Government-Owned Inventions; Availability for Licensing, 3716-3718 [05-1415]
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3716
Federal Register / Vol. 70, No. 16 / Wednesday, January 26, 2005 / Notices
Dated: January 14, 2005.
Dr. Carl Roth,
Associate Director for Scientific Program
Operations, National Heart, Lung, and Blood
Institute.
[FR Doc. 05–1412 Filed 1–25–05; 8:45 am]
BILLING CODE 4140–01–M
DEPARTMENT OF HEALTH AND
HUMAN SERVICES
National Institutes of Health
Government-Owned Inventions;
Availability for Licensing
National Institutes of Health,
Public Health Service, HHS.
ACTION: Notice.
AGENCY:
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
be required to receive copies of the
patent applications.
Treatment of Inappropriate Immune
Responses
Drs. He Xu and Allan D. Kirk (NIDDK)
U.S. Provisional Patent Application
filed Jun 18, 2004 (DHHS Reference
No. E–102–2004/0–US–01)
Licensing Contact: Marlene ShinnAstor; 301/435–4426;
shinnm@mail.nih.gov.
Activated human leukocytes play an
essential role in counter-adaptive
immune responses such as allograft
rejection, autoimmune disease, and
graft-versus-host disease. Depletion of
leukocytes involved in these responses
by using preparations of leukocytesspecific antibodies may be therapeutic
in preventing and reversing these
conditions. To date, however, the
available monoclonal preparations do
not have sufficiently broad specificity to
limit the activity of many types of cells
involved in counter-adaptive immunity,
VerDate jul<14>2003
19:33 Jan 25, 2005
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and the available polyclonal
preparations have significant side
effects caused by their unintended
specificity for bystander cells or cells
with beneficial properties.
The NIH announces a new treatment
for blocking an undesirable immune
response, wherein polyclonal antibodies
are designed to preferentially target
activated immune cells, rather than
resting immune cells or blood cells
involved in non-immune processes.
These antibodies have a heightened
specificity for activated lymphocytes
and monocytes and decreased activity
for resting or beneficial leukocytes and
other blood elements.
A Novel Nuclear Receptor Cofactor
Modulates Glucocorticoid-Responsive
Gene Expression
S. Stoney Simons and Yuanzheng He
(NIDDK);
U.S. Patent Application No. 60/548, 039
filed 26 Feb 2004 (DHHS Reference
No. E–056–2004/0–US–01);
Licensing Contact: Susan Carson, (301)
435–5020; carsonsu@mail.nih.gov.
Nuclear receptors are ligand-activated
transcription factors that regulate a wide
range of biological processes and
dysfunction of these receptors can lead
to proliferative, reproductive and
metabolic diseases, such as cancer,
infertility, obesity and diabetes. Nuclear
receptors are the second largest class of
drug targets and the market for nuclear
receptor targeted drugs is estimated to
be almost 15% of the $400 billion global
pharmaceutical market. Researchers at
the National Institute of Diabetes and
Digestive and Kidney Disease have
isolated a novel protein termed STAMP
(SRC–1 and TIF–2 Associated
Modulatory Protein) that interacts with
the biologically active domains of the
coactivators TIF–2 and SRC–1 (J. Biol.
Chem. (2002) 51, 49256–66) and present
data which support a role for STAMP as
an important new factor in the
glucocorticoid regulatory network.
There remains a need for novel
therapeutics that specifically block or
enhance specific genes and an emerging
therapeutic goal is the discovery of
agents that modulate co-activators or corepressors in a tissue specific manner.
The invention is a novel protein that
plays a key role in modulating
transcriptional properties of
glucocorticoid receptor (GR)-steroid
complexes during both gene induction
and gene repression, and is likely to
modulate the transcriptional properties
of all the steroid receptors including
androgen, mineralocorticoid and
progesterone receptors. The inventors
have shown that ectopically expressed
STAMP protein both modulates the
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EC50 of glucocorticoid receptor-agonist
complexes for induced genes and
increases glucocorticoid receptorrepressive activity of suppressed genes
in a manner that is inhibited by specific
siRNAs under physiologically relevant
conditions. The modulation of STAMP
levels at the cell or organism level could
possibly be used as a therapeutic able to
modify inappropriate gene expression
that occurs in certain diseases or as a
result of long-term steroid treatment.
