National Institutes of Health, Public Health Service, HHS.
The inventions listed below are owned by an agency of the U.S. Government and are available for licensing in the U.S. in accordance with 35 U.S.C. 207 to achieve expeditious commercialization of results of Federally-funded research and development. Foreign patent applications are filed on selected inventions to extend market coverage for companies and may also be available for licensing.
Licensing information and copies of the U.S. patent applications listed below may be obtained by writing to the indicated licensing contact at the Office of Technology Transfer, National Institutes of Health, 6011 Executive Boulevard, Suite 325, Rockville, Maryland 20852-3804; telephone: 301/496-7057; fax: 301/402-0220. A signed Confidential Disclosure Agreement will Start Printed Page 12762be required to receive copies of the patent applications.
Caspase Inhibitors Useful for the Study of Autoimmune or Inflammatory Diseases
Description of Invention: Novel and potent caspase 1 inhibitors are available for licensing. In particular, this technology discloses potent and selective caspase 1 inhibitors that target the active site of the enzyme. Caspase 1 is known to play a pro-inflammatory role in numerous autoimmune and inflammatory diseases and therefore represents an excellent target for treatment of a broad range of diseases, including but not limited to Huntington's, amyotrophic lateral sclerosis, ischemia, rheumatoid arthritis, osteoarthritis, inflammatory bowel disease, and sepsis. Not surprisingly this enormous potential has resulted in at least three caspase 1 inhibitors entering clinical trials (VX-740, IDN-6556, and VX-765) in recent years.
- Potential therapeutic for a broad range of autoimmune diseases.
- Potential therapeutic for a broad range of inflammatory diseases.
Development Status: Early stage.
Market: The market size is potentially very large. For instance, rheumatoid arthritis alone affects 1% of the population, or about 2.5-3 million Americans. Further, it is estimated that osteoarthritis affects at least 16 million people in America.
Inventors: Craig J. Thomas and Matthew B. Boxer (NHGRI).
Publication: Boxer MB, Quinn AM, Shen M, Jadhav A, Leister W, Simeonov A, Auld DS, Thomas CJ. A highly potent and selective caspase 1 inhibitor that utilizes a key 3-cyanopropanoic acid moiety. Chem Med Chem., accepted.
Patent Status: U.S. Provisional Application No. 61/299,790 filed 29 Jan 2010 (HHS Reference No. E-308-2009/0-US-01).
Licensing Status: Available for licensing.
Licensing Contact: Steve Standley, PhD; 301-435-4074; firstname.lastname@example.org.
Collaborative Research Opportunity: The NIH Chemical Genomics Center is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize appropriate lead compounds described in U.S. Provisional Application No. 61/299,790. Please contact Dr. Craig J. Thomas via e-mail (email@example.com) for more information.
Defensin-Based Therapeutics for the Treatment of Pulmonary Disease
Description of Invention: Investigators at the National Heart, Lung and Blood Institute have developed modified defensins that are resistant to degradation, have improved characteristics compared to unmodified defensins, and are promising candidates for pulmonary disease therapeutics.
Defensins are small cationic peptides that defend the lung against pathogenic microorganisms and play an important role in innate immunity. However, during lung inflammation, defensin concentrations can reach levels that are cytotoxic for airway epithelial cells. Therefore, the development of methods to produce modified defensins that exhibit reduced cytotoxicity, while retaining the ability to stimulate the innate immune response, would be of potential therapeutic benefit for pulmonary diseases.
The inventors have previously shown that a defensin, human neutrophil peptide 1 (HNP-1), is elevated in samples from the lungs of patients with inflammatory lung disease, and that the HNP-1 in these samples is ADP-ribosylated at one or both of two arginine residues within the protein. In vitro studies by the inventors show that ADP-ribosyl-HNP-1 has reduced cytotoxic activity compared to HNP-1, while retaining its T cell chemotactic properties and ability to promote neutrophil recruitment, and thus ADP-ribosyl-HNP-1 may play an important role as a regulator of the inflammatory response. These properties would also be useful for treatment of pulmonary inflammation and lung diseases. However, ADP-ribosylated HNP-1 and other defensins are degraded rapidly in vivo due to the susceptibility of the ADP-ribose moiety to attack by hydrolases and pyrophosphatases, which limits their therapeutic potential.
