Compositions and methods for the treatment of Netherton Syndrome

Inventors

Agarwal, Pooja • Krishnan, Suma • FREEDMAN, John C.

Assignees

Krystal Biotech Inc

Abstract

The present disclosure provides recombinant nucleic acids comprising one or more polynucleotides encoding a Serine Protease Inhibitor Kazal-type (SPINK) polypeptide (e.g., a SPINK5 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 the treatment of Netherton Syndrome); and articles of manufacture or kits thereof.

Core Innovation

The disclosed subject matter relates to recombinant nucleic acids and herpes viruses comprising recombinant herpes simplex virus genomes encoding a Serine Protease Inhibitor Kazal-type 5 (SPINK5) polypeptide. The approach is directed to delivering one or more polynucleotides that encode SPINK5 and are operably linked to a promoter suitable for transcription in a mammalian cell. In particular, recombinant herpes simplex virus genomes are described in replication-competent or replication-defective variants carrying SPINK5 expression cassettes integrated at herpes simplex virus loci.

A key aspect is the use of a replication-defective herpes simplex virus comprising a recombinant herpes simplex virus genome with one or more polynucleotides encoding SPINK5. The genome is described as comprising promoter elements for mammalian transcription, with inactivating mutations in herpes simplex virus genes to reduce cytotoxicity. The described integration strategy supports human SPINK5 expression and subsequent functional activity.

The document states that the described recombinant herpes simplex virus approach results in transduction of human keratinocytes and dose-dependent expression of human SPINK5 as DNA, RNA, and protein, followed by secretion of functional SPINK5. Functional inhibition of KLK5 protease activity in vitro is described, and in vivo topical or intradermal delivery is described with detectable human SPINK5 in epidermal layers, including co-staining or localization with filaggrin and absence of inflammatory infiltration or gross histologic abnormalities.

The problem being solved is described as the treatment of Netherton Syndrome and related SPINK-deficiency disorders, including conditions such as Comèl-Netherton Syndrome, by providing SPINK5 activity. The disclosure frames the approach as delivering the SPINK5 polypeptide to affected skin compartments using recombinant herpes virus genomes and corresponding pharmaceutical compositions.

Claims Coverage

The independent claim covers one inventive concept: a replication-defective herpes simplex virus pharmaceutical composition carrying a recombinant genome with SPINK5 polynucleotides under a mammalian-cell transcription promoter, formulated with a pharmaceutically acceptable excipient. Independent claim count in the provided list: 1.

Across the provided independent claim and its dependent refinements, the core coverage is directed to pharmaceutical compositions using a replication-defective herpes simplex virus carrying a recombinant genome with SPINK5 polynucleotides operably linked to a mammalian transcription promoter, formulated with a pharmaceutically acceptable excipient.

Stated Advantages

Documented Applications

No documented applications found