Now that I’ve finished the ride, I wanted to take time to say how proud I am of the College of Science’s contribution to the second annual Michael, Marcia, and Christa Parseghian Scientific Conference for Niemann-Pick Type C Research earlier this month. Several of the conference’s presentations highlighted research contributions from the laboratories of Notre Dame faculty and the efforts of their graduate and undergraduate research students.
Suhail Alam, a postdoctoral researcher working with Prof. Kasturi Haldar, the Julius A. Nieuwland, C.S.C., Professor of Biological Sciences and Director of the Center for Rare and Neglected Diseases, presented the lab’s comparative analysis of mice models with NPC gene mutations. Significant differences were found in the immunoresponse pathways as well as the overexpression of genes in the liver and brain. This information was then utilized to track the response of cyclodextrin treatment on NPC mutant mouse models.
A number of talks focused on the further study of histone deacetylase (HDAC) inhibitors as a treatment for Neimann-Pick Type C disease. HDAC inhibitor activity in NPC was co-discovered by Notre Dame faculty members, Prof. Paul Helquist and Prof. Olaf Wiest. Prof. Helquist is a medicinal chemist in the Department of Chemistry and Biochemistry and has developed a number of synthetic routes to chemical compounds with HDAC inhibitor activity. Prof. Olaf Wiest, also from the Department Chemistry and Biochemistry, is a computational chemist who has analyzed the structures of a number of HDAC isozymes and determined the structural requirements of for HDAC inhibitor selectivity. Another contributor to this area is Dr. Fred Maxfield from Cornell Weill Medical College. Dr. Maxfield spoke about his analysis of HDACi in an NPC mutant cell lines derived from a number of different human patients. The results of his studies showed that HDACi correct cholesterol accumulation in cells with many different NPC protein mutations suggest broad potential benefit. Joyce Repa, Professor of Physiology and Internal Medicine at the University of Texas Southwestern Medical Center, spoke about her efforts to explore the effect of potential NPC therapies on NPC mutant mice models. Her work identified positive effects of LXR agonists, known anti-inflammatory agents. Cyclodextrins also showed positive survival rates on treated mice. Prof. Repa also reported that HDAC inhibitors had no effect on these mice. However, based on the mode of action of HDAC inhibitors, positive effects would not be expected. Finally, Norb Wiech, a Notre Dame alum (’60) who is CEO of Lysomics, LLC, talked about the company. Lysomics has been recently formed to focus on the clinical development of HDAC inhibitors for the treatment of Niemann-Pick Type C. Dr. Wiech spoke about his recent efforts to obtain FDA approval for early clinical exploration of repurposed HDAC inhibitors, some of which are approved drugs for certain forms of cancer.
Two additional talks from Notre Dame scientists reported on the discovery of new potential treatments for NPC disease. Prof. Holly Goodson from the Department of Chemistry and Biochemistry presented work from her lab to analyze the effect of a range of different known drugs, all of which affect gene expression, on NPC mutant cell lines. Interestingly, in addition to HDAC inhibitors, their efforts identified a number of other compounds which favorably lower the amount of unesterified cellular cholesterol while other increased those levels. One of those compounds has known immunosuppressive activity, again supporting the potential importance of the immune system in the progression of the disease. Thus, in addition to identifying potential new leads for NPC therapy, this work is providing valuable insight into the complex biology of NPC. Prof. Kevin Vaughan from the Department of Biological Sciences as well as Profs. Wiest and Helquist also contributed to these studies.
Prof. Rich Taylor, Associate Dean for Research in the College of Science and Professor of Chemistry and Biochemistry, spoke about his study of the natural product herboxidiene. Herboxidiene is a compound produced by bacteria that has been known to have interesting anti-cancer and herbicidal activity for many years. Based on its mode of action in human cell lines Prof. Taylor thought that it might have potential as a treatment for NPC disease. Through isolation of the material from the fermentation of the producing bacteria, Prof. Taylor’s lab produced significant quantities of material for analysis in NPC mutant cell lines. Remarkably, herboxidiene corrects cholesterol accumulation in NPC1 mutant cell lines at similar concentrations to HDAC inhibitors. Moreover, due to a completely different mode of action, Herboxidiene should show similar activity in NPC2 mutant cells as well as the null mouse, a model where HDACs show no effect.