Stc.unm

Unm Rainforest Innovations

Johns Hopkins University

Other

Vojo P Deretic

Graham Timmins

Eliseo F Castillo

Larry A Sklar

William R Bishai

Steven Bradfute

Bhawana Bissa

Jia Cassano

Tomonori Kimura

Suresh Kumar

Sharon Master

Tie present invention relates to compositions and methods of influencing autophagy by modulating TRIM (tripartite motif containing) proteins, especially TRIM 8, TRIM: 10, TRIM 16, TRIM 19 and/or TRIM 51 (preferably TRIM 16} and galectins, especially galectins 3 m order to influence autophagy and treat a number of disease states and/or conditions which are mediated and/or influenced by autophagy, including inflammatory disease states and/or conditions, including a microbial infection such as ainfection, among numerous others, an inflammatory disorder, a lysosomal, storage disorder, an immune disorder, a neurodegenerative disorder and a cancer.

Trim proteins and galectins cooperate and codirect autophagy and are useful in the treatment of autophagy related diseases

The present invention relates to discovery that TBK1 phosphorylates Syntaxin 17 and that phosphorylation of Syntaxin 17 is intimate to control autophagy initiation. The present invention is directed to this discovery and the use of TBK1 inhibitors or inhibitors of Syntaxin 17 phosphorylation alone or in combination with additional bioactive agents to inhibit autophagy in the treatment of disease, especially the treatment of cancers. Methods of treating various cancers are disclosed using TBK1 inhibitors to patients with cancer and into cancerous tissues for the treatment of cancer including the inhibition, amelioration, reduction in metastasis and in recurrence of cancer in remission. Assays and methods for identifying compounds as inhibitors of Syntaxin 17 and as potential therapeutic agents for cancer and autoimmune diseases are also diseased herein.

Phosphorylation of Syntaxin 17 by TBK1 controls autophagy initiation

The present invention is directed to the discovery that AMPK activation through Galectin 9 induces autophagy and affects other related processes in response to lyosomal damage which occurs and the use of that mechanism in the treatment of autophagy disease states and/or conditions. The use of modulators of AMPK and optionally a modulator of Galectin 9, TAK1 and/or a lysosomotropic agent for the treatment of autophagy-mediated disease states and/or conditions is described as are pharmaceutical compositions.

Methods and compositions for treating autophagy related disease states and conditions utilizing AMPK activation

The present invention is directed toC and/orH isotope enhanced ambroxol ('isotope enhanced ambroxol') and its use in the treatment of autophagy infections, especially mycobacterial and other infections, disease states and/or conditions of the lung, such as tuberculosis, especially including drug resistant and multiple drug resistant tuberculosis. Pharmaceutical compositions comprising isotope enhanced ambroxol, alone or in combination with an additional bioactive agent are useful against an autophagy mediated disease state and/or condition, for example, ainfection, Chronic Obstructive Pulmonary Disease (COPD), asthma, pulmonary fibrosis, cystic fibrosis, Sjogren's disease and lung cancer. Methods of treating autophagy disease states and/or conditions, especially including autophagy disease states or conditions which occur principally in the lungs of a patient represent a further embodiment of the present invention. Methods of synthesizing compounds according to the present invention are disclosed herein.

Isotope enhanced ambroxol for long lasting autophagy induction

In one embodiment, the invention provides a method of treating a subject suffering from ainfection by administering to the subject a therapeutically-effective amount of a degradative autophagy agonist or a secretory autophagy antagonist. In another embodiment, the invention provides a method of treating a subject suffering from one or more diseases selected from the group consisting of ainfection, an inflammatory disorder, an immune disorder, a cancer and a neurodegenerative disorder by administering to the subject a therapeutically-effective amount of a TBK-1 antagonist (e.g. BX795 or amlexanox). Related pharmaceutical compositions, diagnostic and screening assays and kits are also provided.