Available for licensing are claims
directed to compositions which are
capable of modulating the GR gene
expression in a mammalian cell using
DNA, siRNA or antibodies and to
methods of shifting a steroid doseresponse curve, where less of the steroid
needs to be administered because the
composition contains the STAMP
polypeptide. The novel STAMP
functional sequence can be used in a
composition of matter claim or as a
target that could be regulated by an
antibody or perhaps other modulator
that would vary the ability of STAMP to
either induce or repress the activity of
glucocorticoid receptors. Diseases that
could be treated include: hypertension,
diabetes, cardiovascular disease,
osteoporosis, Cushing’s Disease as well
as any disease requiring chronic steroid
treatment such as Rheumatoid Arthritis,
Asthma, inflammatory and autoimmune diseases. The present invention
provides a broad, flexible IP platform
that should be of interest to companies
which focus on nuclear receptors as
drug target and lead discovery
generators, as well as to companies
which have the capability to develop
STAMP’s potential as a therapeutic.
In addition to licensing, the
technology is available for further
development through collaborative
research with the inventors via a
Cooperative Research and Development
Agreement (CRADA).
Generation of Smad3-Null Mice and
Smad4-Conditional Mice
Chuxia Deng (NIDDK);
DHHS Reference Nos. E–349–2003/0
and E–350–2003/0—Research Tools;
Licensing Contact: Marlene ShinnAstor; (301) 435–4426;
shinnm@mail.nih.gov.
SMADs are a novel set of mammalian
proteins that act downstream of TGFbeta family ligands. These proteins can
be categorized into three distinct
functional sets, receptor-activated
SMADs (SMADs 1, 2, 3, 5, and 8), the
common mediator SMAD (SMAD 4),
and inhibitory SMADs (SMADs 6 and
7). SMAD proteins are thought to play
a role in vertebrate development and
tumorigenesis.
E:\FR\FM\26JAN1.SGM
26JAN1
Federal Register / Vol. 70, No. 16 / Wednesday, January 26, 2005 / Notices
One of the research tools our NIH
inventors have prepared is the Smad3null mice model, created by disrupting
exon 8 on the Smad3 gene.
Symptomatic mice exhibit leukocytosis,
with massive inflammation and
pyogenous abscess formation adjacent to
mucosal surfaces. Smad3 plays an
important role in mediating TGF-beta
signals in T lymphocytes and in
neutrophils, and demonstrate that
Smad3 deficiency results in immune
dysregulation and susceptibility to
opportunistic infection, ultimately
leading to the lethality of the mice
between 1 and 8 months. TGF-beta
signals also play a role in cancer
formation in multiple organs and
tissues. Smad3-null mice could be used
to clone downstream target genes for
TGF-beta signals, which may be used in
gene therapy and chemoprevention
studies.
Smad4-null mice die around
embryonic day 6.5, so the inventors
prepared the SMAD4-conditional mice
model, created by a Smad4 conditional
knockout allele at exon 8 using Cremediated recombination. PCR analysis
determined Cre-mediated recombination
in the pancreas but not in a number of
other organs, indicating that the Smad4
conditional allele can be recombined to
delete exon 8 in a tissue-specific
fashion. This knockout mouse could be
used to test the function of TGF-beta/
Smad4 signals at all stages of mouse
development. Interestingly, mutation of
human Smad4 has been found in
approximately half of all pancreatic
cancers, 30 percent of colon cancers,
and about 10 percent in other cancers.
The Smad4-conditional mice could be
used to study pathways that are
involved in formation of these tumors or
to clone downstream target genes that
may be used in gene therapy and
chemoprevention studies.
Additional information may be found
in the following research articles: Yang
et al., ‘‘Generation of Smad4/Dpc4
conditional knockout mice,’’ Genesis
2002 Feb; 32(2):80–81, Epub 13 Feb
2002 doi 10.1002/gene.10029; Yang et
al., ‘‘Targeted disruption of SMAD3
results in impaired mucosal immunity
and diminished T cell responsiveness to
TGF-beta,’’ EMBO J. 1999 Mar 1;
18(5):1280–1291, Epub doi: 10.1093/
emboj/18.5.1280.
