[Federal Register Volume 62, Number 156 (Wednesday, August 13, 1997)]
[Notices]
[Pages 43333-43336]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 97-21401]
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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.
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 U.S. 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.
Dvl1-Deficient Mice
AJ Wynshaw-Boris, N Lijam, D Sussman, R Paylor, J Crawley (NHGRI)
OTT Reference No. E-100-97/0
Licensing Contact: David Sadowski; phone: 301/496-7735 ext. 288; e-
mail: [email protected]
Genetic factors are important modifiers of a variety of simple and
complex behaviors in virtually all organisms. Genetic effects have been
inferred from inbred strain analysis in rodents and from linkage
analysis in rodents and humans. More recently, genes influencing
specific behaviors have been identified by analyzing behavioral
abnormalities in mice with targeted gene disruption.
In the present invention, mice completely deficient for Dvl1, a
mouse homolog of the Drosophila segment polarity gene Dishevelled, were
created by gene targeting. These mice demonstrate that Dvl1
participates in complex behaviors in mammals. Dvl1-deficient mice
exhibit reduced social interaction, including differences in whisker-
trimming, deficits in nest-building, less huddling contact during home
cage sleeping, and subordinate responses in a social dominance test. In
addition, Dvl1-deficient mice display striking abnormalities in
sensorimotor gating, as indicated by attenuation of prepulse startle
inhibition in the mutant mice. Prepulse inhibition is abnormal in
several human neuropsychiatric disorders including schizophrenia,
schizotypal personality disorders, obsessive-compulsive disorders,
Huntington's disease, and Tourette syndrome. In addition, many of these
disorders (as well as autism) are characterized by abnormal social
interaction. Hence, Dvl1-deficient mice provide a genetic animal model
of aspects of several human psychiatric disorders and serve as a useful
model for screening drugs that modify
[[Page 43334]]
abnormal social interaction and sensorimotor gating.
Transgenic and Chimeric Viral Delivery Systems
WJ Ramsey, RM Blaese (NHGRI)
OTT Reference No. E-011-97/0 filed 11 Apr 97
Licensing Contact: Larry Tiffany; phone: 301/496-7056 ext. 206; e-mail:
[email protected]
The development of eukaryotic viral vectors has generally focused
on delivery of one or more heterologous genes to target cells,
particularly for gene therapy. Such development has primarily involved
vector systems utilizing retrovirus, adenovirus, herpes virus, vaccinia
virus, and adeno-associated virus particles. However, each of these
viral vector systems has presented one or more of several obstacles
including low viral titers, induced host immune responses, inefficient
transduction, and transient expression of the desired heterologous
gene. This invention addresses the need for improved eukaryotic viral
vectors for diagnostic applications and for delivering heterologous
genes to cells in vitro, ex vivo, and in vivo.
The present invention provides a system for the production of viral
vectors (secondary viruses) whose genome is encoded within another
virus with a different life cycle and biologic characteristics (primary
virus). For example, chimeric primary viruses with high transduction
efficiencies (adenoviruses) can be used to direct the production of
secondary viruses (retroviruses) in a wide range of producer cell
types. Thus single (or panels of) secondary viral vectors containing
identical secondary vector genomes can easily and rapidly be produced
in retroviral vector packaging cells containing different envelope
targeting components with the additional advantage that there will be
little chance for vector rearrangement or recombination. Secondary
viruses also can be readily produced in cells obtained from the
eventual gene therapy target species so that enveloped viruses will
contain membrane constituents from the same, rather than a xenogeneic
species, lessening the chance for neutralizing immune responses to the
vectors. Similarly, serum complement-mediated lysis of retroviral
vectors may be eliminated by the ability to easily use vector producer
cells from the same species as the species to be treated by gene
therapy. Such secondary viruses may comprise an expression cassette
constituting a nucleic acid encoding a heterologous protein and/or an
antisense nuclei acid. Hence, this invention overcomes obstacles
occurring with the in vitro, ex vivo, and in vivo use of common viral
vector systems. In addition, these chimeric primary viruses can be used
to rescue unknown viral genomes from host cells for use in the
development of diagnostic tests or in the development of novel viral
vector systems.
MEN1, The Gene For Multiple Endocrine Neoplasia Type 1
SC Chandrasekharappa (NHGRI), AM Spiegel (NIDDK), LA Liotta (NCI) et
al.
