[Federal Register Volume 75, Number 51 (Wednesday, March 17, 2010)]
[Notices]
[Pages 12761-12764]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2010-5764]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
National Institutes of Health
Government-Owned Inventions; Availability for Licensing
AGENCY: National Institutes of Health, Public Health Service, HHS.
ACTION: Notice.
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SUMMARY: 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.
ADDRESSES: 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
[[Page 12762]]
be 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.
Applications
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;
[email protected].
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 protected]) 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.
Advantages
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).
Related Technologies
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;
[email protected].
Collaborative Research Opportunity: The National Heart, Lung and
Blood Institute Translational Medicine Branch is seeking statements of
capability or
[[Page 12763]]
interest 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 protected] 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.
Advantages
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; [email protected].
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 protected] 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.
Applications
Treating or preventing development of cancer or preventing
progression of premalignant lesions to cancer.
[[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.
Relevant Publications
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. Car[oacute]n 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;
[email protected].
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