In addition to licensing, the
technology is available for further
development through collaborative
research with the inventors via a
Cooperative Research and Development
Agreement (CRADA).
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Anti-Proliferative Activity of an
Unexpected mTOR Kinase Inhibitor
Joel Moss and Arnold Kristof (NHLBI);
U.S. Provisional Patent Application No.
60/528,340 filed 09 Dec 2003 (DHHS
Reference No. E–259–2003/0–US–01);
PCT Application filed 09 Dec 2004
(DHHS Reference No. E–259–2003/0–
PCT–02);
Licensing Contact: Susan Carson; 301/
435–5020; carsonsu@mail.nih.gov.
The second leading cause of death in
the United States is cancer and more
than one million Americans are
diagnosed with cancer each year, with
this number likely to increase as the
population ages. There remains a need
for effective therapeutics with improved
safety profiles, and promising results
have been obtained from targeting the
phosphatidylinositol-3-kinase (PI3K)
signalling cascade (including PI3K,
AKT/PKB and mammalian target of
rapamycin (mTOR/S6K) kinases) which
is integral to the regulation of cell
growth, protein synthesis and apoptosis
in response to nutrients and mitogens,
and which is frequently dysregulated in
different cancers and other proliferative
diseases. In particular, efforts have been
directed at inhibiting specific kinases in
this pathway as effective treatments for
cancer, restenosis and autoimmune
diseases and researchers at the National
Heart, Lung and Blood Institute have
recently shown that one of the 4H-1benzopyran-4—one derivatives is
unexpectedly an effective mTOR
inhibitor.
Proof of concept data is available.
This compound has been shown to
attenuate tumor growth in an in vivo
human xenograft PC–3 prostate tumor
model, without observed toxicity. An
improved therapeutic safety profile is
suggested, as this compound was a weak
inhibitor of PI3K. Further data indicate
that inhibition of cell proliferation
occurs through both mTOR-dependent
and mTOR-independent mechanisms,
suggesting a novel kinase inhibitor.
Additionally, this cytostatic compound
is shown to have an anti-inflammatory
effect in peritoneal macrophages.
Finally, this compound inhibits primary
human smooth muscle cell proliferation
in vitro, suggesting a possible role in the
treatment of vascular restenosis.
This compound may therefore prove
to be an effective anti-proliferative
therapeutic. Available for licensing are
methods of use directed to derivatives of
2-(4-piperazinyl)-substituted 4H-1benzopyran-4—one compounds as
antiproliferative, immunosuppressive
and anti-neoplastic agents.
In addition to licensing, the
technology is available for further
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3717
development through collaborative
research with the inventors via a
Cooperative Research and Development
Agreement (CRADA contact: Vincent
Kolesnitchenko; Tel: (301) 402–5579; Email: kolesniv@nhlbi.nih.gov).
Methods for Making and Using Mass
Tag Standards for Quantitative
Proteomics
David E. Anderson (NIDDK);
U.S. Provisional Application No. 60/
574,612 filed 25 May 2004 (DHHS
Reference No. E–200–2003/0–US–01);
Licensing Contact: Fatima Sayyid; (301)
435–4521; sayyidf@mail.nih.gov.
There is a growing need for peptide
standards for quantitative proteomic
analysis of gene and cellular functions
in cells and tissues. Current methods for
generating peptide standards for
identification and absolute
quantification of proteins rely almost
solely on synthetic approaches which
require expensive reagents, equipment
and rare expertise.
The present invention describes a
process for simultaneously generating
peptide standards of known
concentration for several proteins of
interest within a single easily
parallelized experiment. This process
uses a combination of automated
synthetic gene design, gene synthesis,
cloning, bacterial expression with heavy
isotope incorporation, generic protein
purification, optical quantitation, and
endoprotease cleavage to make sets of
peptides of known concentration. Nonmodified peptides can be made for a
fraction of the cost of synthetic
approaches. Since the main cost
involves the initial production of a DNA
construct, follow-up preparations of
peptides (which can use different
isotope backgrounds) are even cheaper.
A Method of Treating Inflammatory
Bowel Disease (IBD)
Warren Strober, Ivan Fuss, Frank Heller,
Richard Blumberg (NIAID); PCT
Application No. PCT/US2002/018790
filed 14 Jun 2002, which published as
International Publication No. WO
2004/001655 on 31 Dec 2003 (DHHS
Reference No. E–131–2002/0–PCT–
01)
Licensing Contact: Susan Carson; (301)
435–5020; carsonsu@mail.nih.gov.
