[Federal Register Volume 72, Number 80 (Thursday, April 26, 2007)]
[Notices]
[Pages 20858-20862]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: E7-7933]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

National Institutes of Health


Government-Owned Inventions; Availability for Licensing

AGENCY: National Institutes of Health, Public Health Service, HHS.

ACTION: Notice.

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SUMMARY: The inventions listed below are owned by an agency of the U.S. 
Government and are available for licensing in the U.S. in accordance 
with 35 U.S.C. 207 to achieve expeditious commercialization of results 
of federally-funded research and development. Foreign patent 
applications are filed on selected inventions to extend market coverage 
for companies and may also be available for licensing.

ADDRESSES: Licensing information and copies of the U.S. patent 
applications listed below may be obtained by writing

[[Page 20859]]

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.

GDF15, a Marker and Cause of Morbidity in Thalassemia

    Description of Technology: The invention includes methods for the 
measurement of Growth Differentiation Factor 15 (GDF15, also known as 
MIC-1 or NAG-1) levels in order to diagnose or predict disease severity 
in patients with thalassemia and with related complications, as well as 
methods for treating thalassemia by administration of a GDF15 
antagonist. Also disclosed is a method to reduce hepcidin levels by 
administration of GDF15, a GDF15 substitute, or GDF15 agonist.
    GDF15 is a member of the TGF-Beta superfamily of proteins, which 
are known to control cell proliferation, differentiation, and apoptosis 
in numerous cell types. The inventors are additionally interested in 
investigating the role of GDF15 in other disorders characterized by 
ineffective erythropoiesis, as well as the role of GDF15 in the 
regulation of iron metabolism.
    Thalassemia consists of a group of inherited diseases of the red 
blood cells, arising from deficient or absent production of globin 
chains. In beta-thalassemia, also known as Cooley's anemia or 
Mediterranean anemia, defective globin production reduces the number 
and viability of red blood cells, causing anemia and subsequent 
expansion of bone marrow. As a result of marrow expansion distorted 
bone formation ensues. Beta thalassemia, the most severe form of 
thalassemia, also results in iron overload, which is the major cause of 
beta-thalassemia mortality worldwide. As a result of iron overload, the 
patient may develop hypropituitarism, hypothyroidism, 
hypoparathyrodism, diabetes, arthropathy, cirrhosis and cardiopulmonary 
disease. Treatment of beta-thalassemia involves frequent blood 
transfusions and chelation therapy to remove excess iron from the 
blood.
    In thalassemia, the patient's hepcidin expression is pathologically 
suppressed. Hepcidin is a protein synthesized in the liver, which 
reduces iron absorption in the body.
    The inventors have identified GDF15 as a hepcidin-suppressing 
cytokine that is overexpressed in thalassemia. GDF15 levels in blood 
plasma have been found to be dramatically elevated in beta-thalassemia 
patients compared to healthy donors and patients with hereditary 
hemochromatosis, another form of iron overload disease.
    Applications:
    1. Diagnostic test to detect increased risk for thalassemia-related 
complications.
    2. Treatment of thalassemia by administration of a GDF15 
antagonist.
    3. Treatment of iron-dysregulated diseases.
    4. Treatment of ineffective erythropoiesis.
    5. Treatment of anemia of chronic disease.
    Market: Thalassemia is a growing global public health problem. It 
is estimated that seven percent of the world's population are carriers, 
with about 400,000 affected babies born each year. Approximately 1,000 
people in the United States currently have beta-thalassemia; however, 
the number of patients is expected to grow. Prevalence of the disease 
is higher in those of Mediterranean descent and those from China, India 
and other Asian countries. The U.S. Food and Drug Administration 
classifies thalassemia as a rare or orphan disease.
    Development Status: Early stage.
    Inventors: Jeffery L. Miller and Toshihiko Tanno (NIDDK).
    Publications: In Review.
    Patent Status: U.S. Provisional Application No. 60/864,705 filed 07 
Nov. 2006 (HHS Reference No. E-022-2007/0-US-01).
    Licensing Status: Available for exclusive or nonexclusive 
licensing.
    Licensing Contact: Tara L. Kirby, PhD; 301/435-4426; 
<a href="/cdn-cgi/l/email-protection#97e3f6e5f6fcd7faf6fefbb9f9feffb9f0f8e1"><span class="__cf_email__" data-cfemail="fa8e9b889b91ba979b9396d4949392d49d958c">[email protected]</span></a>.
    Collaborative Research Opportunity: The NIDDK's Molecular Medicine 
Branch is seeking statements of capability or interest from parties 
interested in collaborative research to further develop, evaluate, or 
commercialize the role of GDF15 in other disorders characterized by 
ineffective erythropoiesis, as well as the role of GDF15 in the 
regulation of iron metabolism. Please contact Dr. Jeffery L. Miller at 
<a href="/cdn-cgi/l/email-protection#a9e3cccfcf87e4c0c5c5ccdb98e9c7c0c187c1c1da87cec6df"><span class="__cf_email__" data-cfemail="551f3033337b183c3939302764153b3c3d7b3d3d267b323a23">[email protected]</span></a> or 301/402-2373 for more information.

