WO2018195355A1 - Topical delivery of nucleic acid compounds - Google Patents

Topical delivery of nucleic acid compounds Download PDF

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Publication number
WO2018195355A1
WO2018195355A1 PCT/US2018/028436 US2018028436W WO2018195355A1 WO 2018195355 A1 WO2018195355 A1 WO 2018195355A1 US 2018028436 W US2018028436 W US 2018028436W WO 2018195355 A1 WO2018195355 A1 WO 2018195355A1
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WIPO (PCT)
Prior art keywords
composition
subject
pharmaceutical composition
rxrna
chl
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PCT/US2018/028436
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English (en)
French (fr)
Inventor
Richard J. Looby
Melissa MAXWELL
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Phio Pharmaceuticals Corp
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RXi Pharmaceuticals Corp
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Priority to EP18788295.6A priority Critical patent/EP3612152A4/en
Priority to JP2019557353A priority patent/JP7167059B2/ja
Priority to US16/606,669 priority patent/US12544344B2/en
Publication of WO2018195355A1 publication Critical patent/WO2018195355A1/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • 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
    • A61K31/12—Ketones
    • A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • 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
    • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
    • A61K8/35—Ketones, e.g. benzophenone
    • 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
    • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
    • A61K8/36—Carboxylic acids; Salts or anhydrides thereof
    • A61K8/365—Hydroxycarboxylic acids; Ketocarboxylic acids
    • 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
    • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
    • A61K8/36—Carboxylic acids; Salts or anhydrides thereof
    • A61K8/368—Carboxylic acids; Salts or anhydrides thereof with carboxyl groups directly bound to carbon atoms of aromatic rings
    • 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
    • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
    • A61K8/37—Esters of carboxylic acids
    • 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
    • A61K8/40—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing nitrogen
    • A61K8/42—Amides
    • 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
    • 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
    • A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
    • A61K8/73—Polysaccharides
    • A61K8/731—Cellulose; Quaternized cellulose derivatives
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A61Q19/02—Preparations for care of the skin for chemically bleaching or whitening the skin
    • 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

Definitions

  • the disclosure relates, in some aspects, to compositions and methods for delivering nucleic acid molecules to the skin of a subject, for example by topical administration.
  • oligonucleotide sequences are promising therapeutic agents and useful research tools in elucidating gene functions.
  • prior art oligonucleotide molecules suffer from several problems that may impede their clinical development, and frequently make it difficult to achieve intended efficient inhibition or increase of gene expression (including protein synthesis) using such compositions in vivo.
  • RNAi compounds 19-29 bases long, form a highly negatively- charged rigid helix of approximately 1.5 by 10-15 nm in size. This rod type molecule cannot get through the cell-membrane and as a result has very limited efficacy both in vitro and in vivo. As a result, all conventional RNAi compounds require some kind of delivery vehicle to promote their tissue distribution and cellular uptake. This is considered to be a major limitation of the RNAi technology.
  • compositions and methods that are useful for delivering nucleic acid molecules to a subject, for example by topical administration.
  • the disclosure is based on the surprising discovery that therapeutic
  • oligonucleotide gel formulations comprising urea and lactic acid efficiently penetrate through the stratum corneum and into the dermis of a subject when topically applied.
  • the gel formulations are useful for treating disorders affecting the skin, scalp, nails, oral mucosa or genital mucosa of a subject in need thereof.
  • the disclosure provides a pharmaceutical composition comprising one or more therapeutic oligonucleotides, urea, and lactic acid.
  • a pharmaceutical composition further comprises a thickening agent.
  • a thickening agent is methylcellulose (MC) or hydroxypropyl cellulose (HPC).
  • a pharmaceutical composition is formulated in a gel.
  • urea is present in an amount between about 5% and about 40% w/w. In some embodiments, urea is present in an amount between about 5% and about 15% w/w, for example at about 10% w/w.
  • lactic acid is present in an amount between about 2% and about 10% w/w. In some embodiments, lactic acid is present in an amount between about 2% and about 8% w/w, for example at about 5% w/w.
