical structure of the sugar modified ring structure
    • C12N2310/3233—Morpholino-type ring

Definitions

  • Sweating is an important physiological function that helps protect the body from overheating.
  • Human sweat glands are primarily divided into two types: eccrine and apocrine.
  • the majority of sweat glands are "eccrine” sweat glands, which are distributed over the entire skin surface and found in large numbers on the soles of the feet, the palms of the hands, the face, and in the armpits.
  • Eccrine glands secrete an odorless, clear fluid that helps the body control its temperature by promoting heat loss through evaporation.
  • eccrine sweat can cause body odor.
  • eccrine sweat can soften keratin, which can lead to bacterial degradation of the keratin and a corresponding foul smell.
  • Another type of sweat gland is called the "apocrine" gland.
  • Apocrine glands have a more limited distribution on the human body and are found most abundantly in the axilla, genital skin, and breasts. They produce a thick, oily fluid that produces a characteristic body odor when it comes into contact with bacteria on the surface of the skin.
  • Osmidrosis can be challenging to treat or prevent using standard antiperspirants/deodorants.
  • many patients suffering from this condition resort to alternative treatments such as microwave destruction of apocrine glands, botulinum toxin injections, and/or laser destruction of apocrine glands.
  • microwave destruction of apocrine glands such as microwave destruction of apocrine glands, botulinum toxin injections, and/or laser destruction of apocrine glands.
  • surgical removal of the apocrine glands by a radical surgical procedure is viewed as the best solution for osmidrosis.
  • FIG. 1 is a graph illustrating siRNA-mediated inhibition of ABCClla gene expression in human HepG2 cells, in accordance with one aspect of the present disclosure.
  • subject refers to a mammal that can benefit from treatment with an ABCC11 inhibitor.
  • a benefit can be obtained if the subject has a disease or condition, or is at risk of developing a disease or condition for which an ABCCl l inhibitor is a therapeutically effective treatment or preventative measure.
  • such subject may be a human.
  • the terms “treat,” “treatment,” or “treating” when used in conjunction with the administration of an ABCCl l inhibitor, such as an siRNA that targets the ABCCl l gene, including compositions and dosage forms thereof, refers to administration to subjects who are either asymptomatic or symptomatic.
  • “treat,” “treatment,” or “treating” can be to reduce, ameliorate or eliminate symptoms associated with a condition present in a subject, or can be prophylactic, (i.e. to prevent or reduce the occurrence of the symptoms in a subject).
  • prophylactic treatment can also be referred to as prevention of the condition. Treatment outcomes can be expected or unexpected.
  • a treatment outcome can be a delay in occurrence or onset of a disease or conditions or the signs or symptoms thereof.
  • a treatment can be reducing, ameliorating, eliminating, or otherwise providing a subject with relief from (i.e. relieving) the condition with which they are afflicted, or providing relief from signs or symptoms of the condition.
  • a "therapeutic agent,” “drug,” or “active agent” refers to an agent or compound that has a desired or intended biological effect (e.g. beneficial or positive) on a subject when administered to the subject in an appropriate or effective amount.
  • an ABCCl 1 inhibitor can be a therapeutic agent.
  • ABCCl 1 inhibitor or "ABCCll gene-inhibiting agent” refer to agents or compounds that are effective in inhibiting expression of the ABCCl l protein (e.g. the wild type ABCCl l protein).
  • ABCCll is the human ATP-binding cassette (ABC) transport gene and encodes an ATP-driven efflux pump protein.
  • ABCCl l is involved in cellular export of precursor odorants.
  • Examples of ABCCl 1 inhibitors include but are not limited to siRNAs, miRNAs, antisense oligonucleotides, ribozymes, peptide nucleic acids, morpholinos, small molecule inhibitors, the like, or combinations thereof. Expression of the wildtype ABCCll gene could alternatively be blocked by permanent genetic manipulations including homologous recombination, CRISPR/Cas9 gene editing and the like.
  • the terms “inhibit” or “inhibiting” are used to refer to a variety of inhibition techniques.
  • the terms “inhibit” or “inhibiting” can refer to pre- and/or post- transcriptional inhibition.
  • pre-transcription inhibition With respect to pre-transcription inhibition,
  • inhibitor or “inhibiting” can refer to preventing or reducing transcription of a gene, inducing altered transcription of a gene, and/or reducing a rate of transcription of a gene, whether permanent, semi-permanent, or transient.
  • inhibitor or “inhibiting” can refer to permanent changes to the DNA, whereas in other examples no permanent change to the DNA is made.