Methods for Treating Autoimmune Inflammatory Disease by Blocking DR3-
TL1A Interactions

    Description of Technology: As a group, autoimmune inflammatory 
diseases occur in greater than five percent of the United States 
population, and represent the fourth-largest cause of disability among 
women. This disease group includes asthma, multiple sclerosis, 
rheumatoid arthritis, and lupus, among others. Treatments generally 
include immunosuppressants or anti-inflammatory drugs; recently, more 
specific immunomodulatory therapies such as TNF-alpha antagonists have 
been developed.
    The invention discloses methods for treatment of autoimmune 
inflammatory disease by blocking the interaction between one particular 
TNF family ligand, TL1A (or TNFSF15), and its receptor, DR3 (or 
TNFRSF25). The inventors have shown that the DR3-TL1A interaction is 
critical for development of disease in mouse models of asthma and 
multiple sclerosis. Additionally, mice lacking the DR3 receptor have 
normal immune system development and response to immune challenge. 
Thus, a treatment for autoimmune disease that blocks the DR3-TL1A 
interaction may provide a potent therapy without inducing global 
immunosuppression.
    Applications: Development of therapeutics for autoimmune 
inflammatory disease.
    Market: More than five percent of the United States population has 
an autoimmune disease; The market size for rheumatoid arthritis is 
predicted to be $10 billion by 2008.
    Development Status: Early stage.
    Inventors: Richard M. Siegel and Francoise Meylan (NIAMS).
    Patent Status: U.S. Provisional Application No. 60/879,668 filed 10 
Jan 2007 (HHS Reference No. E-011-2007/0-US-01).
    Licensing Status: Available for exclusive or non-exclusive 
licensing.
    Licensing Contact: Tara Kirby, PhD; 301/435-4426; 
<a href="/cdn-cgi/l/email-protection#b2c6d3c0d3d9f2dfd3dbde9cdcdbda9cd5ddc4"><span class="__cf_email__" data-cfemail="ea9e8b988b81aa878b8386c4848382c48d859c">[email protected]</span></a>.

Genetic Markers for Body Size in Dogs

    Description of Technology: Dogs exhibit the greatest diversity in 
body size of any mammalian species. To explore the genetic basis for 
size variation among dogs, the inventors compared the DNA of various 
small dog breeds to larger dog breeds. They found that variation in one 
gene, IGF-1, which codes for the protein hormone insulin-like growth 
factor 1, is very strongly associated with small stature across all dog 
breeds studied. An important determinant of body size in mammals, IGF-1 
induces cell growth and differentiation and is a potent inhibitor of 
apoptosis. Analysis of DNA from over 3,000 dogs and 143 breeds revealed 
a specific IGF-1 gene sequence variant, or haplotype, associated with 
small size in the canine genetic code.
    The invention discloses markers defining chromosomal haplotypes 
associated with adult body size in dogs.

[[Page 20860]]

Also claimed are methods and kits for predicting adult body size in 
dogs using these markers. A genetic test based on this invention would 
be of use to breeders wishing to predict a dog's size, and thus its 
conformance to the breed standard, at adulthood.
    Applications: Canine genetic test to predict adult body size.
    Market: In 2006, over 1.7 million purebred dogs competed in 
American Kennel Club-sanctioned conformance shows in the United States.
    Development Status: Early stage.
    Inventors: Elaine A. Ostrander and Nathaniel B. Sutter (NHGRI).
    Publication: N Sutter et al. A single IGF1 allele is a major 
determinant of small size in dogs. Science 2007 Apr 6;316(5821):112-
115, doi: 10.1126/science.1137045.
    Patent Status: U.S. Provisional Application No. 60/856,411 filed 02 
Nov 2006 (HHS Reference No. E-009-2007/0-US-01).
    Licensing Status: Available for non-exclusive licensing.
    Licensing Contact: Tara L. Kirby, PhD.; 301/435-4426; 
<a href="/cdn-cgi/l/email-protection#e6928794878da68b878f8ac8888f8ec8818990"><span class="__cf_email__" data-cfemail="4d392c3f2c260d202c242163232425632a223b">[email protected]</span></a>.