OTT Reference No. E-094-97/0 filed 05 Mar 97
Licensing Contact: Ken Hemby; phone: 301/496-7735 ext. 265; e-mail:
[email protected]
Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant
familial cancer syndrome characterized by occurrence of tumors in
parathryroids, enteropancreatic endocrine tissues, the anterior
pituitary, and occasionally other sites. The present invention provides
an isolated DNA sequence encoding a gene which when mutated in the
germline is associated with the development of MEN1. This invention
also comprises polyclonal and monoclonal antibodies which selectively
bind to menin, the protein encoded by MEN1. In addition, the present
invention provides methods for immunological detection of menin in
biological samples as well as methods for detecting the presence,
alteration, or absence of MEN1 DNA or RNA. This research has been
published in Science 276: 404-407 (1997).
Potential areas of application of this invention include sporadic
and familial MEN1 diagnostics using immunoassays and nucleic acid
hybridizations, and gene therapy.
Invaginated Liposome Delivery System
N Smyth-Templeton, GN Pavlakis (NCI)
Serial No. 60/024,386 Filed 19 Aug 96
Licensing Contact: Larry Tiffany; phone: 301/496-7056 ext. 206; e-mail:
[email protected]
Liposome formulations for in vivo delivery are valuable
alternatives to viral vectors and avoid the inherent problems
associated with modifying viral genomes to create expression vehicles.
Previous liposome formulations limited therapeutic efficacy due to
generally low expression of the DNA being delivered. In contrast, these
novel liposomes are able to transfect a broad host range and express
the encoded proteins at high titers.
The present technology involves highly efficient cationic liposomes
for increased in vivo delivery of biologically active agents. These
extruded DOTAP:cholesterol complexes allow gene expression to be
improved up to 150-fold over previous liposomes. This improvement is
due to the novel morphology of the DNA:liposome complexes. The
complexes are vaselike structures which invaginate and condense DNA
between two protective lipid bilayers. Because the outside of the
DNA:liposome complexes is substantially free of DNA, targeting ligands
may be placed on the outside of the complexes, without compromising the
effect of the targeting ligand or the ability of DNA to be delivered
and expressed.
The present technology may be used for: systematic or site-specific
delivery and expression of nucleic acid products; production of kits
capable of carrying any biologically active agent; delivery of reagents
for human gene therapy in the treatment of disease; and providing a
method for long term expression of a gene product from a non-integrated
nucleic acid.
Licensees are currently being sought for all therapeutic
applications.
In Vitro Determination Of CD4+ T Cell Depletion In HIV-1
Seropositive Subjects as a Predictor of Future CD4+ T Cell Decline
In Vivo
D Zella, A Riva, M Reitz (NCI)
OTT Reference No. E-061-96/0
Licensing Contact: George Keller; phone: 301/496-7735 ext. 246; e-mail:
[email protected]
The current invention embodies a prognostic method for determining
whether an asymptomatic HIV-1 seropositive individual is a progressor
or a non-progressor to AIDS. The inventors have discovered that in HIV-
1 seropositive persons in the asymptomatic stage of the disease,
peripheral blood mononuclear cells (PBMCs) respond in one of two ways
when isolated and subsequently activated in vitro by IL-2. Either (1)
the CD3+CD4+ cell number increases in culture (non-progressor subjects)
or (2) the CD3+CD4+ number does not increase or decreases in culture
(progressor subjects). This analysis was performed by an automated flow
cytometer. This method, when developed as a commercially-available
test, may represent an economical and accurate assay to determine when
detrimental changes for the immune system occur in asymptomatic HIV-1
seropositive subjects, and for this reason to predict whether an
individual is
[[Page 43335]]
progressing to AIDS. This assay may therefore be a valuable tool to use
in determining the appropriate course of therapy to target not only
HIV-1 replication but also to monitor the effects of therapeutic drugs
on the host immune system response.
Avian Based Retrovirus Vectors
E Barsov, SH Hughes (NCI)
Serial No. 08/445,462 filed 22 May 95
Licensing Contact: Larry Tiffany; phone: 301/496-7056 ext. 206; e-mail:
[email protected]
Recombinant retrovirus vectors based on the Rous sarcoma virus
(RSV) are valuable alternatives to murine based or replication-
defective vectors because they do not require a packaging or helper
cell line. Previous RSV vectors limited efficacy due to their inability
to infect a broad range of mammalian species. In contrast, these novel
vectors are able to infect a wider range of host at high titers while
remaining inherently defective in mammalian cells.
The present technology involves recombinant avian sarcoma leukosis
virus (ASLV) derived retroviral vectors having an expanded host range.
Specifically, the ASLV envelope gene is replaced by the env region
derived from a virus capable of infecting both mammalian and avian
cells. This improvement allows the vectors to produce high titer stock
in avian cells and the resulting virus can infect both avian and
mammalian species efficiently.
