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

a technology of autophagy and autophagy, applied in the field of autophagy-associated disorders, can solve the problems of complicated interpretation, necrosis and active tuberculosis, and excessive proinflammatory response, and achieve the effect of high throughput analysis

Inactive Publication Date: 2017-04-27
STC UNM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention provides a method of modulating autophagy in a biological system, including humans, to treat various disease states. The method involves administering an autophagy modulator (autostatin) to the biological system to enhance or inhibit autophagy. The autostatin can be easily obtained from the blood of patients and can be used as a diagnostic marker to monitor the progression of therapy for autophagy-mediated diseases. The invention provides a versatile approach to diagnose and treat diseases that have been difficult to identify and treat.

Problems solved by technology

When autophagy is deficient in the macrophages of infected mice, not only does this permit bacterial growth but also leads to an excessive proinflammatory response, with partial roots in sterile inflammation, leading to lung tissue destruction, necrosis and active tuberculosis.
We tested whether indications of such alterations may be detectable in animals not infected with M tuberculosis, since infection would complicate interpretations.
Nevertheless, not all aspects of IL-1 signaling are protective.
Whereas beneficial in control of extracellular bacteria, these features may not be desirable against M tuberculosis as discussed above and instead may contribute to immunopathology.

Method used

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

Examples

Experimental program
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Effect test

example 1

References for Example 1

[0216]Abadie, V., Badell, E., Douillard, P., Ensergueix, D., Leenen, P. J., Tanguy, M., Piette, L., Saeland, S., Gicquel, B., and Winter, N. (2005). Neutrophils rapidly migrate via lymphatics after Mycobacterium bovis BCG intradermal vaccination and shuttle live bacilli to the draining lymph nodes. Blood 106, 1843-1850.[0217]Afonina, L S., Tynan, G. A., Logue, S. F., Cullen, S. P., Bots, M., Luthi, A. U., Reeves, E. P., McElvaney, N. G., Medema, J. P., Lavelle, E. C., et al. (2011). Granzyme B-dependent proteolysis acts as a switch to enhance the proinflammatory activity of IL-1alpha. Molecular cell 44, 265-278.[0218]Alonso, S., Pethe, K., Russell, D. G., and Purdy, G. E. (2007). Lysosomal killing of Mycobacterium mediated by ubiquitin-derived peptides is enhanced by autophagy. Proc Natl Acad Sci USA 104, 6031-6036.[0219]Axe, E. L., Walker, S. A., Manifava, M., Chandra, P., Roderick, H. L., Habermann, A., Griffiths, G., and Ktistakis, N. T. (2008). Autophagos...

example 2

TBK-1 Controls Autophagy Pathway in Cell-Autonomous Antimicrobial Defense

[0297]We screened the Rab family of membrane trafficking regulators for effects on autophagic elimination of Mycobacterium tuberculosis var. Bovis BCG and found that Rab8b and its downstream effector, innate immunity regulator TBK-1, are required for autophagic elimination of mycobacteria in macrophages. TBK-1 was necessary for proper autophagic flux via coordinated assembly and function of the autophagic machinery. TBK-1 phosphorylated the autophagic adaptor p62 / sequestosome 1 on Ser-403, a residue essential for its role in autophagic clearance. TBK-1 was required for the execution of IL-1P-induced autophagy and IL-I P-dependent autophagic killing of mycobacteria. Thus, TBK-1 is a key regulator of immunological autophagy and is responsible for the maturation of atophagosomes into lytic bactericidal organelles.

[0298]We approached the far less studied processes governing autophagic flux by a systematic screening...

example 3

References for Example 3

[0449]Alavez S, Vantipalli M C, Zucker D J, Klang I M, Lithgow G J (2011) Amyloid-binding compounds maintain protein homeostasis during ageing and extend lifespan. Nature 472: 226-229[0450]Andersson U, Tracey K J (2011) HMGB1 is a therapeutic target for sterile inflammation and infection. Annu Rev Immunol 29: 139-162[0451]Barr F A, Puype M, Vandekerckhove J, Warren G (1997) GRASP65, a protein involved in the stacking of Golgi cisternae. Cell 91:253-262[0452]Bodemann B O, Orvedahl A, Cheng T, Ram R R, Ou Y H, Formstecher E, Maiti M, Hazelett C C, Wauson E M, Balakireva M, Camonis J H, Yeaman C, Levine B, White M A (2011) RalB and the exocyst mediate the cellular starvation response by direct activation of autophagosome assembly. Cell 144: 253-267[0453]Bravo-Cordero J J, Marrero-Diaz R, Megias D, Genis L, Garcia-Grande A, Garcia M A, Arroyo A G, Montoya M C (2007) MT1-MMP proinvasive activity is regulated by a novel Rab8-dependent exocytic pathway. EMBO J 26: 1...

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Abstract

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.

Description

RELATED APPLICATIONS[0001]This application is a continuation application of U.S. patent application Ser. No. 14 / 116,581, filed Nov. 8, 2013 of identical title which claims priority to International Patent Application No. PCT / US2012 / 037300 filed May 10, 2012, which itself claims priority from U.S. Provisional Application Ser. No. 61 / 484,653 filed May 10, 2011, entitled “Autophagy Diagnostics, Screening, and Therapeutics”, the complete disclosure of each of said applications is hereby incorporated by reference in its entirety.GOVERNMENT SUPPORT[0002]The invention described herein was funded in part by National Institute of Health Grant No. R01 A1069345. Accordingly, the United States has certain rights in the invention.FIELD OF THE INVENTION[0003]The invention provides methods of treating autophagy-associated disorders, and related pharmaceutical compositions, diagnostics, screening techniques and kits.BACKGROUND OF THE INVENTION[0004]Autophagy is a homeostatic process highly conserve...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/436A61K31/136A61K31/12A61K31/4184
CPCA61K31/436A61K31/12A61K31/136A61K31/4184A61K31/4365A61K31/4535A61K31/472A61K31/473A61K31/517A61K31/519A61K31/522A61K31/54A61K31/546A61K31/5685A61K31/585A61K31/65A61P29/00C07K16/18G01N33/6893G01N2333/9015G01N33/56972
Inventor DERETIC, VOJOCASTILLO, ELISEOBRADFUTE, STEVENSKLAR, LARRY A.
Owner STC UNM
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