  • post-transcriptional inhibition With respect to post-transcriptional inhibition,
  • inhibitor or “inhibiting” can refer to preventing or reducing translation of a genetic sequence to a protein, inducing an altered translation of a genetic sequence to an altered protein (e.g. as misfolded protein, etc.), and/or reducing a rate of translation of a genetic sequence to a protein, whether permanent, semi-permanent, or transient.
  • inhibit or “inhibiting” can refer to pre-transcriptional inhibition.
  • inhibit” or “inhibiting” can refer to post-transcriptional inhibition.
  • the type of inhibition can depend on the specific type(s) of inhibitor(s) or therapeutic agent(s) employed.
  • “inhibit” or “inhibiting” can include any decrease in expression of a gene as compared to native expression, whether pre- or post- transcriptional, partial or complete.
  • formulation and “composition” are used interchangeably and refer to a mixture of two or more compounds, elements, or molecules. In some aspects the terms “formulation” and “composition” may be used to refer to a mixture of one or more active agents with a carrier or other excipients. Compositions can take nearly any physical state, including solid, liquid (i.e. solution), or gas. Furthermore, the term “dosage form” can include one or more formulation(s) or composition(s) provided in a format for administration to a subject. In one example, a composition can be a preparation that releases or otherwise administers an ABCC11 inhibitor.
  • an “effective amount,” “therapeutically effective amount,” or “therapeutically effective rate(s)” of an active ingredient refer to a non-toxic, but sufficient amount or delivery rate of the active ingredient or therapeutic agent, to achieve therapeutic results in treating a disease or condition for which the drug or therapeutic is being delivered. It is understood that various biological factors may affect the ability of a substance to perform its intended task. Therefore, an “effective amount,” “therapeutically effective amount,” or “therapeutically effective rate(s)” may be dependent in some instances on such biological factors. Further, while the achievement of therapeutic effects may be measured by a physician or other qualified medical personnel using evaluations known in the art, it is recognized that individual variation and response to treatments may make the achievement of therapeutic effects a subjective decision. The determination of a therapeutically effective amount or delivery rate is well within the ordinary skill in the art of pharmaceutical sciences and medicine. See, for example, Meiner and Tonascia,
  • osmidrosis-reducing amount or “odor-reducing amount” of an ABCCl l inhibitor, such as siRNA, and/or other suitable therapeutic agent refers to a sufficient amount or concentration of an ABCCl l inhibitor and/or other suitable therapeutic agent in a formulation or composition to provide an intended effect and/or achieve an intended result when administered to a subject.
  • an "osmidrosis- reducing amount” or “odor-reducing amount” of an ABCCl l inhibitor and/or other suitable therapeutic agent may be an amount sufficient to treat a particular target indication, e.g.
  • an "osmidrosis-reducing amount” or “odor-reducing amount” can be an amount that induces inhibition of expression of the ABCCll gene in a target cell by at least a target amount.
  • an "osmidrosis-reducing amount” or “odor-reducing amount” can be an amount that reduces apocrine sweat production and/or output in a subject by at least a target amount.
  • an "osmidrosis- reducing amount” or “odor-reducing amount” can be an amount that reduces bacterial loading (e.g. colony forming units [CFU] per unit area) and/or activity on a skin surface by at least a target amount.
  • skin As used herein, “skin,” “skin surface,” “derma,” “epidermis,” and similar terms are used interchangeably, and refer to not only the outer skin of a subject comprising the epidermis, but also to underlying layers and to mucosal surfaces.
  • a “dosing regimen” or “regimen” such as “treatment dosing regimen,” or a “prophylactic dosing regimen,” refers to how, when, how much, and for how long a dose of a composition can or should be administered to a subject in order to achieve an intended treatment or effect.
  • the term “topical formulation” refers to a formulation that may be applied to skin or a mucosa. Topical formulations may, for example, be used to treat a subject by delivering an active agent or drug, such as an ABCCl l inhibitor. Topical formulations can be used for both topical and transdermal administration of substances.
  • topical formulations include but are not limited to ointments, creams, lotions, gels, and pastes.
  • topical administration is used in its conventional sense to mean delivery of a substance, such as a therapeutically active agent, to the skin or a localized region of a subject's body.
  • Topical administration of a drug, such as an ABCC11 inhibitor may often be advantageously applied in, for example, the treatment of osmidrosis in a subject's skin. While topical administration can be for the purpose of treating a local area or region of tissue, such as skin, topical administration can also be for the purpose of providing transdermal administration.