  • a thickening agent is present in an amount between about 0% and about 40% w/w. In some embodiments, a thickening agent is present in an amount between about 0% and about 2%, for example at about 1% w/w.
  • a pharmaceutical composition has a pH between about 3.0 and
  • a pharmaceutical composition has a pH of about 3.5.
  • a pharmaceutical composition further comprises at least one of: a preservative (e.g., sodium benzoate), a salt (e.g., NaCl), a pH adjusting-agent (e.g., NaOH), water, or any combination of the foregoing.
  • a preservative e.g., sodium benzoate
  • a salt e.g., NaCl
  • a pH adjusting-agent e.g., NaOH
  • a pharmaceutical composition comprises at least one therapeutic oligonucleotide that targets: CTGF, VEGF, MAP4K4, PDGF-B, SPP1, TGFB 1, TGFB2, HIF- ⁇ mTOR, PTGS2 (COX-2), PPIB, IL-1 alpha, IL-1 beta, Icam-1, Tie 1, Tie 2, ANG2, Angl, MYC, TNFa, MMP1, TYR or any combination thereof.
  • a pharmaceutical composition comprises at least one therapeutic
  • a pharmaceutical composition comprises 0.1% w/w to 10% w/w therapeutic oligonucleotide.
  • a therapeutic oligonucleotide is an sd-rxRNA.
  • an sd-rxRNA targets CTGF and comprises at least 12 contiguous nucleotides of a sequence set forth in Table 1.
  • an sd- rxRNA comprises a sense strand having a sequence set forth in SEQ ID NO: 359 and an antisense strand having a sequence set forth in SEQ ID NO: 360.
  • an sd-rxRNA targets MMP1 and comprises at least 12 contiguous nucleotides of a sequence set forth in Tables 2, 3, 4, and 5. In some embodiments, an sd-rxRNA comprises a sense strand having a sequence set forth in SEQ ID NO: 540 and an antisense strand having a sequence set forth in SEQ ID NO: 569.
  • an sd-rxRNA targets TYR and comprises at least 12 contiguous nucleotides of a sequence set forth in Tables 6, 7, 8, and 9.
  • an sd-rxRNA comprises a sense strand having a sequence set forth in SEQ ID NO: 696 and an antisense strand having a sequence set forth in SEQ ID NO: 735.
  • an sd-rxRNA targets MAP4k4.
  • an sd- rxRNA comprises a sense strand having a sequence set forth in SEQ ID NO: 739 and an antisense strand having a sequence set forth in SEQ ID NO: 740.
  • an sd-rxRNA comprises a sense strand having a sequence set forth in SEQ ID NO: 741 and an antisense strand having a sequence set forth in SEQ ID NO: 742.
  • a pharmaceutical composition comprises about 1% w/w to about 2% w/w sd-rxRNA.
  • the disclosure provides a kit comprising a pharmaceutical composition as described by the disclosure, for example a kit comprising a container housing a pharmaceutical composition.
  • the disclosure provides a method for delivering a therapeutic oligonucleotide to the dermis of a subject, the method comprising topically administering a pharmaceutical composition as described by the disclosure to the subject.
  • a subject has a disease or disorder of the skin, scalp, nails, oral mucosa or genital mucosa.
  • the disclosure provides a method for treating a skin disorder in a subject, the method comprising topically administering to the subject an effective amount of a pharmaceutical composition as described by the disclosure.
  • a skin disorder is skin cancer, dermal scarring, psoriasis, morphea, post-inflammatory hyperpigmentation, lentigines, uneven skin tone, hyper- pigmentation, or photo ageing.
  • a pharmaceutical composition is administered in an amount effective to reduce expression and/or activity of one or more target genes, for example, CTGF, VEGF, MAP4K4, PDGF-B, SPP1, TGFB 1, TGFB2, HIF- ⁇ mTOR, PTGS2 (COX- 2), PPIB, IL-1 alpha, IL-1 beta, Icam-1, Tie 1, Tie 2, ANG2, Angl, MYC, TNFa, MMP1, TYR or any combination thereof.
