[Federal Register Volume 64, Number 43 (Friday, March 5, 1999)]
[Notices]
[Pages 10665-10667]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 99-5419]
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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, DHHS.
ACTION: Notice.
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SUMMARY: The inventions listed below are owned by agencies 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.
Identification of Polymorphisms of the PCTG-4 Gene
RA Philibert, EI Ginns (NIMH)
Provisional U.S. Patent Application No. 60/083,465 filed 29 Apr 98
Licensing Contact: Leopold J. Luberecki, Jr.; 301/496-7735 ext. 223; e-
mail: 1187a@nih.gov
Mental retardation affects approximately 1-3% of the U.S.
population and results in at least $10 billion in annual treatment
costs. Mutations in the X-chromosome may cause 30-50% of all cases of
mental retardation. This technology is directed to the identification
of an X-linked polymorphism that appears to convey a five-fold increase
in the relative risk for mental retardation and is markedly enriched in
individuals suffering from autism. The various polymorphisms will
likely enable further studies aimed at eliciting the underlying
mechanisms of these diseases and may provide a model system for the
development of new drugs. It may also have a role as a prognostic
indicator.
Combination Therapy with VIP Antagonists
Illana Gozes (Tel Aviv University), Terry W. Moody (NCI), Douglas C.
Brenneman (NICHD), Mati Fridkin (Weizman Institute of Science), Edgar
Gelber (Tel Aviv University) and Albert Levy (Tel Aviv University)
Serial No. 60/104,472 filed 16 Oct 98 and Serial No. 60/104,907 filed
20 Oct 98
Licensing Contact: Dennis Penn; 301/496-7056 ext. 211; e-mail:
dp144q@nih.gov
This invention relates generally to cancer treatment. More
particularly, the present invention relates to combination therapy
using a polypeptide which is an antagonist of the vasoactive intestinal
polypeptide (VIP) and a chemotherapeutic agent, preferably in a
pharmaceutical composition.
Vasoactive intestinal polypeptide (VIP) is a widely distributed
peptide hormone which mediates a variety of physiological responses
including gastrointestinal secretion, relaxation of gastrointestinal
vascular and respiratory smooth muscle, lipolysis in adipocytes,
pituitary hormone secretion, and excitation and hyperthermia after
injection into the central nervous system. Vasoactive intestinal
peptide is a 28 amino acid peptide with an amidated C-terminus, the
peptide results from post translational processing of a hormone
composed of 170 amino acid residues. The VIP peptide has been shown to
contain at least two functional regions, a region involved in receptor
specific binding and a region involved in biological activity (Gozes
and Brenneman, Molecular Neurobiology, 3:201-236 (1989)).
Gozes, et al. have developed a VIP antagonist that has proven
useful for altering the function of the vasoactive intestinal peptide.
(See, U.S. Patent No. 5,217,953 issued to Gozes, et al. (1993)). This
VIP antagonist was designed to retain the binding properties of VIP for
its receptor, but to lack the amino acid sequence necessary for
biological activity. Studies have shown that this VIP antagonist
effectively antagonizes VIP-associated activity. It has been reported
that this VIP antagonist inhibits the growth of VIP receptor bearing
tumor cells such as, for example, lung tumor cells (i.e., non-small
cell lung cancer cells). (See, U.S. Patent No. 5,217,953.)
U.S. Patent No. 5,565,424, which issued to Gozes, et al. on October
15, 1996, discloses another family of polypeptides which are
antagonists of the vasoactive intestinal polypeptide. The VIP
antagonists disclosed therein are 10-1000 times more efficacious, i.e.,
more potent in inhibiting VIP-associated activity than previous VIP
antagonists. These superactive VIP antagonists were shown to inhibit
cancer growth in lung and gioblastoma cells. Examples of superactive
VIP antagonists include amino acid sequences referred to as the
``norleucine-hybrid VIP antagonist'', the ``stearyl-norleucine-hybrid
VIP antagonist'' and the ``stearyl-hybrid VIP antagonist''.