  • transdermal administration refers to administration through the skin. Transdermal administration is often applied where systemic delivery of an active is desired, although it may also be useful for delivering an active to tissues underlying the skin with minimal systemic absorption.
  • carrier and “pharmaceutically acceptable carrier” may be used interchangeably, and refer to any liquid, gel, salve, solvent, liquid, diluent, fluid ointment base, liposome, micelle, giant micelle, or the like, or any other suitable carrier that is suitable for delivery of a therapeutic agent to and/or into a target cell (e.g. an apocrine cell) and for use in contact with a subject or the subject's tissue without causing adverse physiological responses, and which does not interact with the other components of the composition in a deleterious manner.
  • a number of carrier ingredients are known for use in making topical formulations, such as gelatin, polymers, fats and oils, lecithin, collagens, alcohols, water, etc.
  • the term “substantially” refers to the complete or nearly complete extent or degree of an action, characteristic, property, state, structure, item, or result.
  • an object that is “substantially” enclosed would mean that the object is either completely enclosed or nearly completely enclosed.
  • the exact allowable degree of deviation from absolute completeness may in some cases depend on the specific context. However, generally speaking the nearness of completion will be so as to have the same overall result as if absolute and total completion were obtained.
  • the use of “substantially” is equally applicable when used in a negative connotation to refer to the complete or near complete lack of an action, characteristic, property, state, structure, item, or result.
  • compositions that is "substantially free of particles would either completely lack particles, or so nearly completely lack particles that the effect would be the same as if it completely lacked particles.
  • a composition that is “substantially free of an ingredient or element may still actually contain such item as long as there is no measurable effect thereof.
  • the term “about” is used to provide flexibility to a numerical range endpoint by providing that a given value may be “a little above” or “a little below” the endpoint. Unless otherwise stated, use of the term “about” in accordance with a specific number or numerical range should also be understood to provide support for such numerical terms or range without the term “about”.
  • the human ATP -binding cassette (ABC) transport gene (ABCC11), having the gene sequence of SEQ ID NO: 1, encodes an ATP-driven efflux pump protein that has a key role in secretion of components of cerumen (earwax) and body odor precursors from apocrine glands.
  • ABC11 The human ATP -binding cassette (ABC) transport gene (ABCC11), having the gene sequence of SEQ ID NO: 1, encodes an ATP-driven efflux pump protein that has a key role in secretion of components of cerumen (earwax) and body odor precursors from apocrine glands.
  • earwax cerumen
  • body odor precursors from apocrine glands.
  • SNP single-nucleotide polymorphism
  • ABCC11 SNP has both osmidrosis and the earwax type.
  • a dominant inheritance pattern of the GG or GA genotypes is a wet type earwax phenotype and osmidrosis, while the recessive AA genotype results in the dry type earwax phenotype and no osmidrosis.
  • the wildtype ABCCl l protein is N-linked glycosylated, whereas the SNP version is not. Therefore, the lack of N-linked glycosylation results in recognition of the SNP-encoded version as a misfolded protein, with resultant ubiquitination and proteosomal degradation.
  • a method of treating osmidrosis can include inhibiting ABCCll gene expression.
  • inhibiting ABCCll gene expression can include administration of inhibitors such as small interfering RNAs (siRNAs), micro RNAs (miRNAs), morpholinos, antisense oligonucleotides (ASOs), peptide nucleic acids, small molecule inhibitors, the like, or combinations thereof that temporarily inhibit ABCCll expression.
  • a method of inhibiting ABCCll gene expression can include gene therapy. Gene therapy (e.g. homologous recombination, CRISPR/Cas9 gene editing, etc.) can be used to permanently alter the DNA to prevent expression of ABCCll.
  • a method of treating osmidrosis can include both administering an inhibitor and gene therapy.
  • the present invention provides a method of treating a subject with osmidrosis by administering to the subject an RNA sequence that inhibits the expression of the gene encoding the ABCCl l protein (e.g. wildtype ABCCl l).
  • an RNA sequence that inhibits the expression of the gene encoding the ABCCl l protein e.g. wildtype ABCCl l.
  • methods of treating osmidrosis can include identifying a gene that contributes to osmidrosis and inhibiting gene expression contributing to osmidrosis in a target cell. In some additional examples, methods of treating osmidrosis can further include preparing an inhibitor to be administered to a subject having osmidrosis.