A Neuronal Avalanche Size (NAS) Assay to Screen for Cognitive Enhancers 
and Anti-Epileptics

    Description of Technology: Currently available methods of detecting 
and measuring EEG activity only crudely classify normal and abnormal 
activity or distinguish epileptic activity early in the onset of its 
deviation from normal activity. Available for licensing are methods for 
recognizing a new pattern of EEG activity called neuronal avalanche 
size (NAS) that has been correlated with cognitive function and 
epilepsy. The NAS uses extracellular field potentials to measure the 
distribution of synchronized neurons in the cortex (neuronal 
avalanches) and thus the state of the cortical network. When the 
avalanche size reaches a power law with a slope of -\3/2\, the system 
is in the critical state and the cortical network is functioning 
optimally to spread information throughout the network. If the system 
slope deviates from -\3/2\, the system is outside the critical state 
and is either epileptic or sub-critical. In animal studies measurement 
of NAS quantified a drug's potential to increase cognitive functioning 
and induce or reduce epilepsy.
    The NAS assay may thus enable high-throughput in vitro screens to 
select anti-epileptics and cognitive enhancing drugs for continued drug 
development. Because avalanches represent scale-invariant dynamics they 
can also be recorded using surface (EEG) electrodes. This technology 
may thus be useful in assessing cognitive function, epileptic pathology 
and in selecting and monitoring drug therapy for epileptic patients.
    Applications:
    1. In vitro screen to assess drugs for potential use as anti-
epileptics for drugs with the propensity to cause epilepsy.
    2. In vitro screen to assess drugs with the ability to enhance 
cognitive function, and ultimately, relieve cognitive defects 
associated with psychiatric illnesses and neurological disorders.
    3. EEG monitoring of patients for diagnosis and drug selection and 
monitoring.
    Market:
    1. Epilepsy affects approximately 2.7 million people in the United 
States, and over 50 million people worldwide.
    2. The cost of epilepsy in the United States is $12.8 billion per 
year, where eighty percent of this cost is due to patients with 
intractable seizures.
    3. The cost for developing and commercializing new drugs is 
approximately $1 billion.
    4. Schizophrenia affects about 1 out of 100 people in the United 
States, resulting in a public health burden of $40 billion per year in 
the U.S. alone.
    5. Atypical neuroleptics alleviate cognitive deficits in 
schizophrenia and are now prescribed to more than 70 percent of all 
schizophrenic patients, totaling annual sales of $8.7 billion in 2003.
    6. Atypical neuroleptics have variable efficacy in alleviating 
symptoms, and act on multiple, poorly understood pathways 
simultaneously resulting in many side effects.
    7. The proposed in vitro screen could tremendously facilitate the 
development of more efficient and selective psychotropic drugs to 
alleviate cognitive deficits in schizophrenia.
    Development Status: In vivo and in vitro data are available.
    Inventors: Dietmar Plenz (NIMH).
    Publications:
    1. JM Beggs, D Plenz. Neuronal avalanches in neocortical circuits. 
J Neurosci. 2003 Dec 3;23(35):11167-77.
    2. CV Stewart, D Plenz. Inverted-U profile of dopamine-NMDA-
mediated spontaneous avalanche recurrence in superficial layers of rat 
prefrontal cortex. J Neurosci. 2006 Aug 2;26(31):8148-59.
    Patent Status: U.S. Provisional Application No. 60/707,651 filed 12 
Aug 2005 (HHS Reference No. E-294-2005/0-US-01); PCT Application No. 
PCT/US2006/031884 filed 14 Aug 2006 (HHS Reference No. E-294-2005/1-
PCT-01).
    Licensing Status: Available for exclusive or non-exclusive 
licensing.
    Licensing Contact: Norbert Pontzer, J.D., Ph.D.; 301/435-5502; 
<a href="/cdn-cgi/l/email-protection#e7978889939d829589a78a868e8bc9898e8fc9808891"><span class="__cf_email__" data-cfemail="a8d8c7c6dcd2cddac6e8c5c9c1c486c6c1c086cfc7de">[email protected]</span></a>.
    Collaborative Research Opportunity: The NIMH/Section of Neural 
Network physiology is seeking statements of capability or interest from 
parties interested in collaborative research to further develop, 
evaluate, or commercialize the NAS assay. Please contact Dietmar Plenz 
at <a href="/cdn-cgi/l/email-protection#fe8e929b90849abe939f9792d0909796d0999188"><span class="__cf_email__" data-cfemail="c3b3afa6adb9a783aea2aaafedadaaabeda4acb5">[email protected]</span></a> for more information.

