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US-20260125705-A1 - Compositions and Methods for the Treatment of ATPase Disorders or Diseases of the Skin

US20260125705A1US 20260125705 A1US20260125705 A1US 20260125705A1US-20260125705-A1

Abstract

The present disclosure provides recombinant nucleic acids comprising one or more polynucleotides encoding an ATPase polypeptide (e.g., a calcium-transporting ATPase type 2C member 1 polypeptide or a sarcoplasmic/endoplasmic reticulum calcium ATPase 2 polypeptide); viruses comprising the recombinant nucleic acids; compositions and formulations comprising the recombinant nucleic acids and/or viruses; methods of their use (e.g., for treating an ATPase disorder or disease of the skin, for example, Hailey-Hailey disease or Darier disease); and articles of manufacture or kits thereof.

Inventors

  • Suma Krishnan
  • Mary Jane DUERMEYER
  • Bruce Chike Nmezi
  • Trevor PARRY

Assignees

  • Krystal Biotech, Inc.

Dates

Publication Date
20260507
Application Date
20251103

Claims (20)

  1. 1 .- 92 . (canceled)
  2. 93 . A pharmaceutical composition comprising: (a) a replication-defective herpes simplex virus comprising a recombinant herpes simplex virus genome, wherein the recombinant herpes simplex virus genome comprises a polynucleotide encoding a calcium-transporting ATPase type 2C member 1 (ATP2C1) polypeptide; and (b) a pharmaceutically acceptable excipient.
  3. 94 . The pharmaceutical composition of claim 93 , wherein the recombinant herpes simplex virus genome is a recombinant herpes simplex virus type 1 (HSV-1) genome or a recombinant herpes simplex virus type 2 (HSV-2) genome.
  4. 95 . The pharmaceutical composition of claim 93 , wherein the recombinant herpes simplex virus genome comprises an inactivating mutation in a herpes simplex virus gene selected from the group consisting of Infected Cell Protein (ICP) 0, ICP4, ICP22, ICP27, ICP47, thymidine kinase (tk), Long Unique Region (UL) 41, and UL55.
  5. 96 . The pharmaceutical composition of claim 93 , wherein the recombinant herpes simplex virus genome comprises an inactivating mutation in one or both copies of the ICP4 gene.
  6. 97 . The pharmaceutical composition of claim 93 , wherein the ATP2C1 polypeptide comprises a sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 1.
  7. 98 . The pharmaceutical composition of claim 93 , wherein the pharmaceutical composition is suitable for topical, transdermal, subcutaneous, intradermal, oral, sublingual, buccal, rectal, vaginal, inhaled, intravenous, intraarterial, intramuscular, intracardiac, intraosseous, intraperitoneal, transmucosal, intravitreal, subretinal, intraarticular, peri-articular, local, injection, or epicutaneous administration.
  8. 99 . The pharmaceutical composition of claim 93 , wherein the pharmaceutical composition is suitable for topical administration.
  9. 100 . A method of providing prophylactic, palliative, or therapeutic relief of one or more signs or symptoms of Hailey-Hailey disease in a subject in need thereof, the method comprising administering to the subject an effective amount of a pharmaceutical composition comprising: (a) a replication-defective herpes simplex virus comprising a recombinant herpes simplex virus genome, wherein the recombinant herpes simplex virus genome comprises a polynucleotide encoding an ATP2C1 polypeptide; and (b) a pharmaceutically acceptable excipient.
  10. 101 . The method of claim 100 , wherein the pharmaceutical composition is administered via injection, topically, transdermally, subcutaneously, epicutaneously, intradermally, orally, sublingually, buccally, rectally, vaginally, intravenously, intraarterially, intramuscularly, intraosseously, intracardially, intraperitoneally, transmucosally, intravitreally, subretinally, intraarticularly, periarticularly, locally, or via inhalation to the subject.
  11. 102 . The method of claim 100 , wherein the pharmaceutical composition is administered topically to the subject.
  12. 103 . The method of claim 100 , wherein the recombinant herpes simplex virus genome is a recombinant HSV-1 genome or a recombinant HSV-2 genome.
  13. 104 . The method of claim 100 , wherein the recombinant herpes simplex virus genome comprises an inactivating mutation in a herpes simplex virus gene selected from the group consisting of ICPO, ICP4, ICP22, ICP27, ICP47, tk, UL41, and UL55.
  14. 105 . The method of claim 100 , wherein the recombinant herpes simplex virus genome comprises an inactivating mutation in one or both copies of the ICP4 gene.
  15. 106 . The method of claim 100 , wherein the ATP2C1 polypeptide comprises a sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 1.
  16. 107 . A pharmaceutical composition comprising: (a) a replication-defective herpes simplex virus comprising a recombinant herpes simplex virus genome, wherein the recombinant herpes simplex virus genome comprises a polynucleotide encoding a sarcoplasmic/endoplasmic reticulum calcium ATPase 2 (ATP2A2) polypeptide; and (b) a pharmaceutically acceptable excipient.
  17. 108 . The pharmaceutical composition of claim 107 , wherein the recombinant herpes simplex virus genome is a recombinant HSV-1 genome or a recombinant HSV-2 genome.
  18. 109 . The pharmaceutical composition of claim 107 , wherein the recombinant herpes simplex virus genome comprises an inactivating mutation in a herpes simplex virus gene selected from the group consisting of ICPO, ICP4, ICP22, ICP27, ICP47, tk, UL41, and UL55.
  19. 110 . The pharmaceutical composition of claim 107 , wherein the recombinant herpes simplex virus genome comprises an inactivating mutation in one or both copies of the ICP4 gene.
  20. 111 . The pharmaceutical composition of claim 107 , wherein the ATP2A2 polypeptide comprises a sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 2.