The present invention relates to a pharmaceutical composition
comprising a vasoactive intestinal polypeptide (VIP) antagonist, a
chemotherapeutic agent
[[Page 10666]]
(such as platinum coordination compounds, topoisomerase inhibitors,
antibiotics, antimitotic alkaloids, antimicrotubules, and
difluoronucleosides) and a pharmaceutically acceptable carrier. Certain
combinations of a VIP antagonist plus a chemotherapeutic agent resulted
in a synergistic reduction in the IC50 of 2-7 fold. This synergistic
affect was observed in a non-small cell lung cancer, breast cancer,
pancreatic cancer, glioblastoma, ovarian, and prostate cancer cell
lines.
A Test for Both Sensitivity to and Resistance to Warfarin and Other
Drugs Metabolized by CYP2C9 and CYP2A6
Frank J. Gonzalez (NCI) and Jeffery R. Idle (University of Newcastle)
Serial No. 08/750,703 filed 07 Apr 97
Licensing Contact: Dennis Penn; 301/496-7056 ext. 211; e-mail:
dp144q@nih.gov
It is well known that genetic polymorphisms in drug metabolizing
genes give rise to a variety of phenotypes. This information has been
used to advantage in the past for developing genetic assays that
predict phenotype and thus predict an individual's ability to
metabolize a given drug. The information is of particular volume in
determining the likely side effects and therapeutic failures of various
drugs.
Drug metabolism is carried out by the cytochrome P450 family of
enzymes. For example, the cytochrome P450 isozyme gene, CYP2C9 encodes
a high affinity hepatic [S]-warfarin 7-hydroxylase which appears to be
principally responsible for the metabolic clearance of the most potent
enantiomer of warfarin. Similarly, the cytochrome P450 isozyme gene,
CYP2A6, encodes a protein that metabolizes nicotine and coumarin and
activates the tobacco-specific nitrosamine 4-(methyinitrosamino)-1-(3-
pyridyl)-1-butanone) (NNK). The above gene products are also known to
metabolize other substrates, for example, the CYP2C9 gene product is
also know to metabolize Tolbutamide, Phenytoin, Ibuprofen, Naproxen,
Tienilic acid, Diclofenac and Tetrahydrocannabinol. It follows that
genetic polymorphisms or mutations in either of the two aforementioned
genes can lead to an impairment in metabolism of at least the
aforementioned drugs.
The present invention relates to novel variant alleles incytochrome
P450 genes, which express ezymes involved in the metabolism of
particular drugs and/or chemical carcinogens. The present invention
describes a new mutant or variant CYP2A6 allele wherein the human gene
is characterized. This variant allele is designated CYP2A6v2 and its
cDNA and genomic sequence are provided in the present invention.
Another new gene related to CYP2A6 has been discovered and is
designated CYP2A13 and its cDNA and genomic sequence are included.
The objective of this invention is to provide the genetic material,
a method, and a kit which enable genotyping of the CYP2C9 and CYP2A65
gene with a view to providing phenotyping information concerning drug
metabolism for use in screening and evaluating side effects and
therapeutic failures. In addition, the method may be used to screen
patients for a predisposition to cancers related to excessive
nitrosamine activation, which are associated with mutations within the
CYP2A6 gene locus. Further, the method may be used to screen patients
for sensitivity to chemical carcinogens, based upon the genotype of the
CYP2A6 and/or CYP2C9 alleles.
Method for Detecting a Receptor-Ligand Complex Using a Cytochrome
P450 Reporter Gene
Charles L. Crespi (Gentest), Bruce W. Pennman (Gentest), Frank J.
