Use of peptide-based inhibitors of the stat3-IL10 pathway for treating bacterial infection and granulomatous disease
Inventors
Tarasova, Nadya I. • Gonzalez-Juarrero, Mercedes
Assignees
US Department of Health and Human Services • Colorado State University Research Foundation
Publication Number
US-10512673-B2
Publication Date
2019-12-24
Expiration Date
2036-01-07
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Abstract
The invention provides a method of treating pathogenic bacterial infection (e.g., tuberculosis infection) in an animal comprising administering a peptide-based inhibitor of the STAT3-IL10 pathway or a nucleic acid encoding the peptide-based inhibitor to the animal. The invention also provides methods of treating chronic granulomatous disease and Wegener's granulomatosis in an animal comprising administering a peptide-based inhibitor of the STAT3-IL10 pathway or a nucleic acid encoding the peptide-based inhibitor to the animal.
Core Innovation
The invention provides methods of treating pathogenic bacterial infections, including tuberculosis, chronic granulomatous disease, and Wegener's granulomatosis in animals by administering a peptide-based inhibitor of the STAT3-IL10 pathway or a nucleic acid encoding such inhibitors. These inhibitors modulate the host immune response, enhancing bactericidal capacity and reducing bacterial load in infected tissues, as explicitly demonstrated in mice infected with Mycobacterium tuberculosis (Mtb). The peptide-based inhibitors are preferably peptide or peptidomimetics of STAT3 or IL-10, including non-naturally occurring sequences, which interfere with cytokine-receptor signaling complexes.
The background articulates the problem of existing tuberculosis chemotherapy being lengthy, typically requiring 6-9 months for drug-susceptible TB and up to two years with low success rates for multi-drug resistant TB. There is a need for shorter, effective, and well-tolerated treatments, particularly for latent TB infection, to reduce resistance development. The invention addresses this need by providing a host-directed therapeutic approach using peptide-based inhibitors to the STAT3-IL10 pathway, aiming to stimulate immune response and reduce bacterial loads without relying solely on antibiotics.
Claims Coverage
The patent presents two main independent claims addressing methods of treating infections of Mycobacteriaceae and diseases associated with granulomas using peptide-based inhibitors of STAT3 or their encoding nucleic acids.
Use of specific peptide sequences as STAT3 inhibitors
Administering therapeutically effective amounts of peptide-based inhibitors comprising amino acid sequences identified as SEQ ID NOs: 40, 42, 44, 46, 48, 49, 55-57, and 66-76, or their inverse sequences, which inhibit STAT3 activity to treat Mycobacteriaceae infections or related granulomatous diseases.
Treatment of Mycobacterium tuberculosis infections
Applying peptide-based inhibitors of STAT3 to reduce Mycobacterium tuberculosis bacilli load in infected animal lungs, including sequential or simultaneous use with conventional tuberculosis antibiotic therapy.
Inclusion of cell-penetrating and stabilizing motifs in peptide inhibitors
Utilizing peptide-based inhibitors that incorporate D-amino acids, cell-penetrating motifs such as protein transduction domains or fatty acids, and terminal modifications including acetyl or palmitoyl groups to enhance delivery and stability.
Versatility of animal subjects and administration methods
Treating a broad range of animals, including humans and various mammalian species, using therapeutically effective amounts of peptide-based inhibitors or nucleic acids, optionally delivered via pharmaceutical compositions or inhalants.
The independent claims collectively cover methods of treating infections caused by Mycobacteriaceae or granulomatous diseases using peptide-based STAT3 inhibitors with defined amino acid sequences and specific chemical modifications, delivered in various forms to diverse animal subjects, with potential combination with existing therapies.
Stated Advantages
Significantly reduced bacterial load in infected tissues without antibiotics.
Enhanced host immune response by modulating the STAT3-IL10 pathway.
Potential to shorten TB treatment duration and improve control over resistant strains.
Decreased pulmonary bacterial burden demonstrated after local pulmonary administration.
Modulation of antimicrobial effector molecules and cytokine profiles favoring bacterial clearance.
Documented Applications
Treatment of pathogenic bacterial infections, specifically tuberculosis infection caused by Mycobacterium tuberculosis.
Treatment of chronic granulomatous disease associated with lung granulomas.
Treatment of Wegener's granulomatosis, a granulomatous disease affecting the lung.
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