Description of Invention: This invention describes methods of making high yields of biliverdin, the pharmaceutical compositions of biliverdin made using that process, and methods of using the compositions therapeutically.
In reaction to a wide range of cellular stresses, hemoglobin is naturally metabolized to biliverdin, which is then quickly metabolized to bilirubin, a bile pigment, through a highly conserved set of enzymes. Both bilirubin and biliverdin are normally processed for rapid excretion, and excessive serum levels of bilirubin have known toxic effects (most notably jaundice). Surprisingly, research in the past decade has shown that decreasing serum levels correlate inversely with the prognosis of various disorders, such as ischemia/reperfusion injuries, atherosclerosis, organ transplantation, and several autoimmune diseases. Indeed, in animal-model studies, inducing a mild case of jaundice actually improved outcome. Unfortunately, bilirubin is relatively insoluble, and so is not a practical pharmaceutical itself.
Biliverdin has lower direct toxicity and substantially greater solubility than bilirubin, and also appears to have some direct therapeutic effects similar to bilirubin. Accordingly, biliverdin has been widely studied lately. Generating high yields of pure biliverdin is difficult, however, because any system with the enzymes to break down hemoglobin also has enzymes converting biliverdin to bilirubin. The inventors have created a system of generating microorganisms (yeast) lacking the enzymes that break biliverdin down to bilirubin.
Applications: Production of biliverdin for immunomodulatory and cytoprotective therapy (or adjuvant) in any condition involving an overactive immune response.
Advantages:
High yield of biliverdin with low contamination of bilirubin
Produces only active isomers of biliverdin
Unlike prior methods, new method uses starting material that is inexpensive and plentiful
Development Status: Successful generation of Candida albicans with biliverdin-generating system.
ML Pendrak et al. Heme oxygenase in Candida albicans is regulated by hemoglobin and is necessary for metabolism of exogenous heme and hemoglobin to alpha-biliverdin. J Biol Chem. 20 Jan 2004;279(5):3426-3433. [ PubMed abs ]
Licensing Status: Available for licensing.
Collaborative Research Opportunity: The Laboratory of Pathology in the Center for Cancer Research of the National Cancer Institute is seeking parties interested in collaborative research directed toward clinical applications of biliverdin. For more information about the research, please contact either Dr. Michael Pendrak (NCI/CCR Laboratory of Pathology) at (301) 496-6264, or Dr. April Franks (NCI Technology Transfer Center) at (301) 496-0477.
Portfolios: Cancer Cancer - Therapeutics Infectious Diseases Infectious Diseases - Therapeutics Internal Medicine Internal Medicine - Therapeutics Central Nervous System Central Nervous System - Therapeutics
For Additional Information Please Contact: Susan Ano Ph.D. NIH Office of Technology Transfer 6011 Executive Blvd. Suite 325, Rockville, MD 20852 United States Email: anos@mail.nih.gov Phone: 301-435-5515 Fax: 301-402-0220
Description of Invention:
This invention describes methods of making high yields of biliverdin, the pharmaceutical compositions of biliverdin made using that process, and methods of using the compositions therapeutically.
In reaction to a wide range of cellular stresses, hemoglobin is naturally metabolized to biliverdin, which is then quickly metabolized to bilirubin, a bile pigment, through a highly conserved set of enzymes. Both bilirubin and biliverdin are normally processed for rapid excretion, and excessive serum levels of bilirubin have known toxic effects (most notably jaundice). Surprisingly, research in the past decade has shown that decreasing serum levels correlate inversely with the prognosis of various disorders, such as ischemia/reperfusion injuries, atherosclerosis, organ transplantation, and several autoimmune diseases. Indeed, in animal-model studies, inducing a mild case of jaundice actually improved outcome. Unfortunately, bilirubin is relatively insoluble, and so is not a practical pharmaceutical itself.
Biliverdin has lower direct toxicity and substantially greater solubility than bilirubin, and also appears to have some direct therapeutic effects similar to bilirubin. Accordingly, biliverdin has been widely studied lately. Generating high yields of pure biliverdin is difficult, however, because any system with the enzymes to break down hemoglobin also has enzymes converting biliverdin to bilirubin. The inventors have created a system of generating microorganisms (yeast) lacking the enzymes that break biliverdin down to bilirubin.
Applications:
Production of biliverdin for immunomodulatory and cytoprotective therapy (or adjuvant) in any condition involving an overactive immune response.
Advantages:
Development Status:
Successful generation of Candida albicans with biliverdin-generating system.
Inventors:
Michael L Pendrak (NCI)
David D Roberts (NCI)
Patent Status:
HHS, Reference No. E-040-2004/0
US, , Patent No. 7,504,243, Issued 17 Mar 2009
US, Application No. 12/364,054 filed 02 Feb 2009
Relevant Publication:
Licensing Status:
Available for licensing.
Collaborative Research Opportunity:
The Laboratory of Pathology in the Center for Cancer Research of the National Cancer Institute is seeking parties interested in collaborative research directed toward clinical applications of biliverdin. For more information about the research, please contact either Dr. Michael Pendrak (NCI/CCR Laboratory of Pathology) at (301) 496-6264, or Dr. April Franks (NCI Technology Transfer Center) at (301) 496-0477.
Portfolios:
Cancer
Cancer - Therapeutics
Infectious Diseases
Infectious Diseases - Therapeutics
Internal Medicine
Internal Medicine - Therapeutics
Central Nervous System
Central Nervous System - Therapeutics
For Additional Information Please Contact:
Susan Ano Ph.D.
NIH Office of Technology Transfer
6011 Executive Blvd. Suite 325,
Rockville, MD 20852
United States
Email: anos@mail.nih.gov
Phone: 301-435-5515
Fax: 301-402-0220
Ref No: 931
Updated: 07/2009