  • administration of a pharmaceutical composition to a subject results in reduction of expression and/or activity of one or more target genes in the dermis of the subject.
  • methods described herein are for improving the cosmetic appearance of skin.
  • compositions for use in improving cosmetic appearance in a subject comprising one or more therapeutic oligonucleotides, urea, and lactic acid.
  • the composition for use in improving cosmetic appearance in a subject further comprises a thickening agent.
  • the thickening agent is methylcellulose (MC) or hydroxypropyl cellulose (HPC).
  • the composition for use in improving cosmetic appearance in a subject is formulated in a gel.
  • the urea is present in an amount between about 5% and about 40% w/w.
  • the urea is present in an amount between about 5% and about 15% w/w, optionally wherein the urea is present at about 10% w/w.
  • the lactic acid in the composition for use in improving cosmetic appearance in a subject, is present in an amount between about 2% and about 10% w/w. In some embodiments, the lactic acid is present in an amount between about 2% and about 8% w/w, optionally wherein the lactic acid is present at about 5% w/w.
  • the thickening agent in the composition for use in improving cosmetic appearance in a subject, is present in an amount between about 0% and about 40% w/w. In some embodiments, in the composition for use in improving cosmetic appearance in a subject, the thickening agent is present in an amount between about 0% and about 2%, optionally wherein the thickening agent is methylcellulose (MC), further optionally wherein the MC is present at about 1% w/w.
  • MC methylcellulose
  • the composition for use in improving cosmetic appearance in a subject has a pH between about 3.0 and 4.7. In some embodiments, the pH is about 3.5.
  • the composition for use in improving cosmetic appearance in a subject further comprises at least one of: a preservative (e.g., sodium benzoate), a salt (e.g., NaCl), a pH adjusting-agent (e.g., NaOH), water, or any combination of the foregoing.
  • a preservative e.g., sodium benzoate
  • a salt e.g., NaCl
  • a pH adjusting-agent e.g., NaOH
  • At least one of the therapeutic oligonucleotides targets CTGF, VEGF, MAP4K4, PDGF-B, SPP1, TGFB 1, TGFB2, HIF- ⁇ mTOR, PTGS2 (COX-2), PPIB, IL-1 alpha, IL-1 beta, Icam-1, Tie 1, Tie 2, ANG2, Angl, MYC, TNFa, MMP1, TYR or any combination thereof.
  • at least one of the therapeutic oligonucleotides targets a long non-coding RNA (IncRNA).
  • the composition for use in improving cosmetic appearance in a subject at least one of the therapeutic oligonucleotides is an sd-rxRNA.
  • the sd-rxRNA targets CTGF and comprises at least 12 contiguous nucleotides of a sequence set forth in Table 1.
  • the sd-rxRNA comprises a sense strand having a sequence set forth in SEQ ID NO: 359 and an antisense strand having a sequence set forth in SEQ ID NO: 360.
  • the sd-rxRNA targets MMP1 and comprises at least 12 contiguous nucleotides of a sequence set forth in Tables 2, 3, 4, and 5.
  • the sd-rxRNA comprises a sense strand having a sequence set forth in SEQ ID NO: 540 and an antisense strand having a sequence set forth in SEQ ID NO: 569.
  • the sd-rxRNA targets TYR and comprises at least 12 contiguous nucleotides of a sequence set forth in Tables 6, 7, 8, and 9.
  • the sd-rxRNA comprises a sense strand having a sequence set forth in SEQ ID NO: 696 and an antisense strand having a sequence set forth in SEQ ID NO: 735.
  • the sd-rxRNA targets MAP4k4.
  • the sd-rxRNA comprises a sense strand having a sequence set forth in SEQ ID NO: 739 and an antisense strand having a sequence set forth in SEQ ID NO: 740.
  • the sd-rxRNA comprises a sense strand having a sequence set forth in SEQ ID NO: 741 and an antisense strand having a sequence set forth in SEQ ID NO: 742.