Ulcerative colitis (UC) is a chronic
inflammatory disease of the colorectum
and affects approximately 400,000
people in the United States (of these,
approximately 5 percent develop colon
cancer). The cause of UC is not known,
although an abnormal mucosal T cell,
responsive to bacterial antigens in the
gut microflora, is thought to be
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3718
Federal Register / Vol. 70, No. 16 / Wednesday, January 26, 2005 / Notices
involved. Present treatments for UC
include anti-inflammatory therapy using
aminosalicylates or corticosteroids, as
well as immunomodulators and diet.
However, 25–40 percent of ulcerative
colitis patients must eventually have
their colons removed due to massive
bleeding, severe illness, rupture of the
colon, risk of cancer or due to side
effects of corticosteroids and novel
treatments are still actively being
sought. NIH scientists and their
collaborators have used a mouse model
of experimental colitis (OC) to show that
IL–13, a Th2 cytokine, is a significant
pathologic factor in OC and that
neutralizing IL–13 in these animals
effectively prevents colitis (Immunity
(2002) 17, 629–638).
OC is a colitis induced by intrarectal
administration of a relatively low dose
of the haptenating agent oxazolone
subsequent to skin sensitization with
oxazolone. A highly reproducible and
chronic colonic inflammation is
obtained that is histologically similar to
human ulcerative colitis. Studies show
that NKT cells rather than conventional
CD4+T cells mediate oxazolone colitis
and that NKT cells are the source of IL–
13, and are activated by CD1 expressing
intestinal epithelial cells. Tissue
removed from UC patients were also
shown to contain increased numbers of
nonclassical NKT cells that produce
markedly increased amounts of IL–13
and that in keeping with epithelial
damage being a key factor in UC, these
NKT cells are cytotoxic for epithelial
cells (J. Clin. Investigation (2004) 113,
1490–1497).
With obvious implications for the
treatment of human Ulcerative Colitis,
inflammation in this mouse model has
been shown to be effectively blocked by
neutralizing IL–13 or by inhibiting the
activation of NK–T cells through CD1.
Available for licensing are broad claims
covering treatments preventing the
inflammatory response of colitis by
modulating IL–13 and NKT cell activity
and methods for screening for
therapeutic compounds effective for
colitis.
In addition to licensing, the
technology is available for further
development through collaborative
research with the inventors via a
Cooperative Research and Development
Agreement (CRADA).
Dated: January 18, 2005.
Steven M. Ferguson,
Director, Division of Technology Development
and Transfer, Office of Technology Transfer,
National Institutes of Health.
[FR Doc. 05–1415 Filed 1–25–05; 8:45 am]
BILLING CODE 4140–01–P
VerDate jul<14>2003
19:33 Jan 25, 2005
Jkt 205001
DEPARTMENT OF HEALTH AND
HUMAN SERVICES
National Institutes of Health
Government-Owned Inventions;
Availability for Licensing
National Institutes of Health,
Public Health Service, HHS.
ACTION: Notice.
AGENCY:
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
be required to receive copies of the
patent applications.
Null Mutation of the CCAAT/Enhancer
Binding Protein Delta (Cebpd) Gene in
Mice
G. Esta Sterneck et al. (NCI);
DHHS Reference No. E–032–2005/0—
Research Tool;
Licensing Contact: John Stansberry; 301/
435–5236; stansbej@mail.nih.gov.
The invention describes mice with a
deletion of the C/EBPdelta gene and cell
lines derived from such mice. C/
EBPdelta (CCAAT/enhancer binding
protein delta) is implicated in the acute
phase inflammatory response, long-term
memory, fat cell and osteoblast
differentiation, ovarian hormone
responses, mammary gland involution
and cell death. C/EBPdelta may also be
a tumor suppressor. Fibroblasts lacking
C/EBPdelta exhibit transformed features
such as impaired contact inhibition,
reduced serum dependence and
chromosomal instability. The mice and
cell lines of the invention could be
useful for the study of the function of C/
EBPdelta such as its potential role in
cancer, and to investigate how drug
responses are modified in the absence of
C/EBPdelta.