The inventors have recently discovered that the ADP-ribosylated arginine residues in HNP-1 can be converted to ornithine through a non-enzymatic process that results in a peptide with an altered pharmacological profile. The investigators have also successfully generated ornithine-substituted ADP-ribosyl HNP-1 and ornithine-HNP-1 in vitro, which are currently being characterized. Thus, ornithine-substituted ADP-ribosyl HNP-1 and ornithine-HNP-1 may be promising candidates for the development of therapeutics to treat pulmonary disease, and the strategy of replacing ADP-ribosylated residues with ornithine to enhance stability and therapeutic efficacy may also be extended to other defensins
Through an earlier, related invention, the inventors have also demonstrated that recombinant proteins wherein tryptophan or phenylalanine residues substitute for ADP-ribosylarginine have a similar stabilizing impact on polypeptides, making them more suitable as therapeutic agents.
The inventors also hypothesize that it would be possible to develop a treatment that increases levels of an ADP-ribosylated therapeutic protein, such as HNP-1, in the lung via inhalation administration of the therapeutic protein in conjunction with nicotinamide adenine dinucleotide (NAD), which is required for ADP-ribosylation. This could represent a unique therapeutic strategy for treating pulmonary disease.
Applications: Development of defensin-based therapeutics that enhance the immune response in pulmonary disease patients, without damaging the epithelial cells lining the airway.
Modified defensins are less cytotoxic, while retaining ability to stimulate innate immunity.
Ornithine-substituted defensins are resistant to enzymatic degradation, making them more promising as drug candidates.
Development Status: In vitro studies, as well as analysis of patient samples, have been performed.
Inventors: Joel Moss et al. (NHLBI).
Relevant Publication: Stevens LA, Levine RL, Gochuico BR, Moss J. ADP-ribosylation of human defensin HNP-1 results in the replacement of the modified arginine with the noncoded amino acid ornithine. Proc Natl Acad Sci U S A. 2009 Nov 24;106(47):19796-19800. [PubMed: 19897717.]
Patent Status: U.S. Provisional Application No. 61/241,311 filed September 10, 2009 (HHS Reference No. E-243-2009/0-US-01).
- HHS Reference No. E-080-2002/0, “Modified Defensins and Their Use.”
- HHS Reference No. E-160-2002/0, “Tryptophan as a Functional Replacement for ADP-ribose-arginine in Recombinant Proteins.”
Licensing Status: Available for licensing.
Licensing Contact: Tara Kirby, PhD; 301-435-4426; firstname.lastname@example.org.
Collaborative Research Opportunity: The National Heart, Lung and Blood Institute Translational Medicine Branch is seeking statements of capability or Start Printed Page 12763interest from parties interested in collaborative research to further develop, evaluate, or commercialize defensin-based therapeutic agents to treat pulmonary diseases. Please contact Brian W. Bailey, PhD at 301-494-4094 or email@example.com for more information.
HTLV-II Vector and Methods of Use
Description of Invention: The invention hereby offered for licensing is in the field of vaccines and vaccine vectors. More specifically the invention provides compositions and methods of use of HTLV-II viral vector. The vector comprises at least a portion of the HTLV-II genome encoding the gag, pro, and pol genes and lacking all or a portion of the pX region. A heterologous gene is inserted within the deletion of the pX region. The gene of interest may encode all or a portion of a protein that corresponds to a viral protein of a foreign virus. The viral vectors thus constructed are useful for inducing immune response to the viral protein from the foreign virus. In particular the invention claims vaccines against HIV and SIV.
Applications: The technology can be used for DNA-based vaccines.
