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Please Note: The technology listed below is not available to the public at this time. This technology is in the early stage of research and requires further development before it is ready for the marketplace. The VA is currently in the process of identifying potential companies who may be interested in licensing and/or further developing the technology through Cooperative Research and Development Agreements (CRADA). Through cooperative research initiatives such as these, it is our hope and goal that commercial products will be fully developed and made available to benefit veterans and others.
VA TECHNOLOGY OPPORTUNITY BRIEF
Transgenic Screens for Modulators of BDNF Production
(#01-113)
OPPORTUNITY:
The Department of Veterans Affairs (VA) is seeking
a commercial partner to license and/or further develop this technology through
a Cooperative R&D Agreement (CRADA) to expedite bringing it to market.
BACKGROUND:
The trend for identifying novel drugs is via high throughput screening (HTS).
It is a process whereby molecular and cellular therapeutic targets come in contact
with chemical libraries. Hits, compounds active against the target, are then
subjected to physiological and biological testing. Until fairly recently the
bottleneck in the drug discovery process had been the identification of targets;
with only 483 targets accounting for all the drugs on the market. However, as
a result of the progress in genomics research, this bottleneck has largely been
removed and a reasonable estimate of the number of potentially interesting drug
targets is thought to be in the vicinity of 3,000 to 10,000. The current bottleneck
is demonstrating target validity. HTS, a focal point in drug discovery, is often
governed by the principles cheaper, better, faster. Screening for drug targets
is now increasingly being carried out in silico-that is, vast databases of chemical
compounds are being examined in relation to genomic and 3-D protein structure
without any physical laboratory work, simply using computer power.
TECHNOLOGY OVERVIEW:
This technology is a transgenic screening tool to rapidly screen drug candidates
for their ability to influence the production of brain-derived neurotrophic
factor (BDNF). The method also promises to be useful in identifying the complex
genetic pathway affecting BDNF expression, and thus in identifying new targets
for drug discovery efforts. BDNF belongs to a group of nerve growth factors
called neurotrophins (NT). The function of NTs includes fostering the growth
and survival of neurons during development. In adult brains NTs have an influence
on neuronal excitability and, specifically, BDNF appears to regulate neuronal
morphology and synaptogenesis. It is also reputed to exhibit neuroprotective
effects in a range of central nervous system areas (Binder et al. 2001). BDNF
has been shown to enhance motor neuron survival in several experimental animal
models (Department of Neurology, Baylor College of Medicine 2001). Neurodegenerative
diseases such as Huntington's Disease, Parkinson's Disease and Alzheimer's Disease
are expected to show abnormal BDNF expression. Enhancement of BDNF function
is thought to be one of the mechanisms by which anti-depressants work (Russo-Neustadt
et al. 2001) and as such might have a significant effect in treating depression.
This screen uses a zebrafish BDNF promoter sequence inserted upstream of a fluorescent
marker gene, so that the BDNF promoter is marked by fluorescence. This transgene
is injected into zebrafish embryos at the 1- to 8-cell stage of embryonic development
to create a founder line, which is developed using standard breeding and analysis
methods. The embryos are then exposed to a test substance of biological or chemical
nature, after which the level of fluorescent protein reporter is compared to
controls using a fluorescent image analysis system. In this manner factors that
affect the promoter activity can be determined by alterations in the level of
fluorescent signal.
TECHNICAL MERIT:
It is hypothesized that raising the level of BDNF produced within cells may
be an effective method for treating a number of disease conditions. Most established
methods of screening for substances that modulate BDNF production are based
on cell culturing and measure the level of BDNF that is secreted into the culture
medium before and after the introduction of potential modulators. Such in-vitro
tests measure BDNF production directly and are thus valuable, although the tests
do not identify the specific mechanism by which production is increased.
BDNF expression is the result of a complex process with a number of regulatory
("promoter" or "cis-") genes regulating the transcription
of the neurotrophic factor. Because the subject technology allows screening
for the expression of specific genetic segments, researchers are able to identify
factors that affect the activity of specific promoter genes. Such an identification
of genetic and therapeutic agents affecting BDNF transcription suggests commercialization
potential for the subject technology. Although the number of drug candidates
affecting BDNF production that are identified using this screen will be smaller
than if a more broad-based screen were used, the candidates are likely to be
more useful because of their precisely known and potentially narrower action
(i.e., on a single promoter gene).
PATENT STATUS:
A provisional patent application was filed on 11-30-01 for this invention (60/334,079)
U.S. patent application filed November 29, 2002 (S/N 10/306,737)
A Continuation-In-Part application to US application (10/306,737) was filed on
December 23, 2003 (10/742,828)
Federal Register: June 19, 2003 (Vol.68, No.118) p. 36873
FOR MORE INFORMATION CONTACT:
Saleem Sheredos
Program Manager
Technology Transfer Program
Veterans Affairs
Office of Research & Development (12TT)
5th Floor
103 South Gay Street
Baltimore, MD 21202
202-380-5080
Fax 410.962.2141
e-mail: saleem.sheredos@va.gov