[Federal Register Volume 68, Number 236 (Tuesday, December 9, 2003)]
[Notices]
[Pages 68637-68638]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 03-30496]


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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 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.

A Mouse Model for Systemic Inflammation in Glucocerebrosidase-Deficient 
Mice With Minimal Glucosylceramide Storage

    Richard L. Proia (NIDDK). DHHS Reference No. E-256-2003/0--Research 
Tool. Licensing Contact: Susan Carson; (301) 435-5020; 
[email protected].
    Gaucher disease, the most common lysosomal storage disease, is an 
inherited metabolic disorder in which harmful quantities of the lipid 
glucocerebroside accumulate in the spleen, liver, lungs, bone marrow 
and in rare cases in the brain, due to a deficiency of the enzyme 
glucocerebrosidase (Gba) that catalyses the first step in the 
biodegradation of glucocerebrosides. Type 1 Gaucher disease is the most 
common and is distinguished from the other forms of the disease, types 
2 and 3, by the lack of neurologic involvement. The clinical features 
of Type 1 are heterogeneous, vary broadly in clinical severity and 
affect many organ systems. The major disease manifestations include 
enlarged spleen and liver, bone lesions, hematologic abnormalities and 
lung involvement. The disease has also been associated with a sustained 
inflammatory reaction. Gaucher disease is most prevalent in the 
Ashkenazi Jewish population with an incidence of approximately 1 in 450 
persons while in the general public the incidence is 1 in 100,000. 
There are an estimated 30,000 Gaucher disease patients world-wide with 
approximately 3000 patients currently receiving enzyme replacement 
therapy which has been shown to be highly effective in treatment of the 
disease. The cost of therapy is approximately $100,000-$300,000 
annually and is a life-long treatment, which makes the case for 
affordable new therapies urgent.
    The etiology of the disease has been difficult to study due to the 
absence of viable mouse models for the disease, as a complete 
disruption of the glucocerebrosidase (Gba) gene results in rapid 
neonatal death. In an attempt to produce a viable model scientists at 
the NIDDK introduced a human Gaucher disease point mutation, L444P, 
into the mouse Gba gene in order to cause a partial enzyme deficiency 
(J. Clin. Invest (2002) 109, 1215-1221; Proc. Natl. Acad. Sci. USA 
(1998) 95, 2503-2508).
    The mice exhibit a partial glucocerebrosidase deficiency (15-20% of 
normal activity), without bulk accumulation of glucosylceramide or the 
presence of Gaucher cells. The mice demonstrate other clinical features 
of Gaucher disease, including multisystem inflammation, B cell 
hyperproliferation, skin abnormalities, anemia and lymphadenopathy. 
These mice provide a useful model for studying certain aspects of 
Gaucher disease pathology and in evaluating new therapeutic treatments.

Tec Kinase Deficient Mice

Pamela L. Schwartzberg (NHGRI), Michael J. Lenardo (NIAID), Harold 
Varmus (EM), Dan Littman (EM).
DHHS Reference No. E-178-2003/0 and DHHS Reference No. E-178-2003/1--
Research Tools.
Licensing Contact: Susan Carson; (301) 435-5020; [email protected].