Method for Promoting Stem Cell Proliferation and Survival

    Description of Technology: This technology describes a method to 
promote stem cell survival and proliferation by manipulating the 
phosphorylation state of Stat3 protein. This method has been shown to 
enhance survival and proliferation in stem cell cultures in vitro, and 
also in neuronal precursor cells in vivo. The methods include use of a 
Notch ligand and growth factors such as FGF 2 or insulin to promote 
neural stem cell survival and proliferation. The technology is also 
directed to a population of stem cells expressing STAT3 phosphorylated 
at serine 727.
    Applications:
    1. Clinical treatment for stroke and other neurodegenerative 
diseases by administration of agents that promote stem cell survival 
and proliferation.
    2. Increased generation of stem cells in vitro.
    3. Screening assays for agents that promote proliferation of stem 
cells or inhibit proliferation of cancer cells.
    4. Diagnostic assay for cancer to determine the phosphorylation 
state of the protein in tumors.
    Market:
    1. Prognostic marker to help determine response of individuals with 
cancer.
    2. Commercial suppliers or large-scale users of stem cells.
    Development Status:
    1. A method of increasing proliferation and survival of stem cells 
or precursor cells in vitro has been developed. The cells produced by 
this method have been described in an article in Nature 2006 Aug 
17;442(7104):823-826.
    2. The method of increasing proliferation and survival of stem 
cells is efficacious in in vivo rodent models of Parkinson's disease 
and stroke.
    Inventors: Andreas Androutsellis-Theotokis and Ronald D.G. McKay 
(NINDS).
    Publication: A Androutsellis-Theotokis et al. Notch signalling

[[Page 20861]]

regulates stem cell numbers in vitro and in vivo. Nature 2006 Aug 
17;442(7104):823-826.
    Patent Status:
    1. U.S. Provisional Application No. 60/715,935 filed 08 Sep 2005 
(HHS Reference No. E-239-2005/0-US-01).
    2. PCT Application No. PCT/US2006/034988 filed 07 Sep 2006 (HHS 
Reference No. E-239-2005/0-PCT-02).
    Licensing Status: Available for non-exclusive or exclusive 
licensing.
    Licensing Contact: Fatima Sayyid, M.H.P.M.; 301/435-4521; 
<a href="/cdn-cgi/l/email-protection#4d3e2c343424292b0d202c242163232425632a223b"><span class="__cf_email__" data-cfemail="6f1c0e1616060b092f020e06034101060741080019">[email protected]</span></a>.
    Collaborative Research Opportunity: The National Institute of 
Neurological Disorders and Stroke, Laboratory of Molecular Biology, is 
seeking statements of capability or interest from parties interested in 
collaborative research to further develop, evaluate, or commercialize 
agents that inhibit or induce phosphorylation of STAT3 protein and 
survival of stem cells and precursor cells. Please contact Martha Lubet 
at 301/435-3120 or <a href="/cdn-cgi/l/email-protection#d5b9a0b7b0a1b895b8b4bcb9fbbbbcbdfbb2baa3"><span class="__cf_email__" data-cfemail="99f5ecfbfcedf4d9f4f8f0f5b7f7f0f1b7fef6ef">[email protected]</span></a>.

