|Suzanne Pfeffer and Cindy Parseghian, president of the Ara Parseghian Medical Research Foundation.
Imagine a scenario in which a group of scientists with a common goal agree to meet every year at a lovely location to share their results and to discuss the most important next steps needed to move that science forward. The group would work under the presumption that all results, reagents and information would be shared openly and all members would collaborate wherever possible to help the group achieve its shared goal. The meetings would end with a panel discussion to help identify the most important next steps to be taken over the subsequent 12 months. Members would support each other during manuscript and grant reviews and cooperate wherever possible to move the science forward. Sound unusual? If only all research could be carried out this way.
Cindy Parseghian, president of the Ara Parseghian Medical Research Foundation, established precisely this type of framework to bring together researchers seeking a cure (or beneficial treatments) for Niemann-Pick Type C disease. Niemann-Pick Type C is a genetic disorder in which homozygous carriers of mutations in NPC1 or NPC2 proteins accumulate excess cholesterol and glycosphingolipids in their lysosomes. The disease causes progressive neurological deterioration leading to death, usually during childhood. Sadly, Cindy lost three of her four children to NPC disease. In 1994, together with her husband, Michael, and well-known, former Notre Dame football coach (and father-in-law) Ara Parseghian, Cindy created a foundation to support NPC research and bring together clinicians and researchers to try to find a cure. In 1997, with support from the APMRF, the gene for NPC1 was identified (1); in 2000, the gene responsible for NPC2 disease also was identified (2). Cindy has devoted countless hours over many years to fundraising for NPC research; the APMRF recently helped create the Center for Rare and Neglected Diseases at the University of Notre Dame to carry forward NPC disease research. This summer, Notre Dame’s dean of sciences, Gregory Crawford, and his wife, Renate, rode their bicycles more than 2,000 miles to raise funds and awareness for NPC disease.
The APMRF continues to sponsor annual conferences to bring lab findings more quickly to the clinic. Topics presented range from the molecular roles of NPC1 and NPC2 proteins to the initial results of pilot trials of potential drug therapies in affected children. Some scientists report results from high-throughput drug screens designed to identify compounds that clear cholesterol from the lysosomes of cultured mutant cells; others report on studies of genetically modified mice generated to determine which parts of the cerebellum are most sensitive to loss of NPC function or which drugs may benefit mouse or cat models of the disease. Parents of children with NPC disease also attend these meetings and remind the scientists that time is not on their side. The stories told by parents leave every researcher wishing he or she could do more.
What is unique about these meetings is the gathering of basic researchers together with clinicians and families as well as the requirement that all discussions be carried out completely openly. The expertise of everyone present is brought to bear on how best to do more for children with NPC disease. Could this model be applied to other diseases or important scientific questions? Because NPC disease affects only about one in 100,000 individuals, there is not a large number of patients or researchers working in this area. This is a serious disadvantage when planning clinical trials, but it can be a significant advantage in terms of facilitating interactions among key researchers and encouraging open dialogue.
Mutations in NPC1 protein are responsible for 95 percent of disease cases. This protein spans the membrane 13 times and has three large lumenal domains, each containing numerous disulfide bonds. More than 250 different mutations have been described, located in every region of this large glycoprotein. American Society for Biochemistry and Molecular Biology members Daniel Ory (Washington University) and William Balch (the Scripps Research Institute) have shown that NPC mutant proteins are poorly exported from the endoplasmic reticulum after synthesis due to slow folding (3). Similar mutations have been found in the cystic fibrosis anion transporter (CFTR); thus, the same compounds that may help drive misfolded CFTR to the cell surface or increase CFTR expression might also be of value to NPC patients. Indeed, in cell culture models, ASBMB member Frederick Maxfield (Weill Cornell Medical College) and collaborators have found that histone deacetylase inhibitors may increase levels of functional NPC protein in lysosomes (4). Other therapeutic strategies currently being used involve cholesterol chelation by cyclodextrin or glycosphingolipid synthesis inhibition by miglustat (N-butyl-deoxynojirimycin or Zavesca).
These days, there is a lot of interest in translating lab discoveries into patient therapies. Yet there are few examples that I am aware of that demand and reward the kind of close, successful collaboration achieved by APMRF scientists and clinicians. The National Institutes of Health’s Clinical and Translational Science Award consortium was established in 2008 with the goal of reducing the time it takes for laboratory discoveries to become treatments for patients and to engage communities in clinical research efforts. With a budget of $500 million per year and 60 medical school members, the CTSA program also seeks to address the critical need to train the next generation of clinical and translational researchers.
CTSA directors, take note: Cindy Parseghian knows how to foster the most productive interactions between NPC researchers. Her approach should serve as a guide to stimulate collaborative science to tackle any disease. Researchers take note: When we share a common goal, the entire community wins. When we share our results, we can only benefit from the feedback obtained. Cures will be found fastest if we work together. The paths to the cures will be straightest if we draw them together. Cindy Parseghian, we salute you.
1. Carstea E.D., et al. (1997) Niemann-Pick C1 disease gene: homology to mediators of cholesterol homeostasis. Science 277, 228 – 231.
2. Naureckiene, S., Sleat, D.E., Lackland, H., Fensom, A., Vanier, M.T., Wattiaux, R., Jadot, M., and Lobel, P. (2000) Identification of HE1 as the second gene of Niemann-Pick C disease. Science 290, 2298 – 2301.
3. Gelsthorpe, M.E., Baumann, N., Millard, E., Gale, S.E., Langmade, S.J., Schaffer, J.E., Ory, D.S. (2008) Niemann-Pick type C1 I1061T mutant encodes a functional protein that is selected for endoplasmic reticulum-associated degradation due to protein misfolding. J. Biol. Chem. 283, 8229 – 8236.
4. Pipalia, N.H., Cosner, C.C., Huang, A., Chatterjee, A., Bourbon, P., Farley, N., Helquist, P., Wiest, O., Maxfield, F.R. (2011) Histone deacetylase inhibitor treatment dramatically reduces cholesterol accumulation in Niemann-Pick type C1 mutant human fibroblasts. Proc. Natl. Acad. Sci. U.S.A. 108, 5620 – 5625.
ASBMB President Suzanne Pfeffer (firstname.lastname@example.org) is a professor of biochemistry at the Stanford University School of Medicine.