  • the gene that contributes to osmidrosis can be or include ABCC11. A variety of segments or sequences of the ABCCll gene can be targeted using a therapeutic agent to inhibit expression of the ABCCll gene, whether the inhibition is permanent, semi-permanent, or transient. For example, one or more of the gene sequences listed in Table 1 below can be targeted to inhibit ABCC11 gene expression:
  • one or more of SEQ ID NOs: 2-325, or portions thereof can be targeted to inhibit expression of the ABCCll gene.
  • two or more of SEQ ID NOs: 2-325, or portions thereof can be targeted to inhibit expression of the ABCCll gene.
  • three or more, four or more, five or more, or ten or more of SEQ ID NOs: 2-325, or portions thereof can be targeted to inhibit expression of the ABCCll gene.
  • each of SEQ ID NOs: 2-325, or portions thereof can be targeted to inhibit expression of the ABCCll gene.
  • SEQ ID NO: 2, or a portion thereof can be targeted.
  • SEQ ID NO: 3, or a portion thereof can be targeted.
  • SEQ ID NO: 4, or a portion thereof can be targeted.
  • SEQ ID NO: 5, or a portion thereof can be targeted.
  • SEQ ID NO: 6, or a portion thereof can be targeted.
  • SEQ ID NO: 7, or a portion thereof can be targeted.
  • SEQ ID NO: 8, or a portion thereof can be targeted.
  • SEQ ID NO: 9, or a portion thereof can be targeted.
  • SEQ ID NO: 10 or a portion thereof can be targeted.
  • SEQ ID NO: 11 or a portion thereof can be targeted.
  • SEQ ID NO: 12, or a portion thereof can be targeted.
  • SEQ ID NO: 13, or a portion thereof can be targeted.
  • SEQ ID NO: 14, or a portion thereof can be targeted.
  • SEQ ID NO: 15, or a portion thereof can be targeted.
  • SEQ ID NO: 16, or a portion thereof can be targeted.
  • SEQ ID NO: 17, or a portion thereof can be targeted.
  • SEQ ID NO: 18, or a portion thereof can be targeted.
  • SEQ ID NO: 19, or a portion thereof can be targeted.
  • SEQ ID NO: 20, or a portion thereof can be targeted.
  • SEQ ID NO: 21, or a portion thereof can be targeted.
  • SEQ ID NO: 22, or a portion thereof can be targeted.
  • SEQ ID NO: 23, or a portion thereof can be targeted.
  • SEQ ID NO: 24, or a portion thereof can be targeted.
  • SEQ ID NO: 25, or a portion thereof can be targeted.
  • SEQ ID NO: 26, or a portion thereof can be targeted.
  • SEQ ID NO: 27, or a portion thereof can be targeted.
  • SEQ ID NO: 28 or a portion thereof can be targeted.
  • SEQ ID NO: 29, or a portion thereof can be targeted.
  • SEQ ID NO: 30, or a portion thereof can be targeted.
  • SEQ ID NO: 31, or a portion thereof can be targeted.
  • SEQ ID NO: 32, or a portion thereof can be targeted.
  • SEQ ID NO: 33, or a portion thereof can be targeted.
  • SEQ ID NO: 34, or a portion thereof can be targeted.
  • SEQ ID NO: 35, or a portion thereof can be targeted.
  • SEQ ID NO: 36, or a portion thereof can be targeted.
  • SEQ ID NO: 37, or a portion thereof can be targeted.
  • SEQ ID NO: 38, or a portion thereof can be targeted.
  • SEQ ID NO: 39, or a portion thereof can be targeted.
  • SEQ ID NO: 40, or a portion thereof can be targeted.
  • SEQ ID NO: 41, or a portion thereof can be targeted.
  • SEQ ID NO: 42, or a portion thereof can be targeted.
  • SEQ ID NO: 43, or a portion thereof can be targeted.
  • SEQ ID NO: 44, or a portion thereof can be targeted.
  • SEQ ID NO: 45, or a portion thereof can be targeted.
  • SEQ ID NO: 46, or a portion thereof can be targeted.
  • SEQ ID NO: 47, or a portion thereof can be targeted.
  • SEQ ID NO: 48, or a portion thereof can be targeted.
  • SEQ ID NO: 49, or a portion thereof can be targeted.
  • SEQ ID NO: 50, or a portion thereof can be targeted.
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  • ABCCl l inhibitors are a potential class of pharmaceutically active agents that can be useful in treating a variety of conditions or symptoms.
  • An example of such a symptom is osmidrosis.
