Dr. Stephen Gardell on NMN Boosting Drugs

In an interview, this experienced drug hunter shares his insights on how to best raise NAD+ levels.

Interviewer: Could you give me a quick summary of your research background and what got you interested in NAD biology and NAMPT activators?

Dr. Stephen Gardell: I was in the pharmaceutical industry working at Merck, Bayer, and Wyeth. At this time, I became a drug hunter interested in novel therapeutic approaches to treat or prevent human diseases. After 20 years in the pharmaceutical industry, I elected to make a career change and joined the Sanford Burnham Prebys Medical Research Institute in Orlando, Florida. At that time, I set up a laboratory and I searched for an interesting and exciting new drug target. I was introduced to an enzyme nicotinamide phosphoribosyltransferase which was the target of my future research pursuits.

NAMPT is involved in NAD+ biosynthesis. It is the putative rate-determining step for NAD+ biosynthesis. It seemed plausible that stimulating or enhancing the activity of NAMPT would increase intracellular NAD+ levels. There was growing and exciting evidence showing that boosting the levels of NAD+ could confer a host of health benefits. Given my personal interest in drug discovery, my emerging interest in NAMPT, and the capabilities at Sanford Burnham, we embarked upon a drug discovery campaign to identify small molecules that would stimulate NAMPT activity.

NAD+ has long been known as a co-factor for a host of different redox enzymes in the cell.  More recently, a number of other roles have been attributed to NAD+ as a result of its ability to serve as a co-substrate for some very interesting and important classes of enzymes. One class of enzymes is the sirtuins. The sirtuins use NAD+ as a co-substrate. This results in the pruning of a number of post-translational modifications on proteins. The second class of enzymes, which uses NAD+ as a substrate, is the PARPs. The prevailing view is that a number of potential beneficial biological effects will be realized due to the ability of elevated NAD+ to enhance the activities of sirtuins and PARPs.

Interviewer: So, these NAD+-dependent proteins have associations in longevity and many other processes like the health span of the cell in the human body. Are there any direct avenues for the use of NAMPT activators in the treatment of human disease or in medicine? Are there specific diseases this would relate to most specifically that you want to use the NAMPT activators to target?

Dr. Gardell: There’s very intriguing evidence that decreased levels of NAD+ are linked to various diseases as well as aging. So, there are numerous therapeutic indications, which I think would be ripe for drug strategies that boost NAD+.

Interviewer: How do [NAMPT activators] then compare to NAD+ precursors, such as NMN, that are now readily available on the market as supplements?

Dr. Stephen Gardell: Yeah, that’s a very important question. I can tell you that we are busy trying to shed light on that. One of our goals right now with our small molecule NAMPT activators is to recognize how they differ from the alternative strategy for boosting NAD+? As you point out, the alternative strategy is using NAD+ precursors, such as nicotinamide riboside (NR) and NMN. We’re engaged in many investigations in which we are comparing the actions and the efficacy of our small molecule NAMPT activators with the NAD+ precursors.

While not passing judgment or making a qualitative determination of what’s better, I can tell you that there’s a number of discriminators between our small molecule NAMPT activators and the NAD+ precursors.  Perhaps first and foremost is what I refer to as catalytic actions versus stoichiometric actions. What do I mean by that?  For NAD+ precursors, such as nicotinamide riboside, under the most efficient circumstances, one molecule of NR will give rise to one molecule of NAD+. NAD+ is turned over in the cells rapidly. What this means is that there’s a need for relatively large amounts of NAD+ and hence nicotinamide riboside to support the requirements of the cell, which is consuming the NAD+.

On the other hand, I describe our small molecule activators NAMPT activators as acting catalytically. What do I mean by that? One molecule of our small NAMPT activator will bind to NAMPT, and that will serve as a switch to turn on the activity of the enzyme so now this single interaction can produce numerous NAD+ molecules. That’s what I think is one critical difference between our NAD+ booster strategy using small molecule NAMPT activators versus the conventional NAD+ booster strategy using NAD+ precursors.

Interviewer: What is the course or the next steps then for your research with NAMPT activators? Where do you see that going?

Dr. Stephen Gardell: We’re taking a multi-pronged approach. First and foremost, is to pinpoint a promising therapeutic indication. There is a dizzying array of different therapeutic possibilities. This ranges from neurodegeneration to heart failure to metabolic disorders that are associated with diabetes and obesity. The list just goes on. There’s even some fascinating data with NAD boosters for the prevention of hearing loss and vision loss. So, priority number one is to identify what are the small molecule NAMPT activators are going to be good for. We have to be pragmatic about what we choose in order to advance NAMPT activators in drug development. For example, whereas as we had touched earlier in the discussion on the potential utility of NAMPT activators for healthy aging, this certainly would not be a very practical therapeutic indication to pursue.

The second pursuit that we’re heavily engaged in is trying to better understand the molecular and cellular consequences of elevating NAD+ using our NAMPT activators  To this end, stable isotope studies have been extremely valuable.  Insight from these investigations will shed light on attractive therapeutic indications for the NAMPT activators and help to further discriminate our approach from NAD precursors.

Interviewer: It’ll be exciting to see how that all ends up. This whole field has really been picking up a lot of steam. I think that it’s a really compelling subject for people to put on their radar because, as you said, there are so many possibilities and benefits by approaching regulating NAD+ in this way through NAMPT. It’s going to be a really exciting field to keep an eye on.