  • the composition for use in improving cosmetic appearance in a subject comprises 0.1% w/w to 10% w/w therapeutic oligonucleotide. In some embodiments, the composition for use in improving cosmetic appearance in a subject comprises about 1% w/w to about 2% w/w sd-rxRNA.
  • FIG. 1 shows representative images of skin penetration by one embodiment of sd- rxRNA in a formulation comprising urea (e.g., 10% urea) and lactic acid (e.g., 5% lactic acid).
  • urea e.g., 10% urea
  • lactic acid e.g., 5% lactic acid
  • FIG. 2 shows representative images indicating that sd-rxRNA in formulations containing methylcellulose (MC) penetrate into the epidermal layer, and formulations containing hydroxyprolyl cellulose (HPC) penetrate to the stratum corneum, following topical administration.
  • MC methylcellulose
  • HPC hydroxyprolyl cellulose
  • FIG. 3 shows representative images indicating enhanced penetration of sd-rxRNA into epidermis and dermis following topical administration of formulations containing MC and pH adjusted to pH 3.5.
  • FIG. 4 shows representative images indicating penetration of one embodiment of a sd- rxRNA within a formulation comprising urea (e.g., 10% urea) and lactic acid (e.g., 5% lactic acid) into human skin following topical application.
  • urea e.g., 10% urea
  • lactic acid e.g., 5% lactic acid
  • FIG. 5 shows representative data comparing the Melanin Index (MI) change from baseline at each time point for RXI-231 with the time-matched MI change from baseline for vehicle.
  • MI Melanin Index
  • aspects of the invention relate to formulations of therapeutic nucleic acid molecules containing urea and lactic acid for delivery to the skin and other tisusues using topical administration.
  • nucleic acid molecules formulated as described herein were able to penetrate the stratum corneum to the epidermis and dermis of the skin.
  • Formulations described herein can be used, in some embodiments, to treat or prevent indications associated with the skin, scalp, nails, oral mucosa, and/or genital mucosa.
  • nucleic acid molecule includes but is not limited to: sd-rxRNA, rxRNAori, oligonucleotides, ASO, siRNA, shRNA, miRNA, hsiRNA, ncRNA, cp-lasiRNA, aiRNA, BMT-101, RXI-109, RXI-231, EXC-001, single- stranded nucleic acid molecules, double- stranded nucleic acid molecules, RNA and DNA.
  • the nucleic acid molecule is a chemically modified nucleic acid molecule, such as a chemically modified oligonucleotide.
  • therapeutic oligonucleotide refers to a nucleic acid molecule (e.g., an inhibitory nucleic acid molecule) that reduces expression or activity of a target gene associated with a disease or disorder.
  • therapeutic oligonucleotides include sd- rxRNA, rxRNAori, oligonucleotides, ASO, siRNA, shRNA, miRNA, hsiRNA, ncRNA, cp- lasiRNA, aiRNA, BMT-101, RXI-109, RXI-231, EXC-001, single- stranded nucleic acid molecules, double-stranded nucleic acid molecules, RNA and DNA.
  • oligonucleotides can target disease-associated genes, such as CTGF, VEGF, MAP4K4,
  • PDGF-B SPP1, TGFB 1, TGFB2, HIF- ⁇ , mTOR, PTGS2 (COX-2), PPIB, IL-1 alpha, IL-1 beta, Icam-1, Tie 1, Tie 2, ANG2, Angl, MYC, TNFa, MMP1, TYR or any combination thereof.
  • Target gene selection and production of additional therapeutic oligonucleotides may be achieved without undue experimentation by a skilled artisan.
  • an "sd- rxRNA” or an “sd-rxRNA molecule” refers to a self-delivering RNA molecule such as those described in, and incorporated by reference from, US Patent No. 8,796,443, granted on August 5, 2014, entitled “"REDUCED SIZE SELF-DELIVERING RNAI COMPOUNDS” and PCT Publication No. WO2010/033247 (Application No. PCT/US2009/005247), filed on September 22, 2009, and entitled "REDUCED SIZE SELF-DELIVERING RNAI
  • an sd-rxRNA (also referred to as an sd-rxRNA nano ) is an isolated asymmetric double stranded nucleic acid molecule comprising a guide strand, with a minimal length of 16 nucleotides, and a passenger strand of 8-18 nucleotides in length, wherein the double stranded nucleic acid molecule has a double stranded region and a single stranded region, the single stranded region having 4-12 nucleotides in length and having at least three nucleotide backbone modifications.