In addition to licensing, the
technology is available for further
development through collaborative
PO 00000
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Fmt 4703
Sfmt 4703
research with the inventors via a
Cooperative Research and Development
Agreement (CRADA).
Active Chromatin Domains Are Defined
by Acetylation Islands Revealed by
Genome-Wide Mapping
Drs. Keji Zhao and Tae-Young Roh
(NHLBI);
U.S. Provisional Application No. 60/
619,430 filed 15 Oct 2004 (DHHS
Reference No. E–008–2005/0–US–01);
Licensing Contact: John Stansberry; 301/
435–5236; stansbej@mail.nih.gov.
Epigenetics play a critical role in
cellular development and cellular
transformation in many pathogenic
processes. For example, many cancers
are correlated with changes of their
chromatin structure and are sensitive to
drugs that module the levels of histone
acetylation. Epigenetic regulation refers
to the modification of histones, which
does not involve changes of DNA
sequences of target genes. The present
technology maps the genome-wide
distribution of histone H3 acetylation in
human T cells and describes over
40,000 acetylation islands. These
acetylation islands are epigenetic
markers for transcriptional regulatory
elements and chromatin-controlling
elements. Changes in acetylation islands
may be correlated with early
development of T cell lymphoma or
leukemia. Specifically, diseases
characterized by aberrant transcriptional
regulation could be diagnosed earlier
with the application of this technology.
Method of Detecting Cancer Based on
Immune Reaction to BORIS
Victor Lobanenkov et al. (NIAID);
U.S. Provisional Application No. 60/
611,798 filed 21 Sep 2004 (DHHS
Reference No. E–241–2004/0–US–01);
Licensing Contact: Mojdeh Bahar; 301/
435–2950; baharm@mail.nih.gov.
The invention provides a method of
detecting autoantibodies to BORIS
(brother of the regulator of imprinted
sites) as a possible screen for cancer and
a kit comprising BORIS peptides and
epitopes. BORIS is a protein that is
expressed in many cancers but not in
normal tissues (except testis) and thus is
a potential target for a cancer
therapeutic or diagnostic.
Importantly, BORIS is a cancer-testis
(CT) antigen, which despite that it is
intracellular protein upon abnormal
expression in cancer it appears to be
immunogenic in humans. Thus, BORIS
could be employed in cancer diagnosis
using serum from patients. In fact, the
inventors detected BORIS-specific
antibodies in serum from patients with
gliomas, lung, breast and prostate
E:\FR\FM\26JAN1.SGM
26JAN1
]]>Agencies
[Federal Register Volume 70, Number 16 (Wednesday, January 26, 2005)]
[Notices]
[Pages 3716-3718]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[FR Doc No: 05-1415]
-----------------------------------------------------------------------
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.
-----------------------------------------------------------------------
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 be required to receive
copies of the patent applications.
Treatment of Inappropriate Immune Responses
Drs. He Xu and Allan D. Kirk (NIDDK)
U.S. Provisional Patent Application filed Jun 18, 2004 (DHHS Reference
No. E-102-2004/0-US-01)
Licensing Contact: Marlene Shinn-Astor; 301/435-4426;
shinnm@mail.nih.gov.
Activated human leukocytes play an essential role in counter-
adaptive immune responses such as allograft rejection, autoimmune
disease, and graft-versus-host disease. Depletion of leukocytes
involved in these responses by using preparations of leukocytes-
specific antibodies may be therapeutic in preventing and reversing
these conditions. To date, however, the available monoclonal
preparations do not have sufficiently broad specificity to limit the
activity of many types of cells involved in counter-adaptive immunity,
and the available polyclonal preparations have significant side effects
caused by their unintended specificity for bystander cells or cells
with beneficial properties.
The NIH announces a new treatment for blocking an undesirable
immune response, wherein polyclonal antibodies are designed to
preferentially target activated immune cells, rather than resting
immune cells or blood cells involved in non-immune processes. These
antibodies have a heightened specificity for activated lymphocytes and
monocytes and decreased activity for resting or beneficial leukocytes
and other blood elements.
