Compositions and methods for delivering CFTR polypeptides

Inventors

PARRY, Trevor • Krishnan, Suma • Agarwal, Pooja

Assignees

Krystal Biotech Inc

Abstract

The present disclosure provides recombinant nucleic acids comprising one or more polynucleotides encoding a cystic fibrosis transmembrane conductance regulator (CFTR) polypeptide (e.g., a human CFTR 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 a chronic lung disease, such as cystic fibrosis); and articles of manufacture or kits thereof.

Core Innovation

Recombinant nucleic acids are provided as recombinant herpes viruses with recombinant herpes virus genomes engineered to comprise one or more polynucleotides encoding a full-length human CFTR polypeptide under the control of a promoter. The disclosed recombinant herpes virus expresses the CFTR polypeptide from the recombinant herpes virus genome to effect a measurable improvement in or prevention of one or more signs or symptoms of cystic fibrosis.

The disclosure further includes embodiments directed to reducing or inhibiting progressive lung destruction by expressing CFTR from the recombinant herpes virus genome in a subject in need thereof. The invention addresses mucus buildup, airway obstruction, chronic bacterial infections, bronchiectasis, and progressive lung destruction in chronic lung diseases, including cystic fibrosis and COPD.

The recombinant herpes virus genomes are described as replication competent or replication defective, and the herpesviruses include HSV-1, HSV-2, varicella zoster virus, human cytomegalovirus, herpesvirus 6A, herpesvirus 6B, herpesvirus 7, and Kaposi’s sarcoma-associated herpesvirus. Engineering strategies introduce inactivating mutations, including promoter inactivation or inactivating mutations at viral gene loci such as ICP4, ICP22, UL41, ICP0, ICP27, ICP47, and UL55, to reduce toxic or cytotoxic effects.

Pharmaceutical compositions comprising the recombinant herpes virus and a pharmaceutically acceptable excipient are administered using a nebulizer, including inhalation delivery options and vibrating mesh nebulizer administration. The described approaches include prophylactic, palliative, and therapeutic relief of cystic fibrosis signs and symptoms and reduction or inhibition of progressive lung destruction in a subject.

Claims Coverage

The independent claim set includes two independent methods with a shared core structure: administering a nebulized pharmaceutical composition that contains a recombinant herpes virus expressing a CFTR polypeptide from a promoter to achieve defined clinical outcomes. The inventive features include prophylactic, palliative, or therapeutic CF relief; reduction or inhibition of progressive lung destruction; promoter-driven CFTR expression from a recombinant herpes virus genome; nebulizer delivery; and the CFTR sequence identity relationship to defined SEQ IDs.

Across the independent claims, the inventive concept is nebulized administration of a pharmaceutical composition containing a recombinant herpes virus genome with promoter-linked polynucleotides encoding a CFTR polypeptide, where CFTR expression produces measurable improvement or prevention of cystic fibrosis signs or symptoms, or where CFTR expression reduces or inhibits progressive lung destruction. Refinements further specify nebulizer form factor, replication competence, selectable herpes virus types, and CFTR sequence identity relative to SEQ ID NO:5/SEQ ID NO:6.

Stated Advantages

Documented Applications