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2013 Progress Report – Executive Summary

The ultimate goal of our NDC is to develop therapeutic strategies for protein misfolding diseases by harnessing our understanding of chaperonin mechanism and function. To this end, we aim to develop chaperonin-inspired therapeutics and/or substrate adaptor molecules, to prevent aggregation and/or refold proteins responsible for misfolded-protein diseases. Our approach includes developing and integrating new methods to characterize the biophysical and biochemical properties of chaperonins.


Our group continues to evolve, moving from a more basic science-oriented team to one geared towards therapeutic applications, specifically translational and clinical investigation. We focus on two specific diseases: Huntington’s disease (HD) and von Hippel Lindau disease (VHL). Our choice was based on the importance of these disorders with respect both to disease burden and to the opportunity to exploit their underlying biology to create new insights into the pathogenesis and treatment of related protein misfolding disorders. We expect to impact the future treatment of a number of diseases that feature protein misfolding. To achieve our goals, we are currently supporting clinical investigators from M.D. Anderson Cancer Center, University of California at San Diego and the University of California at Irvine; translational researchers from the Massachusetts Institute of Technology and basic science investigators from Baylor College of Medicine and Stanford University.



Both HD and VHL Disease arise as a consequence of well-defined genetic lesions which cause misfolding of chaperonin substrates. However, the underlying molecular nature of their pathology is distinct: HD features the aggregation of a mutant protein that triggers a cascade of pathogenic mechanisms that appear to result in both gain of toxic function and loss of function; in contrast, VHL Disease arises from the loss-of-function of a folding-defective mutant protein. The translational approaches to remedy each disease through chaperonin- based intervention thus differ. In the case of HD, we will use the eukaryotic chaperonin and/or engineered chaperonin-derivatives to prevent the cellular toxicity associated with protein aggregation. In the case of VHL  Disease, we will exploit our knowledge of chaperonin- mediated  action  to  promote  pVHL  refolding  and  restore  functionality  to  tumor-promoting mutants.



In the past year we have developed several translational settings and assays that together with  the  basic  knowledge  obtained  in  the  Program  have  established  proof-of-principle feasibility for our strategy. For VHL Disease we have demonstrated that increasing the protein levels of mutant VHL variants can restore VHL function in the degradation of HIF1alpha. This supports the idea that approaches that prevent degradation and/or enhance folding can restore functionality to miss-sense VHL mutations. For HD we have demonstrated that a chaperonin domain can be exogenously added to a neuronal cell model of HD and alleviate mutant Huntingtin aggregation and toxicity.  Experiments in an animal model of HD also provide encouraging feasibility studies that a chaperonin-based approach may be therapeutically effective. These  findings  open  the  way  to  improve  on  our  therapeutic exploitation  of  the  protein  homeostasis  machinery,  through  a  better  understanding  of chaperonin-based reagents and through the development of better assays and readouts. Our strategy  of  integrating  the  fundamental  understanding  of  molecular  principles  of  protein homeostasis  with  the  biological  understanding  of  disease  pathways  provides  a  powerful paradigm to obtain rationally developed therapeutics for protein misfolding diseases.


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