A Novel Nuclear Receptor Cofactor Modulates Glucocorticoid-Responsive
Gene Expression
S. Stoney Simons and Yuanzheng He (NIDDK);
U.S. Patent Application No. 60/548, 039 filed 26 Feb 2004 (DHHS
Reference No. E-056-2004/0-US-01);
Licensing Contact: Susan Carson, (301) 435-5020; carsonsu@mail.nih.gov.
Nuclear receptors are ligand-activated transcription factors that
regulate a wide range of biological processes and dysfunction of these
receptors can lead to proliferative, reproductive and metabolic
diseases, such as cancer, infertility, obesity and diabetes. Nuclear
receptors are the second largest class of drug targets and the market
for nuclear receptor targeted drugs is estimated to be almost 15% of
the $400 billion global pharmaceutical market. Researchers at the
National Institute of Diabetes and Digestive and Kidney Disease have
isolated a novel protein termed STAMP (SRC-1 and TIF-2 Associated
Modulatory Protein) that interacts with the biologically active domains
of the coactivators TIF-2 and SRC-1 (J. Biol. Chem. (2002) 51, 49256-
66) and present data which support a role for STAMP as an important new
factor in the glucocorticoid regulatory network. There remains a need
for novel therapeutics that specifically block or enhance specific
genes and an emerging therapeutic goal is the discovery of agents that
modulate co-activators or co-repressors in a tissue specific manner.
The invention is a novel protein that plays a key role in
modulating transcriptional properties of glucocorticoid receptor (GR)-
steroid complexes during both gene induction and gene repression, and
is likely to modulate the transcriptional properties of all the steroid
receptors including androgen, mineralocorticoid and progesterone
receptors. The inventors have shown that ectopically expressed STAMP
protein both modulates the EC50 of glucocorticoid receptor-agonist
complexes for induced genes and increases glucocorticoid receptor-
repressive activity of suppressed genes in a manner that is inhibited
by specific siRNAs under physiologically relevant conditions. The
modulation of STAMP levels at the cell or organism level could possibly
be used as a therapeutic able to modify inappropriate gene expression
that occurs in certain diseases or as a result of long-term steroid
treatment.
Available for licensing are claims directed to compositions which
are capable of modulating the GR gene expression in a mammalian cell
using DNA, siRNA or antibodies and to methods of shifting a steroid
dose-response curve, where less of the steroid needs to be administered
because the composition contains the STAMP polypeptide. The novel STAMP
functional sequence can be used in a composition of matter claim or as
a target that could be regulated by an antibody or perhaps other
modulator that would vary the ability of STAMP to either induce or
repress the activity of glucocorticoid receptors. Diseases that could
be treated include: hypertension, diabetes, cardiovascular disease,
osteoporosis, Cushing's Disease as well as any disease requiring
chronic steroid treatment such as Rheumatoid Arthritis, Asthma,
inflammatory and auto-immune diseases. The present invention provides a
broad, flexible IP platform that should be of interest to companies
which focus on nuclear receptors as drug target and lead discovery
generators, as well as to companies which have the capability to
develop STAMP's potential as a therapeutic.
In addition to licensing, the technology is available for further
development through collaborative research with the inventors via a
Cooperative Research and Development Agreement (CRADA).
Generation of Smad3-Null Mice and Smad4-Conditional Mice
Chuxia Deng (NIDDK);
DHHS Reference Nos. E-349-2003/0 and E-350-2003/0--Research Tools;
Licensing Contact: Marlene Shinn-Astor; (301) 435-4426;
shinnm@mail.nih.gov.
SMADs are a novel set of mammalian proteins that act downstream of
TGF-beta family ligands. These proteins can be categorized into three
distinct functional sets, receptor-activated SMADs (SMADs 1, 2, 3, 5,
and 8), the common mediator SMAD (SMAD 4), and inhibitory SMADs (SMADs
6 and 7). SMAD proteins are thought to play a role in vertebrate
development and tumorigenesis.
[[Page 3717]]
One of the research tools our NIH inventors have prepared is the
Smad3-null mice model, created by disrupting exon 8 on the Smad3 gene.
Symptomatic mice exhibit leukocytosis, with massive inflammation and
pyogenous abscess formation adjacent to mucosal surfaces. Smad3 plays
an important role in mediating TGF-beta signals in T lymphocytes and in
neutrophils, and demonstrate that Smad3 deficiency results in immune
dysregulation and susceptibility to opportunistic infection, ultimately
leading to the lethality of the mice between 1 and 8 months. TGF-beta
signals also play a role in cancer formation in multiple organs and
tissues. Smad3-null mice could be used to clone downstream target genes
for TGF-beta signals, which may be used in gene therapy and
chemoprevention studies.