Gonzalez (NCI), Harry V. Gelboin (NCI) and Talia Sher (NCI)
Serial No. 08/697,329 filed 22 Aug 96; U.S. Patent 5,726,041 issued 10
Mar 98
Licensing Contact: Dennis Penn; 301/496-7056 ext. 211; e-mail:
dp144q@nih.gov
The use of reporter genes to measure the relative activity of a
promoter sequence is well known. This invention is directed to methods
and compositions for measuring the activity of a promoter sequence in a
mammalian cell. The methods involve substituting a DNA sequence
encoding a cytochrome P450 for a known reporter gene (e.g. CAT,
luciferase) and measuring the relative activity of the expressed
cytochrome P450 protein. In contrast to the reporter genes of the prior
art, the claimed invention advantageously provides a method for
measuring the activity of a promoter sequence in intact mammalian cells
that contain a P450 catalysis system using real time light
(fluorescence) measurements. Virtually all mammalian cells contain the
requisite cytochrome P450 catalysis system. Thus, the invention
eliminates the labor-intensive aspects (e.g., cell lysis and separation
of cellular components) that are required to practice other methods for
measuring the activity of a promoter sequence in a mammalian cell.
The invention also provides a method for detecting the formation of
a receptor-ligand complex in a mammalian cell. The cell contains a
reported cassette for detecting formation of the receptor-ligand
complex and a cytochrome P450 catalysis system. The reporter cassette
includes a DNA sequence encoding a cytochrome P450 with a
polyadenylation signal sequence operatively coupled to a promoter
sequence that is responsive to (i.e., binds to) a DNA binding element
present in the receptor-ligand complex. According to one aspect of the
invention, this method is useful for detecting the activation of
PPAR by peroxisome proliferators.
Restenosis/Atherosclerosis Diagnosis, Prophylaxis, and Therapy
SE Epstein, T Finkel, EH Speir, Y Zhou, J Zhou, L Erdile, S Pincus
(NHLBI)
Serial No. 08/796,101 filed 05 Feb 97
Licensing Contact: Manja Blazer; 301/496-7735 ext. 224; e-mail:
mb379e@nih.gov
This technology relates to the compositions and methods for the
diagnosis, prevention, and therapy of restenosis and atherosclerosis.
It involves the use of an agent for decreasing viral load, preferably a
vaccine, against cytomegalovirus (CMV) and p53, including a method for
providing the therapy and administering the agent. This invention thus
relates to stimulating an immune response, preferably a cellular immune
response, directed against CMV and p53 inhibit or prevent restenosis,
atherosclerosis, and smooth muscle proliferation. Such a response can
cause cell death and thus inhibition of smooth muscle cell
proliferation, atherosclerosis, and restenosis. Therefore, the
technology offers methods for inducing cell death with the purpose of
inhibiting smooth muscle proliferation as a means of preventing or
treating restenosis and atherosclerosis.
The Use of Lecithin-Cholesterol Acyltransferase (LCAT) in the
Treatment of Atherosclerosis
S Santamarina-Fojo, JM Hoeg, B Brewer Jr. (NHLBI)
DHHS Reference No. E-007-96/1 filed 11 Aug 96
Licensing Contact: Manja Blazer; 301/496-7735 ext. 224; e-mail:
mb379e@nih.gov
This technology relates to methods for the preventive and
therapeutic treatment of atherosclerosis and to diseases relating to a
deficiency of
[[Page 10667]]
lecithin-cholesterol acyltransferase activity. The plasma protein
enzyme lecithin-cholesterol acyltransferase (LCAT) catalyzes the
transfer of fatty acid from the sn-2 position of lecithin to the free
hydroxyl group of cholesterol. Various mutations of the LCAT gene are
known. Individuals who are homozygous for a non-functional LCAT mutant
have classic LCAT deficiency disease, characterized by clouding of the
cornea, normochromic anemia and glomerulosclerosis. Mutations of the
LCAT gene that result in some residual LCAT activity lead to Fish Eye
disease, characterized by opacity of the cornea and
hypoalphalipoproteinemia. Thus there is a need for compositions and
methods for the prevention and therapeutic treatment of atherosclerosis
and conditions associated with LCAT deficiency. This invention
satisfies this need by providing compositions and methods for
increasing the serum level of LCAT activity.
Dated: February 22, 1999.
Jack Spiegel,
Director, Division of Technology Development and Transfer, Office of
Technology Transfer.
[FR Doc. 99-5419 Filed 3-4-99; 8:45 am]
BILLING CODE 4140-01-M