The present technology may be used for in vitro and in vivo
delivery of nucleic acid sequences to avian or mammalian cells and for
treatment or prevention of diseases involving transfer by recombinant
retroviral vectors.
Licensees are currently being sought for all therapeutic
applications.
Nucleotide and Deduced Amino Acid Sequences of a New Tumor Gene,
Int6
R Callahan, A Marchetti, F Buttitta, G Smith (NCI)
OTT Reference Nos. E-265-94/0 and E-265-94/1
Licensing Contact: Ken Hemby; phone: 301/496-7735 ext. 265; e-mail:
[email protected]
Murine retroviruses have been useful in the identification of
mammalian genes involved in tumor development. Five loci have been
previously identified as integration sites for one specific retrovirus,
mouse mammary tumor virus (MMTV). This work describes a sixth site of
integration for MMTV, the Int6 gene. The Int6 gene is highly conserved
among vertebrate species, including humans. This invention embodies a
series of reagents derived from the nucleic acid and amino acid
sequences of the Int6 gene and the use of these reagents in diagnostic
methods, immunotherapy, gene therapy, and as vaccines.
N-(1-thienylcycloalkyl)alkenyl-amines For Treatment Of Neurotoxic
Injury
KC Rice, AE Jacobson, A Thurkauf, MV Mattson, TL O'Donohue, PC
Contreras, NM Gray (NIDDK)
Serial No. 08/344,433 Filed 23 November 94; U.S. Patent 5,604,255
issued 18 February 97
Licensing Contact: Leopold Luberecki, Jr.; phone: 301/496-7735 ext.
223; e-mail: [email protected]
This invention describes compounds, compositions, and methods for
neuroprotective purposes such as controlling brain damage which occurs
during periods of anoxia, or ischemia associated with stroke, cardiac
arrest or perinatal asphyxia. The treatment includes administration of
an N-(1-thienylcycloalkyl) alkylamine compound as an antagonist to
inhibit excitotoxic actions at major neuronal excitatory amino acid
receptor sites. Compounds of most interest are described in detail.
Brain tissue is particularly sensitive to deprivation of oxygen or
energy; permanent damage to neurons can occur during brief periods of
hypoxia, anoxia or ischemia. Neurotoxic injury is known to be caused or
accelerated by certain excitatory amino acids (EAA) found naturally in
the central nervous system. Neurons, which have EEA receptors on their
dendritic or somal surface, undergo acute excitotoxic degeneration when
these receptors are excessively activated by glutamate. Thus agents
which selectively block or antagonize the action of glutamate at the
EAA synaptic receptors of central neurons can prevent neurotoxic injury
associated with anoxia, hypoxia or ischemia caused by stroke, cardiac
arrest or perinatal asphyxia.
The method embodied in the invention may prove valuable for the
control of neuropathological processes and the neurodengenerative
consequences thereof in mammals by treating a mammal susceptible to
neurotoxic injury with an anti-excitotoxic effective amount of a
compound of a class described herein.
A Method for the Liposomal Delivery of Nucleic Acids
AR Thierry (NCI)
Serial No. 08/286,730 Filed 05 August 94 and Serial No. 08/522,246
Filed 04 September 95 (CIP of 08/286,730)
Licensing Contact: Larry Tiffany; phone: 301/496-7056 ext. 206; e-mail:
[email protected]
The present invention is directed to a liposomal preparation of
nucleic acids or analogues and specific lipids which form liposomes.
Liposome vesicles are prepared from a mixture of cationic lipopolyamine
and a neutral lipid. Nucleic acids are associated with the liposomes in
two ways: (1) Complex formation between the cationic lissome vesicle
and negatively charged nucleic acid or (2) partial encapsulation and
partial complex formation in and with the cationic liposome vesicle.
Liposome-encapsulated nucleic acids have been shown to be more
efficient in transducing cells in cell cultures. Sonication of
liposome-complexed nucleic acids allow for more homogenized and smaller
liposome particles, and consequently for the ability to circulate for
longer periods in blood following systemic injection. Nucleic acids
associated with the liposomal carrier are completely protected from
enzymatic attack such as nucleases, and stability in circulating blood
after administration can be achieved. The present invention provides
for the highly efficient delivery of nucleic acids to cells in vitro or
in vivo. Therefore, this invention provides a method for gene therapy.
This liposome method does not have safety concerns associated with gene
therapy based upon viral vectors. However, liposomal delivery in
accordance with the present invention may be used for increasing
recombinant retrovirus infection by enhancing the penetration and/or
expression of the viral agents.
The patent application includes claims to liposome compositions and
method of use. These materials and methods are useful in the delivery
of nucleic acids to cells and tissues.