Smad4-null mice die around embryonic day 6.5, so the inventors
prepared the SMAD4-conditional mice model, created by a Smad4
conditional knockout allele at exon 8 using Cre-mediated recombination.
PCR analysis determined Cre-mediated recombination in the pancreas but
not in a number of other organs, indicating that the Smad4 conditional
allele can be recombined to delete exon 8 in a tissue-specific fashion.
This knockout mouse could be used to test the function of TGF-beta/
Smad4 signals at all stages of mouse development. Interestingly,
mutation of human Smad4 has been found in approximately half of all
pancreatic cancers, 30 percent of colon cancers, and about 10 percent
in other cancers. The Smad4-conditional mice could be used to study
pathways that are involved in formation of these tumors or to clone
downstream target genes that may be used in gene therapy and
chemoprevention studies.
Additional information may be found in the following research
articles: Yang et al., ``Generation of Smad4/Dpc4 conditional knockout
mice,'' Genesis 2002 Feb; 32(2):80-81, Epub 13 Feb 2002 doi 10.1002/
gene.10029; Yang et al., ``Targeted disruption of SMAD3 results in
impaired mucosal immunity and diminished T cell responsiveness to TGF-
beta,'' EMBO J. 1999 Mar 1; 18(5):1280-1291, Epub doi: 10.1093/emboj/
18.5.1280.
In addition to licensing, the technology is available for further
development through collaborative research with the inventors via a
Cooperative Research and Development Agreement (CRADA).
Anti-Proliferative Activity of an Unexpected mTOR Kinase Inhibitor
Joel Moss and Arnold Kristof (NHLBI);
U.S. Provisional Patent Application No. 60/528,340 filed 09 Dec 2003
(DHHS Reference No. E-259-2003/0-US-01); PCT Application filed 09 Dec
2004 (DHHS Reference No. E-259-2003/0-PCT-02);
Licensing Contact: Susan Carson; 301/435-5020; carsonsu@mail.nih.gov.
The second leading cause of death in the United States is cancer
and more than one million Americans are diagnosed with cancer each
year, with this number likely to increase as the population ages. There
remains a need for effective therapeutics with improved safety
profiles, and promising results have been obtained from targeting the
phosphatidylinositol-3-kinase (PI3K) signalling cascade (including
PI3K, AKT/PKB and mammalian target of rapamycin (mTOR/S6K) kinases)
which is integral to the regulation of cell growth, protein synthesis
and apoptosis in response to nutrients and mitogens, and which is
frequently dysregulated in different cancers and other proliferative
diseases. In particular, efforts have been directed at inhibiting
specific kinases in this pathway as effective treatments for cancer,
restenosis and autoimmune diseases and researchers at the National
Heart, Lung and Blood Institute have recently shown that one of the 4H-
1-benzopyran-4--one derivatives is unexpectedly an effective mTOR
inhibitor.
Proof of concept data is available. This compound has been shown to
attenuate tumor growth in an in vivo human xenograft PC-3 prostate
tumor model, without observed toxicity. An improved therapeutic safety
profile is suggested, as this compound was a weak inhibitor of PI3K.
Further data indicate that inhibition of cell proliferation occurs
through both mTOR-dependent and mTOR-independent mechanisms, suggesting
a novel kinase inhibitor. Additionally, this cytostatic compound is
shown to have an anti-inflammatory effect in peritoneal macrophages.
Finally, this compound inhibits primary human smooth muscle cell
proliferation in vitro, suggesting a possible role in the treatment of
vascular restenosis.
This compound may therefore prove to be an effective anti-
proliferative therapeutic. Available for licensing are methods of use
directed to derivatives of 2-(4-piperazinyl)-substituted 4H-1-
benzopyran-4--one compounds as antiproliferative, immunosuppressive and
anti-neoplastic agents.
In addition to licensing, the technology is available for further
development through collaborative research with the inventors via a
Cooperative Research and Development Agreement (CRADA contact: Vincent
Kolesnitchenko; Tel: (301) 402-5579; E-mail: kolesniv@nhlbi.nih.gov).
