Compositions and methods for the treatment of wounds, disorders, and diseases of the skin

Inventors

Krishnan, Suma • Agarwal, Pooja

Assignees

Krystal Biotech Inc

Abstract

The present disclosure relates, in part, to pharmaceutical compositions comprising one or more polynucleotides suitable for enhancing, increasing, augmenting, and/or supplementing the levels of Collagen alpha-1 (VII) chain polypeptide and/or Lysyl hydroxylase 3 polypeptide and/or Keratin type I cytoskeletal 17 polypeptide in a subject. The present disclosure also relates, in part, to pharmaceutical compositions and methods of use for providing prophylactic, palliative, or therapeutic relief of a wound, disorder, or disease of the skin in a subject, including a subject having, or at risk of developing, one or more symptoms of epidermolysis bullosa.

Core Innovation

The invention relates to delivering a transgene to the skin of a subject by administering a pharmaceutical composition comprising a replication-defective herpes simplex virus (HSV) having a recombinant herpes simplex virus genome. The recombinant HSV genome comprises one or more polynucleotides encoding the transgene, and the recombinant genome includes an inactivating mutation in one or both copies of the ICP4 herpes simplex virus gene. The pharmaceutical composition is topically or transdermally administered to areas of the subject affected by a wound, disorder, or disease of the skin.

The transgene encoded by the polynucleotides comprises Collagen alpha-1 (VII) chain (COL7/Col7) and/or Lysyl hydroxylase 3 (LH3/PLOD3-related), and optionally comprises Keratin type I cytoskeletal 17 (KRT17) and/or a chimeric COL7-LH3 polypeptide. The described rationale is that COL7 restores dermal-epidermal anchoring and that LH3 restores hydroxylation needed for functional COL7 fibrils. Together, these actions are described as improving basement membrane integrity and wound healing associated with the epithelial basement membrane and dermoepidermal junction integrity.

The document further describes engineering and formulation options for the replication-defective HSV composition. Vector design options include HSV amplicons and hybrid amplicons, recombinant HSV genomes, and replication-defective vectors, with transgene placement in HSV gene loci such as ICP4 and UL41 and attenuation through inactivating mutations or deletions in immediate early HSV genes including ICP0, ICP4, ICP22, ICP27, ICP47 and in UL55. Additional options include miRNA binding sites and heterologous promoters such as HCMV immediate early and EF1, and administration using topical or transdermal carriers including ointments, creams, gels, patches, and microneedle arrays.

Claims Coverage

The independent claims are two. The claim set centers on delivering a transgene to skin using a replication-defective HSV recombinant genome administered in a pharmaceutically acceptable carrier, with ICP4 inactivation as a required feature, and adds further inventive features that define topical or transdermal skin-area administration, specific formulation types, and target epidermal and/or dermal cells.

Overall, the claims coverage centers on delivering transgene-encoding polynucleotides using a replication-defective HSV recombinant genome containing an inactivating ICP4 mutation, with administration to skin areas affected by a skin wound, disorder, or disease, and with defined topical formulation types and target epidermal and/or dermal cells.

Stated Advantages

Documented Applications