- Vaccines based on HTLV-II vectors have exhibited the capability to eliciting T cell response effectively. In particular they induce specific CD4+ and CD8+ T cell response. Antibody response to the HTLV-II vector is almost undetectable. The vector is infectious, but highly attenuated, with respect to the wild type HTLV-II. Desirably, the HTLV-II viral vector induces antibodies that can participate in Antibody-Dependent-Cell-Mediated Cytotoxicity (ADCC), a mechanism that enhances its effectiveness.
- Most of the T-cell vaccines developed for HIV are based on microbial vectors that have limited replication capacity and do not persist in the host. Such vaccines do not protect macaques from SIV infection and their ability to protect against high virus load is merely transient (approximately six months). They are perceived to elicit too “small T-cell responses” that expand “too late”. In addition, few of these vectors target mucosal sites, the first portal of HIV entry. In contrast, an HTLV II based vaccine is anticipated to infect macaques and replicate at very low level in lymphoid tissue and particularly in the gut which may enable them to maintain sufficient level of effectors CD8 memory cells to decrease early seeding of the virus, and sufficient level of central memory cells in lymph nodes that may limit the broadcasting of the virus at distal sites. These features make an HTLV-II based vaccine for HIV an excellent unique candidate to target mucosal tissues and provide long lasting mucosal immunity to HIV. In addition, the HTLV II infects dendritic cells both in vivo and in vitro, and the HTLV II infected dendritic cells have a mature phenotype, suggesting that HIV antigens expressed within dendritic cells could be effectively presented to the immune system.
- HTLV II is a human retrovirus with no clear disease associations neither in healthy nor in HIV infected individuals
- HTLV shares many biological and molecular characteristics of HIV, including routes of transmission, a T-cell tropism and gut tropism.
- Based on the above, it is believed that HIV vaccines based on HTLV II vector will exhibit superiority compared to other vaccines in development.
Development Status: At the present only in vitro as well as animal (macaques) data that demonstrate the proof of concept are available. The data indicates that an HTLV II based vaccine could replicate in the appropriate body compartment and confer immunity in humans. The inventors continue to work on the development of this approach.
Market: In spite of major global efforts of more than 25 years in developing a vaccine against HIV/AIDS, such a vaccine is still not in existence but yet very much needed for the fight against the global epidemic of HIV/AIDS. The market for HIV/AIDS drugs is currently at the level of approximately $6 billion a year and is expected to grow to $13 billion by the year 2015. Should an effective vaccine be developed the market for such a vaccine may exceed this level. The instant technology may offer superiority to existence approaches in the area of HIV vaccines and thus a huge commercial opportunity for pharmaceutical/vaccine enterprises as well as a major contribution for global public health.
Inventors: Genoveffa Franchini et al. (NCI).
Publications: Paper in preparation.
Patent Status: PCT Application No. PCT/US2009/051138 filed 20 Jul 2009, which published as WO 2010/009465 on 21 Jan 2010 (HHS Reference No. E-269-2008/1-PCT-01).
Related Technologies: RhCMV SIV vaccine (Picker et al.)
Licensing Status: Available for licensing.
Licensing Contact: Susan Ano, PhD; 301-435-5515; firstname.lastname@example.org.
Collaborative Research Opportunity: The National Cancer Institute, Animal Models & Retroviral Vaccine Section, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize HTLV-II vectored HIV vaccines. Please contact John D. Hewes, PhD at 301-435-3121 or email@example.com for more information.
Prevention and Treatment of Cancer With Kinase Inhibitors Targeting the PH Domain of AKT
Description of Invention: Activation of the PI3K/Akt signaling pathway has been implicated in the development of cancer. Akt, a kinase that is central to this pathway, is found at elevated levels in many tumors and is associated with a poor disease prognosis. Further research has validated Akt as a therapeutic target for the development of anti-cancer drugs. Most efforts of drug development targeting Akt have focused on inhibitors of the ATP-binding domain which have the drawback that they interfere with other physiologically important kinases. This is reflected in that no Akt inhibitors have been clinically approved. However, investigators at the National Institutes of Health (NIH) and Georgetown University (GU) have developed an alternative strategy that improves Akt specificity by targeting the unique pleckstrin homology (PH) domain of Akt.
