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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

Human Sodium Channel Promoter Region

(#05-151)

Technology Background and Description

Heart disease is the number one cause of death in the United States, surpassing even cancer. The National Center for Chronic Disease Prevention and Health Promotion estimates that approximately 950,000 Americans die of cardiovascular disease every year, accounting for more than 40 percent of all deaths. One form of cardiovascular disease, arrhythmia, is associated with very high levels of morbidity and mortality. Sudden arrhythmic death claims more than 300,000 lives each year.

Arrhythmia is defined as abnormal beating of the heart. Heart beat, a complex process of contraction and expansion, is controlled by electrical impulses, which are, in turn, regulated by the flow of specific ions (K+, Na+ and Ca+2) across cellular membranes. Integral membrane proteins, or channels, act as gates, controlling the flow of ions in and out of cells. Sodium, calcium and potassium channels play pivotal roles in generating cardiac action potential, which triggers contraction. Ion channel dysfunction resulting from genetic mutation is a primary cause of arrhythmia.

The cardiac voltage-sensitive sodium (Na+) channel is composed of α and β subunits. The gene encoding the α-subunit, SCN5A, has been cloned and found to consist of 28 exons spanning over 80kb of DNA. The protein is responsible for the rapid influx of sodium ions that initiate and propagate action potential in the heart and the large peak sodium influxes responsible for excitability and conduction in myocardium and special conduction tissues. Mutations within the SCN5A gene are responsible for a number of cardiac arrhythmias, including Long QT-3 (LQT3), Brugada Syndrome and isolated cardiac conduction disease (ICCD).

Despite the large number of arrhythmia-linked SCN5A mutations identified to date, there is a clear need to identify additional arrhythmia-linked genetic mutations as many individuals afflicted with arrhythmia, or with a family history of the disease, test negative for genetic mutations. The subject technology represents a potentially useful tool for future genetic testing for SCN5A-linked cardiac arrhythmias. The search for SCN5A mutations has focused primarily on coding regions. In contrast, the subject technology focuses analysis on the promoter and 5' and 3' untranslated regions (UTRs) of the SCN5A gene. Approximately 100kb of the SCN5A promoter of the human voltage-gated sodium channel has been sequenced. Alterations within the promoter region could potentially alter the expression of the SCN5A protein, leading to an arrhythmic state. Significantly, multiple 5' and 3' mRNA splice variants have also been identified. These could encode SCN5A isoforms possessing different, perhaps cardiac disease-associated, biological activities. Thus, these findings could potentially impact genetic testing and treatment for SCN5A-linked arrhythmias

BENEFITS

1. Potential to impact cardiac arrhythmia treatments

• Patients affected with or destined to acquire arrhythmias are often asymptomatic
• Poor prognoses exist for individuals not receiving treatment for their arrhythmias
• Proper identification of an arrhythmia-linked mutation may allow for mutation-specific pharmacological intervention
• Results - Greater patient survival

2. Potential to improve arrhythmia-specific genetic testing

• Almost 30 percent of individuals affected by LQTS or having a family history of LQTS do not test positive for any of the currently identified LQTS-linked mutations
• Only 20 percent of patients with Brugada Syndrome (a known SCN5A-linked arrhythmia) possess SCN5A mutations
• The majority of the arrhythmia-linked SCN5A mutations identified to date are localized to coding regions - little research has focused on the expansive regulatory and non-coding regions of the SCN5A gene
• Extensive (100kb) SCN5A promoter sequence and multiple UTR mRNA splice variants have recently been identified
• Results - Enhanced diagnostic and prognostic value

3. Market Opportunity

• Annually, 300,000-400,000 Americans die from arrhythmia-mediated cardiac arrest
• The U.S. genetic testing market is in its earliest stages and the potential exists for significant growth
• Genetic testing market produced $320 million in 2000, and is forecasted to reach $1.5 billion by 2011
• Minimal competition exists as only a small number of labs provide clinical testing for cardiac arrhythmias
• Results - Significant commercial potential

IP STATUS:

US provisional patent application was filed on Feb 17, 2006 (60/774,226).
US provisional patent application was filed on Sept 26, 2006 (60/847,084).
US non-provisional patent application was filed on 2-20-07 (11/707,882) combines both provisionals.

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

Last Updated - May 1, 2007