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-10525090-B2
Publication Date
2020-01-07
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 relates to pharmaceutical compositions comprising a herpes virus that includes a recombinant herpes virus genome having one or more polynucleotides encoding a transglutaminase 1 (TGM1) polypeptide, together with a pharmaceutically acceptable excipient. The recombinant herpes virus genome is engineered to provide TGM1 polypeptide expression, and the compositions define conditions for the recombinant genome, including selection of herpes virus types and possible functional constraints such as whether the virus is replication competent or replication defective.
In particular embodiments, the recombinant genome encodes a human TGM1 polypeptide and the TGM1 polypeptide is characterized by sequence identity relative to SEQ ID NO: 5. The recombinant genome can further include inactivating mutations in selected herpes simplex virus genes, including ICP0, ICP4, ICP22, ICP27, ICP47, thymidine kinase (tk), UL41, or UL55. The engineered herpes virus variant is also defined in terms of reduced cytotoxicity compared with a corresponding wild-type herpes virus.
The document further describes methods of providing prophylactic, palliative, or therapeutic relief to one or more signs or symptoms of TGM1-deficient autosomal recessive congenital ichthyosis (ARCI) in a subject in need thereof. Such methods administer an effective amount of the pharmaceutical composition topically, transdermally, or intradermally, and require that administration affects a measurable improvement or prevention of the one or more signs or symptoms.
Claims Coverage
The provided excerpt contains two independent claims: a composition claim and a method claim. Together they cover a recombinant herpes-virus-based pharmaceutical composition encoding TGM1 and topical, transdermal, or intradermal administration to improve or prevent signs and symptoms of TGM1-deficient ARCI, with additional claim refinements including eligible herpes virus types, replication capability, specific HSV gene inactivations, TGM1 sequence identity to SEQ ID NO: 5, and reduced cytotoxicity versus wild-type.
Recombinant herpes virus pharmaceutical composition encoding TGM1
A pharmaceutical composition comprising a herpes virus with a recombinant herpes virus genome comprising one or more polynucleotides encoding a transglutaminase 1 (TGM1) polypeptide, and a pharmaceutically acceptable excipient.
Topical, transdermal, or intradermal treatment of TGM1-deficient ARCI with TGM1-encoding recombinant herpes virus composition
A method providing prophylactic, palliative, or therapeutic relief to one or more signs or symptoms of TGM1-deficient autosomal recessive congenital ichthyosis (ARCI) by administering topically, transdermally, or intradermally an effective amount of a pharmaceutical composition comprising a herpes virus with a recombinant herpes virus genome comprising one or more polynucleotides encoding a transglutaminase 1 (TGM1) polypeptide, and a pharmaceutically acceptable excipient, wherein administration affects a measurable improvement or prevention of the one or more signs or symptoms of TGM1-deficient ARCI.
Across the independent claims, the core coverage is the use of a recombinant herpes virus genome encoding TGM1 in a pharmaceutical composition containing a pharmaceutically acceptable excipient, and the topical, transdermal, or intradermal administration of that composition to provide prophylactic, palliative, or therapeutic relief for TGM1-deficient ARCI signs and symptoms. The excerpted claim refinements further constrain eligible viral genomes, replication capability, specific HSV gene inactivations, TGM1 sequence identity to SEQ ID NO: 5, and reduced cytotoxicity versus a corresponding wild-type herpes virus.
Stated Advantages
Promoting cornified envelope formation and barrier function, including effects on stratum corneum features and transepidermal water loss (TEWL).
Reduced cytotoxicity compared with a corresponding wild-type herpes virus.
Constraints intended to reduce cytotoxicity.
Limited tissue damage reported in mice.
Documented Applications
Topical, transdermal, and intradermal administration.
Prophylactic, palliative, or therapeutic relief for TGM1-deficient autosomal recessive congenital ichthyosis (ARCI).
In vitro and in vivo expression and activity assays.
Prophylactic, palliative, or therapeutic relief of one or more signs or symptoms of TGM1-deficient autosomal recessive congenital ichthyosis (ARCI) in a subject in need thereof.
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