Modified Sodium Channels for Use in Drug Development and Testing
Therapeutics treat a variety of diseases by targeting specific voltage-gated sodium (Nav) channels, and new drugs are continually being developed to improve both the safety and efficacy of treating Nav-related diseases. Abnormal sodium channels which open persistently can cause conditions such as chronic pain, cardiac arrhythmia, and muscle weakness or paralysis. The diseased channels’ persistent late currents are generally small in size (less than 2% of the peak current amplitude), making these channels difficult to study or use in the screening of new drug candidates. Additionally, the large size of the Nav proteins and the number of different Nav gene variants complicate the ability to optimize screening methods. To solve these problems, researchers at the University at Albany have generated and characterized a panel of modified Nav channels which open persistently like their diseased counterparts, but have considerably larger late sodium currents. UAlbany’s patented Nav channels open normally in response to stimuli, but remain in the open state over a 100 times longer than corresponding wild-type channels. The extended opening time allows more time for the drug molecules to bind to the channels, leading to more sensitive measurements of the effects of therapeutic candidates.
Because of the number of different sodium channels and their various patterns of expression, our panel of patented inactivation-deficient Nav proteins would have wide-ranging utility, including the following fields:
- Central nervous system disorders, including epilepsy, affective disorders, and schizophrenia.
- Pain research, such as the development of new anesthetics and analgesics.
- Cardiovascular disease, particularly arrhythmias such as long QT-3 syndromes.
- Cancer therapy, including breast cancer, colorectal cancer, ovarian cancer, prostate cancer, etc.
- Familial periodic paralysis.
- Toxicology and the pre-clinical safety evaluation for potential off-target effects of new drugs.
- In drug screening, our inactivation-deficient Nav channels more closely mimic diseased channels than do wild-type channels, but have larger persistent currents, making therapeutic effects more detectable.
- The prolonged opening of our sodium channels facilitates drug binding at lower concentrations and allows time for thorough kinetics studies.
- Our modified recombinant Nav channels express well in host cells and are useful in patch-clamp assays.
The voltage-gated sodium channel protein family comprises nine large a-subunits, termed Nav 1.1 – 1.9, and four smaller b-subunits. Each a-subunit alone is able to form a functional channel. These a-subunits are highly homologous with one another, and the structure of each a-subunit consists of four repeated domains (D1 – D4) that in turn contain six membrane-spanning regions (S1 – S6). Mutations of just a few of the amino acid residues in the S6 domains are sufficient to cause a defect in the fast inactivation process. Normally, the Nav channels open in response to a change in electrical potential, allowing sodium ions to enter the cell, but then the channels inactivate quickly, usually in a few milliseconds. The fast inactivation-deficient variants open normally but inactivate very slowly, remaining open at least a hundred times longer than does a wild-type channel. Since most drugs which block sodium channels target the open state of the channel, and the fast inactivation-deficient mutations extend the time the open state exists, the variants allow drug candidate molecules to bind more effectively and allow researchers an extended amount of time in which to study the interaction of the drug with the channel. In the example shown below, low concentrations of lidocaine had minimal effects on the peak channel response, but the effects on the late current response were much more pronounced. These late currents can best be studied using the fast inactivation-deficient Nav variants.
Stage of Development
This invention has been extensively developed by Dr. Sho-Ya Wang, Professor of Biological Sciences at the University at Albany, SUNY. The modified sodium channels are the subject of four issued U.S. patents. The portfolio covers recombinant DNA, transfected cells, and methods of use:
Dr. Wang continues to conduct research into sodium channel functions. For further information and to see a list of her publications, please go to: http://www.albany.edu/biology/faculty/sywang/index.shtml.
For More Information Please Contact:
Theresa A. Walker
Office for Innovation Development and Commercialization
University at Albany, SUNY
1400 Washington Avenue
Albany, NY 12222