  • the double stranded nucleic acid molecule has one end that is blunt or includes a one or two nucleotide overhang
  • sd- rxRNA molecules can be optimized through chemical modification, and in some instances through attachment of hydrophobic conjugates.
  • an sd-rxRNA comprises an isolated double stranded nucleic acid molecule comprising a guide strand and a passenger strand, wherein the region of the molecule that is double stranded is from 8-15 nucleotides long, wherein the guide strand contains a single stranded region that is 4-12 nucleotides long, wherein the single stranded region of the guide strand contains 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 phosphorothioate modifications, and wherein at least 40% of the nucleotides of the double stranded nucleic acid are modified.
  • polynucleotides described by the disclosure are referred to herein as isolated double stranded or duplex nucleic acids, oligonucleotides or
  • polynucleotides polynucleotides, nano molecules, nano RNA, sd-rxRNA nano , sd-rxRNA or RNA molecules.
  • sd-rxRNAs are much more effectively taken up by cells compared to conventional siRNAs. These molecules are highly efficient in silencing of target gene expression and offer significant advantages over previously described RNAi molecules including high activity in the presence of serum, efficient self-delivery, compatibility with a wide variety of linkers, and reduced presence or complete absence of chemical modifications that are associated with toxicity.
  • duplex polynucleotides In contrast to single-stranded polynucleotides, duplex polynucleotides have traditionally been difficult to deliver to a cell as they have rigid structures and a large number of negative charges which makes membrane transfer difficult. sd-rxRNAs however, although partially double- stranded, are recognized in vivo as single- stranded and, as such, are capable of efficiently being delivered across cell membranes. As a result the polynucleotides described by the disclosure are capable in many instances of self-delivery. Thus, the polynucleotides described herein may be formulated in a manner similar to conventional RNAi agents, or they may be delivered to the cell or subject alone (or with non-delivery type carriers) and allowed to self-deliver. In some embodiments, self-delivering asymmetric double- stranded RNA molecules are provided in which one portion of the molecule resembles a conventional RNA duplex and a second portion of the molecule is single stranded.
  • Oligonucleotides described by the disclosure have a combination of asymmetric structures including a double stranded region and a single stranded region of 5 nucleotides or longer, specific chemical modification patterns and are conjugated to lipophilic or hydrophobic molecules.
  • This class of RNAi like compounds have superior efficacy in vitro and in vivo. It is believed that the reduction in the size of the rigid duplex region in combination with phosphorothioate modifications applied to a single stranded region contribute to the observed superior efficacy.
  • Figure 42 in US Patent No. 9,340,786 demonstrates CTGF silencing following intradermal injection of RXI-109 in vivo (Rat skin) after two intradermal injections of RXI-109 (CTGF-targeting sd-rxRNA).
  • CTGF-targeting sd-rxRNA CTGF-targeting sd-rxRNA
  • RXI-109 or non-targeting control was administered by intradermal injection (300 or 600 ug per 200 uL injection) to each of four sites on the dorsum of rats on Days 1 and 3. A 4 mm excisional wound was made at each injection site -30 min after the second dose (Day 3). Terminal biopsy samples encompassing the wound site and surrounding tissue were harvested on Day 8. RNA was isolated and subjected to gene expression analysis by qPCR. Data are normalized to the level of the TATA box binding protein (TBP) housekeeping gene and graphed relative to the PBS vehicle control set at 1.0. Error bars represent standard deviation between the individual biopsy samples. P values for RXI-109- treated groups vs dose-mathced non-targeting control groups were ** p ⁇ 0.001 for 600 ⁇ g, * p ⁇ 0.01 for 300 ⁇ g.