Preparation and Use of Androgenic Compounds: Nandrolone 17beta-
carbonates

    Description of Invention: Hypogonadism is defined as deficient or 
absent male gonadal function that results in insufficient testosterone 
secretion. Hypogonadism can be caused by surgery; radiation; genetic 
and developmental disorders; liver and kidney disease; infection; and 
certain auto-immune disorders. The most common genetic disorders are 
Klinefelter syndrome found in men and Turner syndrome in women.
    Hypogonadism affects an estimated 4 to 5 million men in the United 
States, and although it may occur in men at any age, low testosterone 
levels are especially common in older males. More than 60% of men over 
age 65 have free testosterone levels below the normal values of men 
aged 30 to 35. Studies suggest that hypogonadism in adult men is often 
underdiagnosed and under treated. This may be because the symptoms are 
easily attributed to aging or other medical causes, or ignored by 
patients and physicians. In fact, only about 5% of hypogonadal men 
receive testosterone replacement. Some experts also believe that we 
need to reevaluate normal testosterone levels and lower the diagnostic 
cutoff for hypogonadism. By doing so, many patients who we now consider 
to be ``low-normal'' would probably be considered candidates for 
androgen replacement.
    The inventors have discovered androgenic compounds, the lead 
compound being 17beta-carbonates of nandrolone derivatives. These 
compounds can be used to treat hypogonadism, as hormonal therapy and as 
a male contraceptive. The disclosed carbonates have potent activity 
when administered as an oral composition. In addition, long-lasting 
activity has also been observed with subcutaneous administration in 
laboratory animals. It is foreseen that these androgens can be utilized 
in hormonal replacement therapy for both men and women, which 
constitute a huge market both in the United States and abroad.
    Inventors: Richard P. Blye and Hyun K. Kim (NICHD).
    Patent Status: U.S. Provisional Application No. 60/650,376 filed 04 
Feb 2005 (HHS Reference No. E-181-2004/0-US-01); PCT Application No. 
PCT/US2006/02436 filed 24 Jan 2006 (HHS Reference No. E-181-2004/0-PCT-
02).
    Licensing Status: Available for non-exclusive or exclusive 
licensing.
    Licensing Contact: Tara L. Kirby, PhD; 301/435-4426; 
<a href="/cdn-cgi/l/email-protection#c2b6a3b0a3a982afa3abaeecacabaaeca5adb4"><span class="__cf_email__" data-cfemail="75011407141e3518141c195b1b1c1d5b121a03">[email protected]</span></a>.
    Collaborative Research Opportunity: The NICHD Contraception & 
Reproductive Health Branch is seeking statements of capability or 
interest from parties interested in collaborative research to further 
develop, evaluate, or commercialize this technology. Please contact 
John D. Hewes, Ph.D. at 301-435-3121 or <a href="/cdn-cgi/l/email-protection#bad2dfcddfc9d0fad7dbd3d694d4d3d294ddd5cc"><span class="__cf_email__" data-cfemail="afc7cad8cadcc5efc2cec6c381c1c6c781c8c0d9">[email protected]</span></a> for more 
information.

Neural Crest-Melanocyte cDNA Based Microarray Analysis for Human Skin 
Pigmentation Research

    Description of Technology: Microarrays have wide applications in 
basic research and are used for the discovery of candidate genes as 
markers for disease and for therapeutic intervention. This invention 
pertains to the identification of a set of neural crest-melanocyte (NC-
M) genes through microarray analysis and informatic analysis. Utilizing 
the extensive sequence information in the expressed sequence tag 
database (dbEST), the specific set of cDNA sequence was identified for 
microarray analysis of melanocyte function and diseases. This 
integrated technique of sequencing with bioinformatics led to the 
discovery of novel genes. The cDNA sequences selected in this invention 
are differently expressed in neural crest melanocyte derivates relative 
to non-neural derived samples. Given that many of the neural-crest 
melanocyte genes are expressed at embryonic stages of neural crest-
melanocyte development, the gene set identified in this invention 
should provide a useful tool for the analysis of patterns of 
transcriptional regulation of NC-M development. Thus, this technology 
will be useful for the characterization of altered expression patterns 
in diseases such as melanoma. Further, this new microarray research 
tool has been developed using the set of genes that are likely to be 
involved in the control of human skin pigmentation. The microarray 
system utilizing these genes is of significant importance in 
identifying small molecules that may modulate their activity leading to 
alterations in human skin pigmentation. Therefore, this invention is 
significantly useful to the researchers to study alterations in human 
skin pigment amount and type.
    Inventors: William J. Pavan and Stacie K. Loftus (NHGRI).
    Patent Status: HHS Reference No. E-014-2002/0--Research Tool.
    Licensing Status: Available for licensing under a Biological 
Materials License.
    Licensing Contact: Tara L. Kirby, PhD; 301/435-4426; 
<a href="/cdn-cgi/l/email-protection#b6c2d7c4d7ddf6dbd7dfda98d8dfde98d1d9c0"><span class="__cf_email__" data-cfemail="dfabbeadbeb49fb2beb6b3f1b1b6b7f1b8b0a9">[email protected]</span></a>.