Description

CROSS REFERENCE TO RELATED APPLICATIONS This application claims the priority benefit of U.S. Provisional Application Ser. No. 63/715,105, filed Nov. 1, 2024, the contents of which are incorporated herein by reference in their entirety. SUBMISSION OF SEQUENCE LISTING ON ASCII TEXT FILE The Sequence Listing associated with this application is filed in electronic format via Patent Center and is hereby incorporated by reference into the specification in its entirety. The name of the file containing the Sequence Listing is 2504921.xml. The size of the file is 37,677 bytes, and the file was created on Oct. 29, 2025. FIELD OF THE INVENTION The present disclosure relates, in part, to recombinant nucleic acids comprising one or more polynucleotides encoding an ATPase polypeptide (e.g., a calcium-transporting ATPase type 2C member 1 polypeptide or a sarcoplasmic/endoplasmic reticulum calcium ATPase 2 polypeptide), viruses comprising the same, pharmaceutical compositions and formulations thereof, and methods of their use (e.g., for treating an ATPase disorder or disease of the skin, for example, Hailey-Hailey disease or Darier disease). BACKGROUND Hailey-Hailey disease (also known as familial benign chronic pemphigus) and Darier disease (also known as follicular dyskeratosis) are genodermatoses. Both Hailey-Hailey disease and Darier disease are characterized by impaired adhesion of epidermal keratinocytes. Hailey-Hailey is characterized by mutations in the ATP2C1 gene which encodes a calcium pump termed Calcium-transporting ATPase type 2C member 1 (also referred to as “SPCA1” or “ATPase2C1”) resulting in decreased calcium concentration within the Golgi apparatus leading to impaired adhesion of epidermal keratinocytes. Individuals with Hailey-Hailey disease develop intertriginous papulovesicles and small blisters, which often evolve into erythematous plaques with erosions and painful fissures Darier disease is characterized by mutations in the ATP2A2 gene which encodes a calcium pump termed Sarcoplasmic/endoplasmic reticulum calcium ATPase 2 (also referred to as “SERCA2” or “SR Ca2+-ATPase2”) resulting in impaired calcium homeostasis in keratinocytes and decreased cell-cell adhesion. Individuals with Darier disease are characterized by reddish brown, keratotic papules in seborrheic and intertriginous areas, which may coalesce into extensive lesions. Individuals with Hailey-Hailey disease or Darier disease have significantly reduced quality of life due to, for example, itching, burning sensation, pain, and body malodor. Therapeutic options remain limited, and thus, there exists a need for more effective therapies. All references cited herein, including patent applications, patent publications, non-patent literature, and NCBI/UniProtKB/Swiss-Prot Accession numbers are herein incorporated by reference in their entirety, as if each individual reference were specifically and individually indicated to be incorporated by reference. BRIEF SUMMARY In order to meet these and other needs, provided herein are recombinant nucleic acids (e.g., recombinant herpes virus genomes) encoding one or more polypeptides (e.g., one or more ATPase polypeptides such as Calcium-transporting ATPase type 2C member 1 or Sarcoplasmic/endoplasmic reticulum calcium ATPase 2) for use in viruses (e.g., herpes viruses), pharmaceutical compositions and formulations, medicaments, and/or methods useful for treating a condition or disease in a subject in need thereof (e.g., a disease associated with a mutation in an underlying ATPase gene). Accordingly, certain aspects of the present disclosure relate to a recombinant herpes virus genome comprising one or more polynucleotides encoding an ATPase polypeptide (e.g., a Calcium-transporting ATPase type 2C member 1 polypeptide or a Sarcoplasmic/endoplasmic reticulum calcium ATPase 2 polypeptide). In some embodiments, the recombinant herpes virus genome comprises two or more polynucleotides encoding an ATPase polypeptide. In some embodiments, the recombinant herpes virus genome is replication competent. In some embodiments, the recombinant herpes virus genome is replication defective. In some embodiments that may be combined with any of the preceding embodiments, the recombinant herpes virus genome comprises the one or more polynucleotides encoding the ATPase polypeptide within one or more viral gene loci. In some embodiments that may be combined with any of the preceding embodiments, the recombinant herpes virus genome is selected from a recombinant herpes simplex virus genome, a recombinant varicella zoster virus genome, a recombinant human cytomegalovirus genome, a recombinant herpesvirus 6A genome, a recombinant herpesvirus 6B genome, a recombinant herpesvirus 7 genome, an Epstein-Barr virus genome, a recombinant Kaposi's sarcoma-associated herpesvirus genome, and any combinations or derivatives thereof. In some embodiments that may be combined with any of the preceding embodiments, the recombinant herpes virus