How the FDA’s NicScreen project is developing potential scientific tools for tobacco product regulation
Tobacco use is widely recognized as a deadly, but avoidable health hazard. More than 16 million Americans are living with a disease caused by smoking, suggests the US Centers for Disease Control and Prevention. Yet until recently, the manufacture of tobacco products was unregulated in the U.S. That changed six years ago when the Tobacco Control Act was signed into law giving the US Food and Drug Administration (FDA) immediate responsibility for regulating the manufacture, distribution and marketing of tobacco products, specifically, cigarettes, cigarette tobacco, roll-your-own tobacco and smokeless tobacco products.
The Act also gave the FDA the ability to extend the regulations—the so-called deeming rule—to cover all other categories of products that meet the Tobacco Control Act definition of “tobacco product”. These products include electronic cigarettes (e-cigarettes), cigars, pipe tobacco, waterpipe (hookah) tobacco, and novel products like nicotine gels, or tobacco sticks, pellets and strips that dissolve in your mouth.
Under the proposed deeming rule manufacturers would be required to register products with the FDA and list ingredients. New products would have to undergo a rigorous pre-market FDA review. In addition, claims of reduced risk would have to be evaluated by FDA to confirm that the scientific evidence supports the claim.
A deeming rule change is close to finalization, and the FDA has been actively engaged in supporting scientific research in order to understand the diversity of tobacco products, and to investigate the toxicity and risk of newly deemed products, as well as conventional tobacco products. This effort isn’t merely academic. Scientific studies that provide a basis for regulation are required by law and are necessary to counter legal challenges.
Creating science-based regulation is a daunting task, though, given that the products in question are complex mixtures of literally hundreds of constituents and materials. Moreover, high-throughput tools for characterizing the components and projecting their potential physiological impact haven’t been developed yet.
The FDA created the NicScreen project in 2013 to help better understand the activity of tobacco products and/or individual constituents contained in tobacco products at the nicotine receptor subtype level. NicScreen, sponsored by the FDA and conducted by Charles River’s ChanTest site in Cleveland, Ohio, addresses the throughput and physiological aspects of the receptor activity through a combination of molecular biology and high-throughput, cell-based functional assays.
We already know a great deal about nicotine. It mimics the neurotransmitter acetylcholine (ACh), activates nicotinic ACh receptors and enhances the release of other neurotransmitters such as dopamine, which stimulates pleasure and reward circuits in the brain.
What is not as clear is how nicotine from tobacco use modulates the brain’s different nicotine receptor subtypes and how the complex molecular interactions effects nicotine addiction. A variety of nicotinic receptor subtypes, each composed of five protein subunits, reside on the surface of nerve cells. Different subtypes are defined by their α- and β-subunit composition and functional properties, such as nicotine or acetylcholine sensitivity, pharmacological profile, and Ca2+ permeability. Several subtypes have been closely associated with nicotine addiction, but in order to inform regulations we need to understand how tobacco product constituents interact with the different subtypes.
Phase I of the NicScreen project, which was completed last year by ChanTest-CRL, developed and validated five recombinant cell lines that each expressed a different subtype of human nicotinic receptor: α3β4, α3β4α5, α4β2, α6β2β3, and α7.
Assays for each subtype were developed and pharmacologically validated with reference compounds in an automated electrophysiology system (IonWorks Barracuda) and a fluorescent plate reader (FLIPR tetra).
Phase II and Phase III, which starts in September, and will last about two years, will use the validated IonWorks assays to explore nAChR subtype selectivity of tobacco product constituents. The FDA will then submit the results for publication in scientific journals.
The developments from this research could have further uses beyond that of the FDA’s tobacco regulatory science goals. The assays and cell lines will be made available for pharmaceutical research to help identify subtype-selective drugs for treatment of nicotine addiction and other neurological diseases. It’s noteworthy that the α4β2 subtype, widely distributed throughout the brain, and the more localized α6β2β3 subtype show below in Figure 1, are targets of drugs that may help people kick the unhealthy nicotine dependence.
Thus, the collaborative efforts of the FDA and Charles River could have a significant impact on global tobacco-related human health issues and public health.
Figure 1. Diagram of two nicotinic receptor subtypes (α4β2 and α6β2β3) embedded in the surface of nerve cells. These subtypes are thought to be particularly important in nicotine addiction. Nicotinic receptors in the brain function as ion channels that are activated by acetylcholine, the endogenous neurotransmitter. Nicotine mimics acetylcholine, binds and activates the receptors and modulates the secretion of other neurotransmitters such as dopamine, leading to nicotine dependence. Drugs such as Chantix®, an effective treatment for nicotine addiction, target α4β2 receptors. Also, α6β2β3, because of its importance in modulating dopamine and its more limited distribution, is a potentially important therapeutic target for subtype-selective addiction treatment.
How to Cite
Kirsch, Glenn E., Smoking Guns. Eureka blog. Sept 14, 2015. Available: http://eureka.criver.com/smoking-guns/