RAB38, a Target for Treatment of Melanoma and Pigmentation Disorders

    Description of Technology: Melanocytes are specialized pigment-
producing cells that are responsible for coloration of skin, eyes and 
hair. Using cDNA microarray expression profiling, the inventors have 
identified RAB38, a small GTP-binding protein, as an important gene 
involved in melanocyte function. Human RAB38 was localized to the mouse 
chocolate (cht) locus, and mutation of this gene in mice changes hair 
color from black to brown, similar to OCAIII mice, which have a 
mutation in TYRP1, another melanosomal gene, and are used as a model 
for oculocutaneous albinism.
    The inventors have demonstrated that RAB38 is important for 
trafficking of the TYRP1 protein; thus, RAB38 mutant mice are 
genocopies of TYRP1 mutant mice. Modulation of RAB38 activity, such as 
by pharmacologic intervention, might alter pigmentation in human skin. 
Recently, RAB38 has also been identified as a melanocyte 
differentiation antigen that is strongly immunogenic, leading to 
spontaneous antibody responses in a significant proportion of melanoma 
patients. Thus, RAB38 may also have applications for melanoma 
diagnostics and treatment.
    This invention discloses RAB38 nucleic acids and protein, and 
methods for detecting mutations in RAB38. Also disclosed are methods 
for screening for agents to modulate RAB38 activity, and for modulating 
pigmentation through modulation of RAB38 activity.
    Applications:

[[Page 20862]]

    1. Marker protein and target for antigen-specific immunotherapy in 
patients with malignant melanoma.
    2. Therapeutics and diagnostics for melanin-related disorders.
    Development Status: Early stage.
    Inventors: William J. Pavan and Stacie K. Loftus (NHGRI).
    Publications: Stacie K. Loftus, Denise M. Larson, Laura L. Baxter, 
Anthony Antonellis, Yidong Chen, Xufeng Wu, Yuan Jiang, Michael 
Bittner, John A. Hammer III, and William J. Pavan. Mutation of 
melanosome protein RAB38 in chocolate mice. Proc Natl Acad Sci U.S.A. 
2002 Apr 2;99(7):4471-4476.
    Patent Status:
    1. U.S. National Stage Application No. 10/501,611 filed 20 Nov 
2005, claiming priority to 18 Jan 2002 (HHS Reference No. E-315-2001/0-
US-07).
    2. Foreign counterparts pending in Australia, Canada, Europe, and 
Japan.
    Licensing Status: Available for exclusive or non-exclusive 
licensing.
    Licensing Contact: Tara L. Kirby, Ph.D; 301/435-4426; 
<a href="/cdn-cgi/l/email-protection#96e2f7e4f7fdd6fbf7fffab8f8fffeb8f1f9e0"><span class="__cf_email__" data-cfemail="6c180d1e0d072c010d050042020504420b031a">[email protected]</span></a>.