Nitrogen-Containing Cyclohetero Alkylamino Aryl Derivatives for CNS
Disorders
BR De Costa, WD Bowen, X-S He, L Radesca, KC Rice (NIDDK)
Serial No. 08/261,796 Filed 20 June 94; U.S. Patent 5,571,832 Issued 05
Nov 96
Licensing Contact: Leopold Luberecki, Jr.; phone: 301/496-7735 ext.
223; e-mail: [email protected]
This invention describes a class of therapeutically useful
compounds
[[Page 43336]]
comprising a pyrrolidinyl ring, compositions and methods for treatment
of Central Nervous System (CNS) dysfunctions, neurotoxic damage, or
neurodegenerative diseases. These compounds are particularly useful for
treating neurotoxic injury which follows periods of hypoxia, anoxia or
ischemia associated with stroke, cardiac arrest or perinatal asphyxia.
In addition these compounds are also useful as antipsychotics and
anticonvulsives.
Unlike other tissues which can survive extended periods of hypoxia,
brain tissue is particularly sensitive to deprivation of oxygen or
energy. Permanent damage to neurons can occur during brief periods of
hypoxia, anoxia or ischemia. Neurotoxic injury is known to be caused or
accelerated by certain excitatory amino acids (EAA) found naturally in
the CNS. Compounds as described herein block the action of EEA synaptic
receptors and thus can prevent neurotoxic injury.
Treatment of CNS disorders and diseases such as cerebral ischemia,
psychotic disorders, convulsions and parkinsonism, as well as
prevention of neurotoxic damage and neurodegenerative diseases, may be
accomplished by administration of a therapeutically-effective amount of
a compound of a class described herein.
Severe Renal Glomerular Disease in Mice Homozygous for Targeted
Disruption of Uteroglobin Gene: A Model for Human Hereditary
Glomerulopathies
AB Mukherjee, Z Zhang (NICHD)
OTT Reference No. E-164-96/0
Licensing Contact: David Sadowski; phone: 301/496-7735 ext. 288; e-
mail: [email protected]
Uteroglobin (UG) is a protein fraction of pregnant uterine fluid
which can induce and regulate blastocystic development and also
possesses important anti-inflammatory properties. This invention
describes a novel physiological function of UG, which is its role in
preventing severe fibronectin (Fn) deposit-associated renal glomerular
disease. Uteroglobin binds to Fn thereby inhibiting the formation of
Fn-Fn aggregates and Fn-collagen aggregates, thus preventing the
disease. Uteroglobin knockout mice (UG-/-) were generated by targeted
disruption of the UG gene. These mice developed glomerular disease,
became cachectic and died within 4-5 weeks after birth.
This mouse could potentially be a valuable model system for the
study and treatment of glomerular disease.
A description of this research may be found in Science, vol. 276,
pp. 1408-1412, 1997.
A Method for Producing Retrovirus RNA Packaging Cassettes Amplified
in the Cytoplasm by Autocatalytic Togavirus Vectors
R Morgan, J Wahlfors, K Xanthopoulos (NHGRI)
OTT Reference No. E-135-96/0 filed 25 Sep 96
Licensing Contact: Larry Tiffany; phone: 301/496-7056 ext. 206; e-mail:
[email protected]
Retroviral vectors are currently the most advanced system available
for mammalian gene therapy. The major obstacle with the previous
methods is that the transfer of complex or large genomic elements is
virtually impossible. This technology obviates the need for the
retrovirus DNA provirus stage of the life cycle via retroviral RNA
vectors. Specifically, this invention utilizes Togaviruses, especially
the Semliki Forest virus (SFV), to produce recombinant retroviral
vector RNA in the cytoplasm of a retrovirus packaging cell. Using the
SFV system, a retroviral cassette with a heterologous gene is cloned
into an SFV expression vector. This in vitro transcribed RNA vector is
used to transduce packaging cells. The retroviral RNA vector is
amplified in the cytoplasm using the SFV system, and packaged into
infectious viral particles. This system represents a means by which
large fragments of viral RNA, or complex gene structures, can be
transferred via retroviral vectors. An additional advantage is that by
using the SFV production system, it is able to produce high titers of
retrovirus particles, due to its self-amplification capabilities.
Potential areas of application include: ex vivo and in vivo gene
therapy for infectious (e.g., HIV) and noninfectious (e.g., cancer,
birth defects) disease; untranslated genomic regions of DNA may be
important for regulation of gene expression.
Dated: August 5, 1997.
Barbara M. McGarey,
Deputy Director, Office of Technology Transfer.
[FR Doc. 97-21401 Filed 8-12-97; 8:45 am]
BILLING CODE 4140-01-P
