Compositions and methods for the treatment of autosomal recessive congenital ichthyosis
Inventors
Krishnan, Suma • Agarwal, Pooja • FREEDMAN, John C. • O'MALLEY, Mark E. • REGULA, Lauren K.
Assignees
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Publication Number
US-11717547-B2
Publication Date
2023-08-08
Expiration Date
Abstract
The present disclosure provides recombinant nucleic acids comprising one or more polynucleotides encoding a transglutaminase (TGM) polypeptide (e.g., a Transglutaminase-1 (TGM1) polypeptide); viruses comprising the recombinant nucleic acids; compositions comprising the recombinant nucleic acids and/or viruses; methods of their use; and articles of manufacture or kits thereof.
Core Innovation
The invention provides a replication defective recombinant herpes simplex virus type 1 (HSV-1) comprising a recombinant HSV-1 genome that comprises one or more polynucleotides encoding a transglutaminase (TGM) polypeptide. The recombinant HSV-1 genome carries human TGM polypeptides and human TGM1, and the TGM polynucleotides are positioned in viral gene loci including the UL41 locus, ICP4, and ICP22.
The disclosure describes treatment of autosomal recessive congenital ichthyosis (ARCI), including lamellar ichthyosis (LI) and non-bullous congenital ichthyosiform erythroderma (NCIE). It delivers one or more polynucleotides encoding a transglutaminase polypeptide in a subject by expressing TGM polypeptide in relevant cells, including keratinocytes and skin cells, to enhance TGM levels and improve barrier function.
The invention further describes recombinant herpesvirus constructs, including replication-defective recombinant HSV-1 and recombinant HSV-2, with optional glycoprotein H (gH) and inactivating mutations in essential immediate early genes such as ICP27. The constructs are associated with increased cornified cell envelope formation, stabilization of the stratum corneum, improved skin barrier function, and reduced transepidermal water loss (TEWL).
Claims Coverage
The independent claims center on a replication-defective recombinant HSV-1 pharmaceutical composition encoding transglutaminase polypeptides and on a method of delivering human transglutaminase polypeptide-encoding polynucleotides into cells of a subject using that composition. The inventive features include replication-defective recombinant HSV-1 genomes encoding TGM polypeptides, a pharmaceutically acceptable excipient, human TGM1 through human TGM7, optional glycoprotein H (gH), inactivating mutations in essential immediate early genes, and administration to skin cells.
Replication defective recombinant HSV-1 encoding a transglutaminase polypeptide
A replication defective herpes simplex virus type 1 (HSV-1) comprising a recombinant HSV-1 genome, wherein the recombinant HSV-1 genome comprises one or more polynucleotides encoding a transglutaminase (TGM) polypeptide.
Human transglutaminase polypeptide delivery by replication defective HSV-1
A replication defective herpes simplex virus type 1 (HSV-1) comprising a recombinant HSV-1 genome, wherein the recombinant HSV-1 genome comprises the one or more polynucleotides encoding a human transglutaminase (TGM) polypeptide, administered to deliver the polynucleotides into one or more cells of a subject.
Pharmaceutically acceptable excipient with the recombinant HSV-1
The pharmaceutical composition further comprises a pharmaceutically acceptable excipient.
TGM polypeptide selected from TGM1 through TGM7
The TGM polypeptide is selected from TGM1 through TGM7 polypeptides.
Human TGM polypeptide selected from human TGM1 through human TGM7
The human TGM polypeptide is selected from human TGM1, TGM2, TGM3, TGM4, TGM5, TGM6, and TGM7.
Inclusion of glycoprotein H (gH) polypeptide-encoding polynucleotides
The recombinant HSV-1 genome further engineered to include one or more polynucleotides that encode a glycoprotein H (gH) polypeptide.
Inactivating mutation in an essential immediate early gene
The recombinant HSV-1 genome further containing an inactivating mutation in an essential immediate early gene.
Essential immediate early gene specified as ICP27
The essential immediate early gene is an ICP27 gene.
Topical, transdermal, subcutaneous, intradermal, or transmucosal administration routes
Formulated for administration via topical, transdermal, subcutaneous, intradermal, or transmucosal routes.
Cells of the skin as the delivery target
The one or more cells are cells of the skin.
Overall, the claims focus on replication-defective recombinant HSV-1 carrying TGM-encoding polynucleotides, including human TGM1 through human TGM7, in a pharmaceutical composition with a pharmaceutically acceptable excipient, and on administering that composition to deliver the TGM-encoding polynucleotides into cells of a subject, particularly skin cells, with optional gH and attenuation by inactivating mutations in essential immediate early genes.
Stated Advantages
Reduced cytotoxicity in target epidermis/dermis cells.
Improving cornified cell envelope and stratum corneum stability.
Providing prophylactic and therapeutic relief of ARCI signs and symptoms.
Improved skin barrier function and reduced transepidermal water loss (TEWL).
Increased cornified cell envelope formation and stabilization of the stratum corneum.
Reported reduced inflammation/necrosis.
Documented Applications
Therapeutic use for autosomal recessive congenital ichthyosis (ARCI), including lamellar ichthyosis (LI) and non-bullous congenital ichthyosiform erythroderma (NCIE).
Prophylactic, palliative, and therapeutic use for relief of ARCI signs and symptoms.
Topical and intradermal delivery contexts for expression of TGM1 in keratinocytes and in vivo.
Use of engineered HSV vectors to deliver TGM polypeptide into keratinocytes, including LI patient-derived keratinocytes.
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