Novel Dmt-Tic Analogues Specific for Delta- and Mu-Opioid Receptors

    Description of Technology: Opioid receptor modulators, used 
historically for pain control, have more recently been shown to possess 
broader therapeutic potential in areas such as opiate and alcohol 
abuse, neurological disease or injury, neuropeptide or neurotransmitter 
imbalance, and immune system dysfunction. Furthermore, their 
interaction with key reward pathways presents interesting avenues for 
exploration in the treatment of food as an addictive substance, due to 
the fact that obesity is a major health problem in the U.S. Also, 
evidence of modulatory interactions between delta- and mu-opioid 
receptors has spurred interest in new opioid ligands possessing mixed 
and dual specificity for these receptors. These bifunctional compounds 
are particularly promising for treatment of addiction and treatment of 
pain with the elimination of drug tolerance.
    The inventors have developed a wide variety of highly selective 
Dmt-Tic analogues with potential therapeutic applications. These 
analogues include specific agonists and antagonists of the delta- and 
mu-opioid receptors and combinations thereof.
    Some disclosed analogues are di- and tri-peptidic derivatives of 
the Dmt-Tic pharmacophore; in addition to opioid receptor specificity, 
two of these derivatives have been shown to inhibit the activity of 
human multidrug resistance glycoprotein 1 (hMDR1) and may represent a 
novel chemosensitizing agent for treating cancer, and may also be used 
for reducing tolerance to morphine, the drug of choice in most 
hospitals around the world, thereby increasing its effectiveness. Also 
disclosed are compounds produced through derivatization of Dmt-Tic 
reference compounds with lysine, resulting in an unexpected and broad 
range of delta-and/or mu-opioid receptor modulation. The inventors have 
also prepared symmetric and asymmetric Dmt-Tic di-peptides that are 
potent dual delta- and mu-opioid receptor antagonists and that can pass 
through the gastrointestinal and blood-brain barriers. Finally, the 
inventors have prepared various fluorescent Dmt-Tic analogs that are 
useful for study of delta- and mu-opioid receptor structure and 
function.
    Applications:
    1. Potential opiate, food, and alcohol addiction therapeutics.
    2. Potential therapeutics for pain treatment.
    3. Potential therapeutics for cancer.
    4. Tools for screening ligand binding activity and differentiating 
between delta- and mu-opioid receptors.
    Market:
    1. In 2004, approximately 22 million Americans over the age of 12 
required treatment for alcohol or illicit drug abuse and addiction; 13 
million of these were classified as alcoholics.
    2. Approximately 50 million Americans suffer from pain, and an 
estimated 1.5 billion people suffer from moderate to severe pain 
worldwide.
    3. Two-thirds of the U.S. population is overweight, with a quarter 
designated as obese (9 million of whom are children); the number of 
overweight Americans doubled between 1980-1999 and is predicted to 
increase 20% by 2013 to 140 million.
    Development Status: In vitro data are available.
    Inventors: Lawrence H. Lazarus (NIEHS) et al.
    Publications:
    1. G. Balboni et al. Effect of lysine at C-terminus of the Dmt-Tic 
opioid pharmacophore. J Med Chem. 2006 Sep 7;49(18):5610-5617.
    2. T Lovekamp et al. Inhibition of human multidrug resistance P-
glycoprotein 1 by analogues of a potent delta-opioid antagonist. Brain 
Res. 2001 May 25;902(1):131-134.
    3. T Li et al. Potent Dmt-Tic pharmacophoric delta- and mu-opioid 
receptor antagonists. J Med Chem. 2005 Dec 15;48(25):8035-8044.
    4. T Li et al. Transformation of a mu-opioid agonist into 
biologically potent mu-opioid antagonists. Bioorg Med Chem. 2007 Feb 
1;15(3):1237-1251.
    5. G. Balboni et al. Highly selective fluorescent analogue of the 
potent *elta-opioid receptor antagonist Dmt-Tic. J Med Chem. 2004 Dec 
16:47(26):6541-6546.
    Patent Status:
    1. U.S. Patent No. 6,753,317 issued 22 Jun 2004 (HHS Reference No. 
E-103-2000/0-US-02).
    2. U.S. Patent No. 6,916,905 issued 12 Jul 2005 (HHS Reference No. 
E-103-2000/1-US-01).
    3. U.S. Patent Application No. 10/280,752 filed 16 Nov 2005 (HHS 
Reference No. E-103-2000/2-US-02).
    4. U.S. Provisional Application No. 60/834,438 filed 31 Jul 2006 
(HHS Reference No. E-103-2000/3-US-01).
    5. PCT Application No. PCT/US06/33560 filed 30 Aug 2006 (HHS 
Reference No. E-305-2005/0-PCT-02).
    Licensing Status: Available for exclusive or nonexclusive 
licensing.
    Licensing Contact: Tara L. Kirby, PhD; 301/435-4426; 
<a href="/cdn-cgi/l/email-protection#d1a5b0a3b0ba91bcb0b8bdffbfb8b9ffb6bea7"><span class="__cf_email__" data-cfemail="f88c998a9993b895999194d6969190d69f978e">[email protected]</span></a>.

    Dated: April 17, 2007.
Steven M. Ferguson,
Director, Division of Technology Development and Transfer, Office of 
Technology Transfer, National Institutes of Health.
 [FR Doc. E7-7933 Filed 4-25-07; 8:45 am]
BILLING CODE 4140-01-P


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