[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