South to Arizona – Phoenix, Tucson, then Day 1 (Wednesday, July 21)

We are traveling south today, heading to our final two club events in Phoenix and Tucson. We will drive 12 hours to Flagstaff, stop for a morning to see the Grand Canyon, and then onward to Phoenix for a Thursday night event. Prior to departure in Denver, we were able to get in a two-hour workout at high altitude. The scenery down to Flagstaff was stunning.

Since today is a driving day, it is an ideal opportunity for me to elaborate on one of the historic partnerships between Notre Dame scientists and the Ara Parseghian Medical Research Foundation (APMRF)—a partnership that began about five years ago. At the various club events I keep getting the question: how did it all begin?

About five years ago, Cindy and Mike Parseghian paid a visit to Notre Dame, hosted by the Office of Research, to learn more about the scientific expertise that faculty in the College of Science could contribute in the search for a treatment for Niemann-Pick Type C disease (NPC). Stemming directly from this meeting, a group of chemistry, biochemistry, and biology faculty members was assembled to begin planning new research projects on NPC. Through the auspices of the Office of Research, Professor Anthony Hyder ( provided seed funding for one year to support initial investigations that could then parlay into external grant applications. Within one-two years, two groups of faculty received a pair of research grants from the APMRF for a combination of studies directed at both gaining a greater understanding of NPC at the cellular level and beginning the initial stages of small molecule drug development to treat the disease. One of these groups has since received a third such grant from the APMRF.

Especially prominent among these research activities has been the establishment of a Drug Development Chemistry Core by chemistry professors Paul Helquist ( and Olaf Wiest ( This Core was funded by the APMRF three years ago to interface with other investigators throughout the nation-wide NPC research community. The role of this Core is to provide the necessary chemistry expertise needed in many of the stages of drug development. In particular, the Core works closely with biological and clinical investigators, located primarily at major medical schools, who have found clues for how the defects seen in the cells of NPC patients may respond favorably upon treatment with appropriate small molecules. The Helquist and Wiest labs at Notre Dame design and synthesize the molecules, which are then provided back to the medical school investigators for studies in NPC cells and in animal models of the disease. Molecules that promote a positive effect, for example lowering of the abnormal cholesterol accumulation that occurs in NPC, are then regarded as initial hits for further drug development efforts.

So far, this effort has involved collaborations between Core researchers and NPC researchers at Cornell University, Columbia University, Tufts University, Washington University, the University of Texas Southwestern Medical Center in Dallas, Scripps Research Institute, Purdue University, and Notre Dame. These joint research activities have led to several hits that may serve as precursors of new drugs. Most recently, a three-way study by the Core at Notre Dame and the partners at the Weill Cornell Medical College and Southwestern Medical Center has resulted in the identification of a relatively simple molecule that shows a spectacular response in NPC cells. Extremely small amounts cause the abnormal cholesterol accumulation to essentially vanish entirely. Also, these small amounts cause an important protein that is deficient in NPC cells to be produced in normal quantities. The amounts of the small molecule that affect these changes in cells correspond to just 10 billionths of an ounce of the molecule dissolved in an ounce of water (in more scientific language, 30 nanomolar concentration). This kind of potency of the small molecule is unprecedented in NPC research. Of course, larger quantities would be required to treat an entire person, but the amounts would theoretically still be quite small compared to many other drugs.

Where does the Core go from here? The path for drug development is long, arduous, and expensive before government approval will permit the use of a new drug in human patients. The Core is only at the initial “hit” stage. A huge number of additional studies is required to prove how the molecule actually works in cells, how effective it is in treating NPC in animals, how it is metabolized, how long it lasts after it is administered, whether it has any adverse toxicity. To answer all of these questions will require additional research supported by foundations, private donors, government agencies, and perhaps new start-up companies. A huge advantage of this particular molecule is that it is already in human clinical trials for treatment of another disease. Therefore, it has already cleared many of the safety hurdles that surround the development of a new drug.

There is never a guarantee at this stage of pre-clinical research that the results will ultimately translate into successful clinical use of the molecule as a new drug. Fortunately, the Core has many other hits to follow up as secondary strategies for drug development if the need arises.

1 Comment so far

  1.    Tillie Lang on July 22nd, 2010

    Good luck to you and Renate on your journey. This is a great thing that you are both doing. My daughter Erin had a classmate die of Niemann-Pick disease in the 4th grade. His name was Graham Kehoe and he was the only child in RI and Southern New England at that time with the disease. A cure is needed and with your commitment to this ride, I am sure that you will inspire many to join you or to donate what they can to help out. You’re a wonderful person and I admire you both.

    Take care of yourself along the way 🙂