  • TCP TATA box binding protein
  • compositions can be administered to the skin in the same manner as the sd-rxRNA molecules disclosed in US Patent No. 9,340,786, incorporated by reference in its entirety.
  • the disclosure relates to the surprising discovery that topical administration of certain formulations of therapeutic oligonucleotides (e.g., sd-rxRNAs) comprising urea, lactic acid, and certain thickening agents (e.g., methylcellulose, "MC") to a subject.
  • therapeutic oligonucleotides e.g., sd-rxRNAs
  • MC methylcellulose
  • administration of therapeutic oligonucleotides results in delivery of the therapeutic oligonucleotides through the stratum corneum and into the dermis of the skin of the subject.
  • a pharmaceutical composition as described by the disclosure comprises urea.
  • the urea is present in an amount between 5% and about 40% w/w (e.g., about 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, or 40%, inclusive).
  • urea is present in an amount between about 5% and about 15% w/w (about 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, or 15%, inclusive). In some embodiments, urea is present in the pharmaceutical composition at about 10% w/w. In some embodiments, urea is present in the pharmaceutical composition at greater than 40% w/w.
  • a pharmaceutical composition as described by the disclosure comprises lactic acid.
  • lactic acid is present in an amount between about 2% and about 10% w/w (e.g., about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10%, inclusive).
  • lactic acid is present in an amount between about 2% and about 8% (e.g., about 2%, 3%, 4%, 5%, 6%, 7%, or 8%, inclusive).
  • lactic acid is present at about 5% w/w.
  • lactic acid is present at greater than 10% w/w.
  • a pharmaceutical composition described by the disclosure comprises a thickening agent (e.g., an agent that increases the viscosity of a liquid without substantially changing the other properties of the liquid).
  • thickening agents are polysaccharides or peptides (e.g., proteins).
  • polysaccharide thickening agents include but are not limited to sugars (e.g., agar, carrageenan, etc.), cellulose (e.g., cellulose, methylcellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, etc.) and derivates thereof, starches (e.g., corn starch, potato starch, tapioca, etc.) and derivatives thereof, vegetable gums (e.g., alginin, guar gum, xanthan gum, etc.) and derivates thereof, pectin, etc.
  • protein thickening agents include but are not limited to collagen, albumin (e.g., egg whites), gelatin, etc.
  • a thickening agent is present in an amount between about 0% and about 40% w/w (e.g., not present, present at about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, or 40% w/w, inclusive).
  • a thickening agent is present in an amount between about 0% and about 2% (e.g., not present, present at about 1%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, or about 2% w/w, inclusive).
  • a thickening agent is present in a pharmaceutical composition at about 1% w/w.
  • a thickening agent is present in a pharmaceutical composition at greater than 40% w/w.
  • the amount of active ingredient (e.g., therapeutic oligonucleotide or oligonucleotides) in a pharmaceutical composition generally depends upon the effectiveness of the active ingredient, and other factors such as the species, size (e.g., mass), target tissue, etc. of a subject. In some embodiments, the amount of therapeutic oligonucleotide in a pharmaceutical composition
  • the amount of therapeutic oligonucleotide in a pharmaceutical composition as described by the disclosure ranges from about 1% to 2% w/w (e.g., about 1.0%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%. or 2.0% w/w, inclusive). In some embodiments, the amount of therapeutic oligonucleotide in a pharmaceutical composition is greater than 10%.
  • the disclosure relates to the discovery that altering the pH of a pharmaceutical composition as described by the disclosure results in improved delivery of therapeutic oligonucleotides into the skin (e.g. the dermis) of a subject.
  • the pH of a composition may be adjusted by adding a pH adjusting agent, for example an acid (e.g., hydrochloric acid, HCl) or a base (e.g., sodium hydroxide, NaOH), to the composition until a desired pH is reached.
  • a pH adjusting agent for example an acid (e.g., hydrochloric acid, HCl) or a base (e.g., sodium hydroxide, NaOH)
  • a pharmaceutical composition has a pH between about 3.0 and 5.0 (e.g., about 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, or 5.0, inclusive). In some embodiments, a pharmaceutical composition has a pH of about 3.5.