Methods for Making and Using Mass Tag Standards for Quantitative
Proteomics
David E. Anderson (NIDDK);
U.S. Provisional Application No. 60/574,612 filed 25 May 2004 (DHHS
Reference No. E-200-2003/0-US-01);
Licensing Contact: Fatima Sayyid; (301) 435-4521; sayyidf@mail.nih.gov.
There is a growing need for peptide standards for quantitative
proteomic analysis of gene and cellular functions in cells and tissues.
Current methods for generating peptide standards for identification and
absolute quantification of proteins rely almost solely on synthetic
approaches which require expensive reagents, equipment and rare
expertise.
The present invention describes a process for simultaneously
generating peptide standards of known concentration for several
proteins of interest within a single easily parallelized experiment.
This process uses a combination of automated synthetic gene design,
gene synthesis, cloning, bacterial expression with heavy isotope
incorporation, generic protein purification, optical quantitation, and
endoprotease cleavage to make sets of peptides of known concentration.
Non-modified peptides can be made for a fraction of the cost of
synthetic approaches. Since the main cost involves the initial
production of a DNA construct, follow-up preparations of peptides
(which can use different isotope backgrounds) are even cheaper.
A Method of Treating Inflammatory Bowel Disease (IBD)
Warren Strober, Ivan Fuss, Frank Heller, Richard Blumberg (NIAID); PCT
Application No. PCT/US2002/018790 filed 14 Jun 2002, which published as
International Publication No. WO 2004/001655 on 31 Dec 2003 (DHHS
Reference No. E-131-2002/0-PCT-01)
Licensing Contact: Susan Carson; (301) 435-5020; carsonsu@mail.nih.gov.
Ulcerative colitis (UC) is a chronic inflammatory disease of the
colorectum and affects approximately 400,000 people in the United
States (of these, approximately 5 percent develop colon cancer). The
cause of UC is not known, although an abnormal mucosal T cell,
responsive to bacterial antigens in the gut microflora, is thought to
be
[[Page 3718]]
involved. Present treatments for UC include anti-inflammatory therapy
using aminosalicylates or corticosteroids, as well as immunomodulators
and diet. However, 25-40 percent of ulcerative colitis patients must
eventually have their colons removed due to massive bleeding, severe
illness, rupture of the colon, risk of cancer or due to side effects of
corticosteroids and novel treatments are still actively being sought.
NIH scientists and their collaborators have used a mouse model of
experimental colitis (OC) to show that IL-13, a Th2 cytokine, is a
significant pathologic factor in OC and that neutralizing IL-13 in
these animals effectively prevents colitis (Immunity (2002) 17, 629-
638).
OC is a colitis induced by intrarectal administration of a
relatively low dose of the haptenating agent oxazolone subsequent to
skin sensitization with oxazolone. A highly reproducible and chronic
colonic inflammation is obtained that is histologically similar to
human ulcerative colitis. Studies show that NKT cells rather than
conventional CD4+T cells mediate oxazolone colitis and that NKT cells
are the source of IL-13, and are activated by CD1 expressing intestinal
epithelial cells. Tissue removed from UC patients were also shown to
contain increased numbers of nonclassical NKT cells that produce
markedly increased amounts of IL-13 and that in keeping with epithelial
damage being a key factor in UC, these NKT cells are cytotoxic for
epithelial cells (J. Clin. Investigation (2004) 113, 1490-1497).
With obvious implications for the treatment of human Ulcerative
Colitis, inflammation in this mouse model has been shown to be
effectively blocked by neutralizing IL-13 or by inhibiting the
activation of NK-T cells through CD1. Available for licensing are broad
claims covering treatments preventing the inflammatory response of
colitis by modulating IL-13 and NKT cell activity and methods for
screening for therapeutic compounds effective for colitis.
In addition to licensing, the technology is available for further
development through collaborative research with the inventors via a
Cooperative Research and Development Agreement (CRADA).
Dated: January 18, 2005.
Steven M. Ferguson,
Director, Division of Technology Development and Transfer, Office of
Technology Transfer, National Institutes of Health.
[FR Doc. 05-1415 Filed 1-25-05; 8:45 am]
BILLING CODE 4140-01-P
