BACKGROUND:  Mycobacterium tuberculosis infects 2 billion people worldwide and causes 8 million new cases of pulmonary tuberculosis and 2 million deaths annually. Tuberculosis is the world's leading cause of death from a single infectious agent. The rising incidence of tuberculosis worldwide in large part is due to the AIDS epidemic and has been accompanied by the emergence of multi-drug-resistant strains. These factors underscore a serious public health threat and the need to develop novel methods to treat and prevent the disease.

INNOVATION:  Previously it was not known that antisense oligonucleotides directed against mRNA of genes encoding M. tuberculosis proteins could be used therapeutically or prophylactically. Researchers at UCLA have demonstrated that several different antisense oligonucleotides targeted against the mRNA or DNA of M. tuberculosis genes act in ways previously not anticipated and can significantly inhibit the growth of the pathogen, suggesting a novel approach to therapy and prevention. Possibility of human applications is strong, as related pharmacokinetic studies and animal models have shown positive results with using antisense therapy.

POTENTIAL APPLICATIONS:  These antisense oligonucleotides could potentially be administered to people with active tuberculosis or people harboring M. tuberculosis in a latent state as evidenced by a positive diagnostic test for this organism. Appropriately formulated, the oligonucleotides in various combinations, could be administered by any number of routes such as intravenously, intramuscularly, intraperotoneally, subcutaneously or orally to both active and latent cases.

ADVANTAGES

• With the rising rates of drug resistant tuberculosis strains, this technology provides thousands of new mRNA or DNA targets and a highly specific method of targeting.
• Uptake of antisense molecules can be achieved even without the combination use of antibiotics that increase bacterial cell wall permeability.
• Antisense oligonucleotides are directed at key mycobacterial metabolic and/or cell wall synthesis pathways such as: glutamine sythetase, alanine racemase, and mycolyl transferase.

DEVELOPMENT-TO-DATE:  Significant research has been completed, manifested by the publications of three journal publications in this technology. UCLA researchers are further developing methods to increase the uptake of antisense molecules into the M. tuberculosis while also investigating methods of incorporating antisense with traditional antibiotic treatments.

Related Papers (Selected) Harth G, Horwitz MA, Tabatadze D, Zamecnik PC. Targeting the Mycobacterium tuberculosis 30/32-kDa mycolyl transferase complex as a therapeutic strategy against tuberculosis: Proof of principle by using antisense technology. Proc Natl Acad Sci U S A. 2002 Nov 26; 99(24):15614-15619. more... Harth G, Zamecnik PC, Tang JY, Tabatadze D, Horwitz MA. Treatment of Mycobacterium tuberculosis with antisense oligonucleotides to glutamine synthetase mRNA inhibits glutamine synthetase activity, formation of the poly-L-glutamate/glutamine cell wall structure, and bacterial replication. Proc Natl Acad Sci U S A. 2000 Jan 4; 97(1):418-23. more... Harth G, Horwitz MA. An inhibitor of exported Mycobacterium tuberculosis glutamine synthetase selectively blocks the growth of pathogenic mycobacteria in axenic culture and in human monocytes: extracellular proteins as potential novel drug targets. J Exp Med. 1999 May 3; 189(9):1425-36. more...

Reference: UCLA Case No. 2000-203

US Patent Application: 10/478,268