  • ABCCl l inhibitors can be administered in a variety of ways, including, but not limited to, oral, topical, intravenous, intrathecal, intradermal, and transdermal administration. Therefore, ABCCl l inhibitors can be used to treat osmidrosis symptoms both systemically and in targeted regions or areas of a subject's body. For example, a subject may experience osmidrosis due to expression of the wildtype ABCC11 gene. Accordingly, an ABCC11 inhibitor can be administered as a first line of treatment to reduce odor.
  • the situs can include the axillary region (e.g. armpits), the pectoral region (e.g. chest/breasts), or the genital region.
  • inhibitors or therapeutic agents can be those used for gene therapy.
  • CRISPR-Cas9 systems can be employed. For example, by delivering a Cas9 nuclease complexed with a synthetic guide RNA into a cell, the cell's genome can be cut as a desired location, allowing existing genes to be removed and/or altered genes to be added.
  • a CRISPR-Cas9 system can be administered to an individual having a GG or GA genotype to remove this particular version of the ABCCll gene and replace it with a version that includes the SNP version (538G- ⁇ A, Glyl80Arg, rsl7822931) of the gene.
  • a therapeutic nucleotide including the rs 17822931 SNP can be introduced into a target cell via a viral vector or via non-viral methods.
  • any suitable viral vector can be employed.
  • Non-limiting examples can include adenovirus, adeno- associated virus, retrovirus, lentivirus, herpes simplex, vaccinia, the like, or combinations thereof.
  • any suitable non-viral method can additionally or alternatively be employed.
  • Non-limiting examples of non-viral methods can include electroporation, iontophoresis sonoporation, magnetofection, use of carriers (e.g. polymeric, dendritic, liposomic, etc.), gene gun, injection (including by arrays of microneedles) of naked or modified nucleotides, the like, or combinations thereof.
  • inhibitors or therapeutic agents can include siRNAs, miRNAs, morpholinos, ASOs, peptide nucleic acids, small molecule inhibitors, analogues thereof, derivatives thereof, the like, or combinations thereof.
  • any therapeutic agent that can inhibit the expression of the ABCCll gene or facilitate targeted degradation of the ABCCl l protein can be used.
  • the inhibitor can include an siRNA.
  • the inhibitor can include an miRNA.
  • the inhibitor can include a morpholino.
  • the inhibitor can include an ASO.
  • the inhibitor can include a peptide nucleic acid.
  • the inhibitor can include a small molecule inhibitor.
  • the inhibitor can include an RNA sequence, such as an siRNA, miRNA, morpholino, ASO, analogues thereof, derivatives thereof, the like, or a combination thereof.
  • the RNA sequence can be administered to a target cell of a subject having osmidrosis.
  • Target cells can include any suitable apocrine target cell.
  • the target cells can be or include any suitable ductal epithelial apocrine cell.
  • target cells can include axillary apocrine cells, pectoral apocrine cells, genital apocrine cells, or a combination thereof.
  • the prepared inhibitory sequences can vary in length but generally are from about 15 to 31 bases in length. In some examples, these prepared sequences can be siRNAs. A variety of siRNAs can be used, such as one or more (i.e. any suitable combination) of those listed in Table 2 below:
  • GAAAAUCUGUGAAAAUGGAAC 635 UUAACUCACUGUGAGUUCCAU 636

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US16/321,583 US20210301289A1 (en) 2016-07-29 2017-07-31 Methods of treating osmidrosis
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JP2022127495A JP2022169627A (ja) 2016-07-29 2022-08-10 腋臭を治療する方法
US18/131,509 US20240167028A1 (en) 2016-07-29 2023-04-06 Methods of treating osmidrosis
US18/959,170 US20250188461A1 (en) 2016-07-29 2024-11-25 Methods of treating osmidrosis

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CN110124042A (zh) * 2019-05-28 2019-08-16 赵叶莲 不含铝的抑制腋臭的组合物
JPWO2021033773A1 (enExample) * 2019-08-21 2021-02-25
WO2021033773A1 (ja) * 2019-08-21 2021-02-25 国立大学法人東京大学 Ａｂｃｃ１１阻害剤
US20220288038A1 (en) * 2019-08-21 2022-09-15 The University Of Tokyo Abcc11 inhibitor
JP7440934B2 (ja) 2019-08-21 2024-02-29 国立大学法人 東京大学 Ａｂｃｃ１１阻害剤
WO2021257630A3 (en) * 2020-06-15 2022-02-10 Cutler Richelle Drugs and methods for reducing body odor and sweat
WO2024104663A1 (en) 2022-11-16 2024-05-23 Unilever Ip Holdings B.V. Method of reducing malodour

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