    Stimulation of T lymphocytes through the T Cell Receptor (TCR) 
elicits broad responses required for proper immune function, including 
cell proliferation, cytokine production and apoptosis. Activation of 
distinct families of tyrosine kinases (Zap-70, Src) are important in 
TCR signalling, while the role of other tyrosine kinases, such as the 
Tec Kinases Rlk and Itk is less clear. However, evidence suggests that 
these kinases play a role in CD4+ T helper (Th) cell differentiation. 
Responses to infection are regulated in part by two distinct types of T 
helper cells, type 1 (Th1) and Th2 subclasses which produce different 
cytokines and have discrete effector functions. Th1 cells produce 
interferon-gamma (IFN-gamma), which is a key mediator of cellular 
immunity. In contrast Th2 cells produce interleukin 4 (IL-4), Il-5, Il-
10, and Il-13 which assist humoral immunity and dominate immune 
responses to both helminths and allergens. Regulation of these 
subclasses is important not only for normal immune response, but also 
for abnormal disease processes, including autoimmunity and 
hypersensitivity. Generation of type 1 and type 2 Th cells is 
influenced by multiple factors including cytokines, costimulation and 
TCR-based signals. Understanding the mechanisms and signals important 
in T cell signalling is important for identifying new therapeutics that 
target Th1 and Th2-mediated pathologies (for example autoimmune 
disorders and asthma, respectively).
    The Tec family of tyrosine kinases have been implicated as 
important mediators of polarized cytokine production and Th2 cell 
differentiation. Rlk is preferentially expressed in Th1 cells and Itk 
is important in Th2 response. Numerous studies have implicated 
alterations in the strength of TCR-mediated signals as playing 
important roles in Th cell differentiation. Researchers at the NIH have 
developed transgenic mouse models in order to address these issues. 
Rlk-deficient mice and Rlk/Itk double-deficient mice were generated and 
have been shown to have defects in TCR responses including 
proliferation, cytokine production and apoptosis in vitro and adaptive 
immune response to infectious agents in vivo (Science (1999) 284, 638-
641; Nature Immunol (2001) 2: 1183-188). Molecular analyses of cells 
from these mice indicate that these kinases are critical for proper 
regulation of phospholipase C, calcium mobilisation and ERK activation 
as well as activation of downstream transcription factors in response 
to T cell receptor stimulation. Defects are minor in Rlk-deficient 
animals and most severe in Rlk/Itk double-deficient mice.

[[Page 68638]]

These mice provide a useful mechanistic model for dissecting out the 
complex interactions of TCR signalling. Additionally, the mice are 
useful for evaluation of therapeutics directed at specific classes of 
diseases (Th1 or Th2) and the utility of potential global Tec kinase 
inhibitors.

A Mouse Model for Type 2 Diabetes

Derek LeRoith and Ana M. Fernandez (NIDDK).
DHHS Reference No. E-132-2003/0--Research Tool.
Licensing Contact: Pradeep Ghosh; (301) 435-5282; [email protected].

    Diabetes affects over 120 million people worldwide (16 million in 
the US) and is a major health problem with associated health costs 
estimated at almost $100 billion dollars. Type 2 diabetes affects as 
many as 10% of the population of the Western World (with 15 million 
patients in the U.S. alone) and arises from a heterogeneous etiology, 
with secondary effects from environmental influences. Risk factors for 
type 2 diabetes include obesity, high blood pressure, high 
triglycerides and age. Type 2 diabetes is an active area for drug 
development and there continues to be a need for novel animal models 
and research tools to aid in the discovery and development of new, more 
efficient and cost-effective therapeutics.
    Peripheral insulin resistance and impaired insulin action are the 
primary characteristics of type 2 diabetes. The first observable defect 
in this major disorder occurs in muscle, where glucose disposal in 
response to insulin is impaired. In an effort to study the progression 
of diabetes, researchers at NIDDK have developed a transgenic mouse 
strain (MKR) with a dominant-negative insulin-like growth factor-I 
receptor (KR-IGF-IR) specifically targeted to skeletal muscle (Genes & 
Development (2001) 15, 1926-1934). Expression of KR-IGF-IR resulted in 
the formation of hybrid receptors between the mutant and the endogenous 
IGF-I and insulin receptors, thereby abrogating the normal function of 
these receptors and leading to insulin resistance. Pancreatic [beta]-
cell dysfunction developed at a relative early age, resulting in 
diabetes.
    One of the great advantages of the MKR mouse over other mouse 
models is the early onset of the disease phenotype as seen by insulin 
resistance (as early as 4 weeks), fasting hyperglycemia (from 5 weeks) 
and abnormal glucose tolerance (at 7-12 weeks). The MKR mice provide an 
extremely useful model for the study of type 2 diabetes, its 
pathogenesis and potential new therapies.

A Tet-Regulated Mouse Model for Cataract

Robert W. Sobol, Samuel H. Wilson (NIEHS). DHHS Reference No. E-316-
2002/0--Research Tool. Licensing Contact: Susan Carson; (301) 435-5020; 
[email protected].