Treatment of autophagy-based disorders and related pharmaceutical compositions, diagnostic and screening assays and kits

The present invention relates to the discovery that IRGM, encoded by a uniquely human gene which confers risk for inflammatory diseases, affects autoophagy through a hitherto unknown mechanism. The present invention shows that IRGM controls autophagy and that IRGM modulators, in particular, double-stranded RNA, including poly I:C, poly-UG (polyUGUGU) and polyICLC and muramyldipeptide and related analogs of same, including N-acetyl muramyl-L-alanyl-D-isoglutamine (Muramyl dipeptide or MDP) and numerous other compounds as identified herein, which may be used alone, in combination, or in combination with alternative autophagy modulators and additional bioactive agents to provide effective therapies for a number of diseases, including cancer, bacterial infections and inflammatory diseases, especially including tuberculosis infections and Crohn's disease, among others. The present invention is also directed to compositions and methods for treating inflammatory or autophagy-related diseases including diseases which cause excessive inflammation in patients.

IRGM and precision autophagy controls for antimicrobial and inflammatory disease states and methods of detection of autophagy

The present invention is directed toH isotope enhanced ambroxol ('isotope enhanced ambroxol') and its use in the treatment of autophagy infections, especially mycobacterial and other infections, disease states and/or conditions of the lung, such as tuberculosis, especially including drug resistant and multiple drug resistant tuberculosis. Pharmaceutical compositions comprising isotope enhanced ambroxol, alone or in combination with an additional bioactive agent, especially rifamycin antibiotics, including an additional autophagy modulator (an agent which is active to promote or inhibit autophagy) are also disclosed. These compositions are useful against an autophagy mediated disease state and/or condition), especially an autophagy mediated disease state and/or condition which occurs in the lungs.

The invention provides methods of treating autophagy mediated diseases and disorders and related pharmaceutical compositions, diagnostics, screening techniques and kits. In one embodiment, the invention provides a method of determining whether a subject suffers from, or is at risk of developing, and autophagy mediated disease state and/or condition by evaluating LC3 levels.

Methods of treating autophagy-associated disorders and related pharmaceutical compositions, diagnostics, screening techniques and kits

The present invention relates to the use of isotopically labeled derivatives of isoniazid, ethionamide and related compounds as effective therapy for the treatment of mycobacterial diseases, including

Rationally improved isoniazid and ethionamide derivatives and activity through selective isotopic substitution

The present invention relates to methods for detecting P aeruginosa infection and bacterial burden in the lungs of patients who are at risk for P. aeruginosa infections, especially including patients with Cystic Fibrosis (CF). The present method provides numerous tests (breath, blood, urine) which are readily administered to a patient that will sensitively and specifically detect the presence and extent of lung infection P. aeruginosa (both mucoid and non-mucoid), and allow monitoring of bacterial load as a parameter in monitoring treatment.

Diagnosis of infection in the lungs of patients

This invention relates to a test for detecting a(tuberculosis or TB) infection in a patient or subject, specifically a diagnostic test, including a breath test, whereby patients are provided a small dose of an isotopically labeled TB drug, Isoniazid (INH) orally or directly to the lungs of the patient or subject. If TB is present, a TB enzyme mycobacterial peroxidase KatG oxidizes the INH; and KatG specific metabolites, in particular, isotopically labeled nitric oxide (NO), nitrites, nitrates, carbon monoxide (CO) or carbon dioxide converted from carbon monoxide of INH cleavage are measured. Other embodiments relate to a diagnostic breath test for detecting TB utilizing isotopically labeled urea (preferably, carbon-13 labeled urea), alone or in combination with isotopically labeled isoniazid (preferably, nitrogen-15 labeled isoniazid), whereinorganism, if present in the patient or subject's lungs (or other tissues), will metabolize the isotopically labeled urea to isotopically labeled carbon dioxide (CO) such that a determination of the residence of, including residence of an isoniazid resistant strain of, may be made.

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The present invention relates to methods for detectinginfection and bacterial burden in the lungs of patients who are at risk forinfections, especially including patients with Cystic Fibrosis (CF). The present method provides numerous tests (breath, blood, urine) which are readily administered to a patient that will sensitively and specifically detect the presence and extent of lung infection(both mucoid and non-mucoid), and allow monitoring of bacterial load as a parameter in monitoring treatment.

Growing community of inventors

Placitas, NM, United States of America

Vojo P Deretic