Scientists at NIH and GU have discovered several lipid-based inhibitors of Akt called phosphatidylinositol ether lipid analogues (PIAs) that target the pleckstrin homology (PH) domain of Akt. These PIAs, which are analogues of the products of phosphatidylinositol 3-kinase (PI3K), inhibit Akt within minutes and selectively kill cancer cells that contain high levels of Akt activation. The mechanism of action of these compounds has been intensively studied providing much insight into how PIAs inhibit the growth of cancer cells. In addition, several molecular targets have been identified that highly correlate with cancer cell sensitivity to PIA that potentially could serve as clinical biomarkers predictive of responsiveness to PIAs. U.S. and Australian patents issued for this invention have composition and method of use claims.
- Treating or preventing development of cancer or preventing progression of premalignant lesions to cancer.Start Printed Page 12764
- Used as single agents or in combination with other anti-cancer treatments like chemotherapy, biological therapy, or radiation.
Advantages: Targeting the PH domain improves specificity against Akt kinase in comparison to inhibitors of the ATP domain which typically are unspecific.
Inventors: Phillip A. Dennis (NCI) et al.
1. Memmott RM, Gills JJ, Hollingshead M, Powers MC, Chen Z, Kemp B, Kozikowski A, Dennis PA. Phosphatidylinositol ether lipid analogues induce AMP-activated protein kinase-dependent death in LKB1-mutant non small cell lung cancer cells. Cancer Res. 2008 Jan 15;68(2):580-588. [PubMed: 18199555.]
2. Gills JJ, Castillo SS, Zhang C, Petukhov PA, Memmott RM, Hollingshead M, Warfel N, Han J, Kozikowski AP, Dennis PA. Phosphatidylinositol ether lipid analogues that inhibit AKT also independently activate the stress kinase, p38alpha, through MKK3/6-independent and -dependent mechanisms. J Biol Chem. 2007 Sep 14;282(37):27020-27029. [PubMed: 17631503.]
3. Gills JJ, Holbeck S, Hollingshead M, Hewitt SM, Kozikowski AP, Dennis PA. Spectrum of activity and molecular correlates of response to phosphatidylinositol ether lipid analogues, novel lipid-based inhibitors of Akt. Mol Cancer Ther. 2006 Mar;5(3):713-722. [PubMed: 16546986.]
4. Carón RW, Yacoub A, Li M, Zhu X, Mitchell C, Hong Y, Hawkins W, Sasazuki T, Shirasawa S, Kozikowski AP, Dennis PA, Hagan MP, Grant S, Dent P. Activated forms of H-RAS and K-RAS differentially regulate membrane association of PI3K, PDK-1, and AKT and the effect of therapeutic kinase inhibitors on cell survival. Mol Cancer Ther. 2005 Feb;4(2):257-270. [PubMed: 15713897.]
5. Castillo SS, Brognard J, Petukhov PA, Zhang C, Tsurutani J, Granville CA, Li M, Jung M, West KA, Gills JG, Kozikowski AP, Dennis PA. Preferential inhibition of Akt and killing of Akt-dependent cancer cells by rationally designed phosphatidylinositol ether lipid analogues. Cancer Res. 2004 Apr 15;64(8):2782-2792. [PubMed: 15087394.]
6. Kozikowski AP, Sun H, Brognard J, Dennis PA. Novel PI analogues selectively block activation of the pro-survival serine/threonine kinase Akt. J Am Chem Soc. 2003 Feb 5;125(5):1144-1145. [PubMed: 12553797.]
Patent Status: U.S. Patent No. 7,378,403 issued 27 May 2008 (HHS Reference No. E-245-2002/0-US-03), and related international filings.
Licensing Status: Available for licensing.
Licensing Contact: Surekha Vathyam, PhD; 301-435-4076; firstname.lastname@example.org.Start Signature
Dated: March 10, 2010.
Richard U. Rodriguez,
Director, Division of Technology Development and Transfer, Office of Technology Transfer, National Institutes of Health.
[FR Doc. 2010-5764 Filed 3-16-10; 8:45 am]
BILLING CODE 4140-01-P