    Cataract is the most common cause of blindness worldwide, with an 
estimated 25 million blind and 119 million visually impaired 
individuals worldwide. Over 20 million adults in the U.S. alone are 
currently diagnosed with cataracts making this disease a major health 
concern. The incidence of cataract increases with age and a number of 
etiologic factors have been proposed in the pathogenesis of age-related 
cataract in humans including genetic factors, environmental factors and 
metabolic and biochemical changes in the crystalline lens. Ultraviolet 
radiation exposure and oxidative injury to the lens has been considered 
by some to be one of the most important factors in cataractogenesis. 
The present therapy of choice for cataract is laser surgery.
    Experimental investigation of human age-related cataract is 
hindered by a lack of available animal models of cataract. Several 
laboratory mice strains with heritable cataracts have been studied 
including the Nakona, Frasier and the Philly mouse strains. An animal 
model with a predictable phenotype of cataract, particularly one with a 
pathogenesis relating to oxidative injury to the lens (the proposed 
central factor in human-related cataract) would be of great value to 
ophthalmic researchers and in the development of pharmacological agents 
for delaying or preventing cataract.
    Researchers at the NIEHS have developed a transgenic mouse model in 
which the DNA repair gene DNA polymerase [beta] ([beta]-pol) is highly 
over-expressed in the lens epithelial cells of the eye (DNA Repair 
(2003) 609-622). A bicistronic tetracycline-responsive transgenic 
system was used to over-express [beta]-pol in mice. Over-expression of 
[beta]-pol in the lens epithelium results in the early onset of severe 
cortical cataract with cataractogenesis beginning within 4 days after 
birth. In utero and post-natal suppression of transgenic Flag-[beta]-
pol-expression by doxycycline administration completely prevents 
cataract formation through adulthood, yet cataract is subsequently 
observed following removal of doxycycline and re-expression of the 
transgene. This predictable and regulated onset of cataract makes this 
mouse an ideal animal model both for evaluating new therapeutics for 
delaying or preventing cataract as well as for understanding the 
mechanisms responsible for cataract formation.

A Mouse Model for Human Osteoarthritis

    Laurent G. Ameye (NIDCR), Marian F. Young (NIDCR), Ake Oldberg 
(EM), Tianshun Xu (NIDCR). DHHS Reference No. E-081-2002/0--Research 
Tool. Licensing Contact: Susan Carson; (301) 435-5020; 
[email protected].
    Osteoarthritis (OA) is the most common form of arthritis and 
affects more than 20 million Americans, costing billions of dollars in 
health care annually. Osteoarthritis is caused by the breakdown of 
joint cartilage, leading to a loss of the cartilage ``cushion'' between 
the bones of the joints. Risk factors associated with OA include age, 
obesity, traumatic injury and overuse due to sports or occupational 
stresses. There is no cure for OA and current treatments are directed 
at the symptomatic relief of pain, and at improving and maintaining 
joint function. There remains, however, a critical need both to develop 
OA treatments that focus on slowing down the degenerative process of 
the disease and for validated animal models to test these new 
treatments. NIH scientists at the NIDCR have generated a mouse model 
for osteoarthritis (FASEB J. (2002) 16, 673-680) that fills one part of 
this important gap.
    The mouse model is a double knockout mouse that lacks biglycan and 
fibromodulin, two members of the small leucine-rich proteoglycan 
family, and that spontaneously develops OA. All the hallmarks of human 
osteoarthritis are present, including: progressive degeneration of the 
articular cartilage from early fibrillation to complete erosion, 
subchondral sclerosis, an absence of inflammation and development of 
osteophytes and cysts. Advantages over the existing models for 
osteoarthritis include: high phenotypic penetrance, early onset (at 1-2 
months) and a rapid disease progression (between 3-6 months) which can 
be accelerated by moderate levels of exercise, such as treadmill 
running. These properties, combined with a normal life span, make the 
biglycan/fibromodulin-deficient mouse an ideal animal model for 
evaluating new drugs and treatments for osteoarthritis.

    Dated: December 1, 2003.
Steven M. Ferguson,
Director, Division of Technology Development and Transfer, Office of 
Technology Transfer, National Institutes of Health.
[FR Doc. 03-30496 Filed 12-8-03; 8:45 am]
BILLING CODE 4140-01-P