  • a pharmaceutical composition comprises at least one additional component (e.g., a pharmaceutically acceptable excipient), for example a preservative, a salt, a pH adjusting-agent, water, or any combination of the foregoing.
  • a pharmaceutically acceptable excipient for example a preservative, a salt, a pH adjusting-agent, water, or any combination of the foregoing.
  • preservatives include but are not limited to sodium benzoate, benzoic acid, boric acid, methylparaben, ethylparaben, sodium propionate, potassium sorbate, chlorobutantol, benzyl alcohol, phenols (e.g., phenol, chlorocrescol), mercurial compounds (e.g., thiomersal, nitromersal), and quartenary ammonium compounds (e.g., benzalkonium chloride, cetyl pyridinium chloride).
  • salts include but are not limited to sodium chloride, sodium nitrite, potassium nitrite, etc. Additional examples of pharmaceutically acceptable excipients are disclosed for example in REMINGTON'S PHARMACEUTICAL SCIENCES, 18th Ed. (1990).
  • CTGF REMINGTON'S PHARMACEUTICAL SCIENCES, 18th Ed. (1990).
  • the instant disclosure relates to the use of nucleic acids, such as sd- rxRNA, targeting Connective Tissue Growth Factor (CTGF).
  • nucleic acids such as sd- rxRNA, targeting Connective Tissue Growth Factor (CTGF).
  • CTGF Connective Tissue Growth Factor
  • CTGF sd-rxRNA sequences (Accession Number: NM_001901.2)
  • G.Chi 110 A*mC*mC* A* U. 88% mU. A.mC.mC. G. P.mC.fU.fU.fC.fC. A.
  • G. A.fU.fC. G. A.fC. A.
  • the nucleic acid molecule is RXI-109, comprising a sense strand sequence of: G.mC. A.mC.mC.mU.mU.mU.mC.mU. A*mG*mA.TEG-Chl (e.g., SEQ ID NO: 359) and an antisense strand sequence of: P.mU.fC.fU. A. G.mA. A.mA. G. G.fU.
  • G.mC* A* A* A*mC* A* U (e.g., SEQ ID NO: 360).
  • the disclosure relates to the use of nucleic acids, such as sd-rxRNA, targeting matrix metalloproteinases (MMPs).
  • matrix metalloproteinase refers to a zinc-dependent endopeptidase that is capable of degrading extracellular matrix proteins, including but not limited to collagen, gelatin, fibronectin, laminin, cholesterol sulfate, aggrecan, fibrinogen and fibrin.
  • MMPs have been linked to several cell behaviors, for example cell proliferation, cell migration, cell differentiation, angiogenesis, apoptosis and immune function.
  • the sd-rxRNA targets an MMP that degrades or breaks down interstitial collagen.
  • the interstitial collagen is collagen I, collagen II and/or collagen III.
  • the sd-rxRNA targets MMPl .
  • nucleic acids e.g. , sd-rxRNAs
  • Tables 2-5 examples of nucleic acids targeting MMPl are shown in Tables 2-5, below, incorporated by reference from PCT Publication No. WO 2016/037071.
  • MMP1-14 1150 452 AUGAAGUCCGGUA mmOOmOmmmOOmm-Chl oooooooooosso
  • MMP1-21 1330 459 GGAGGUAUGAUGA mmOOOmOmOOmmm-Chl oooooooooosso
  • MMP1-22 1331 460 GAGGUAUGAUGAA mmOOmOmOOmOmm-Chl oooooooooosso
  • MMP1-35 1520 474 UAGCUGGUUCAAA mmOmmOOmmmOmm-Chl oooooooooosso
  • MMP1-36 1521 475 AGCUGGUUCAACA rrimrrimOOmrnmOOmm-Chl oooooooooosso
  • o phosphodiester
  • s phosphorothioate
  • P 5' phosphorylation
  • 0 2'-OH
  • f 2'-fluoro
  • m 2'

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