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NewsProteostasis Advisors Publish Research in Nature Chemical Biology Demonstrating Improved Lung Cell Function in Cystic Fibrosis --Promising Effects Achieved by Influencing the Proteostasis Network-- December 6, 2009, Cambridge, Mass. - Proteostasis Therapeutics announced today that a team led by William Balch, Ph.D., one of the Company’s scientific advisors and a professor in the departments of Cell Biology and Chemical Physiology at The Scripps Research Institute, as well as the Institute for Childhood and Neglected Disease, published research in the December 6, 2009 advance online edition of Nature Chemical Biology. According to the paper, the researchers were able to restore partial function to human lung airway cells from patients with cystic fibrosis, achieved by modulating the Proteostasis Network (PN) with a small molecule. These results support Proteostasis’ approach of targeting this network with Proteostasis Regulators (PR), small molecules that restore proper protein function. Jeffery Kelly, Ph.D., one of Proteostasis’ scientific founders and the Lita Annenberg Hazen Professor of Chemistry and Chairman, Molecular and Experimental Medicine at The Scripps Research Institute, collaborated on the study and publication.. Dr. Balch’s team demonstrated that a histone deacetylase (HDAC) inhibitor that is FDA-approved for the treatment of lymphoma restored about 28% of normal function to the lung surface cells in patients with the most severe cystic fibrosis mutation, referred to as Phe 508 delete or DF508 in the cystic fibrosis transmembrane regulator (CFTR) chloride channel. DF508 CFTR is the most common disease allele, affecting greater than 90% of cystic fibrosis patients. CFTR is normally responsible for hydration of the lung cells’ surface and is completely lost in patients with the severe form of cystic fibrosis. In the study, an HDAC was used to adjust the PN in order to make the cellular environment more compatible with mutant CFTR, rather than previously unsuccessful approaches of directly targeting or replacing the malfunctioning chloride channel. The HDAC inhibitor was chosen for the study in human airway cells because it has been found to be most effective in restoring surface channel activity of CFTR lung cell lines in a screen of known HDAC inhibitors. “This result is clinically meaningful, because patients with other mutations that result in a milder effect on CFTR chloride channel function, comparable to the activity restored by an HDAC, have typically milder cases of disease and may live a more normal lifestyle,” said Dr. Balch. “Because cystic fibrosis is such a complex disease, the traditional approach of finding a drug to influence a single molecular target may not be sufficient; instead, targeting the entire PN, which is compromised in cystic fibrosis patients, may potentially give us a better chance at restoring normal protein function. This approach has promising applications across a broad range of other complex diseases.” Christopher Mirabelli , Ph.D., Chairman of the Board of Proteostasis, added, “This study is relevant to the work that Proteostasis is pursuing, because the researchers used a drug compound to influence the entire PN, which encompasses over a dozen biological pathways responsible for maintaining a critical balance among protein synthesis, folding, aggregation, trafficking and clearance. Proteostasis is focused on discovering small molecules that pharmacologically direct the network in order to restore normal protein function. This publication substantiates the importance of the PN to disease and the role small molecules could play in impacting the network in order to restore health.” Authors of the paper, titled “Reduced Histone Deacetylase 7 Activity Restores Function to Misfolded CFTR in Cystic Fibrosis,” are: William Balch, Darren Hutt, David Herman, Jeanne Matteson, Ben Hoch, Wendy Kellner, Jeffery Kelly and Joel M. Gottesfeld, of Scripps Research; Ana Rodrigues and Gerard Manning of the Salk Institute for Biological Studies; Sabrina Noel, Joe Pilewski and Ray Frizzell of University of Pittsburgh School of Medicine; Andre Schmidt and Philip Thomas of the University of Texas Southwestern Medical Center; Yoshihiro Matsumura and William Skach of Oregon Health and Sciences University; Martina Gentzsch and John R. Riordan of University of North Carolina, Chapel Hill; Eric J. Sorscher of University of Alabama at Birmingham; and Tsukasa Okiyonad and Gergely L. Lukacs of McGill University. About Proteostasis Therapeutics, Inc. Proteostasis Therapeutics is discovering “Proteostasis Regulators” (PRs), small molecule drugs that restore proper protein function to treat neurodegenerative, metabolic, genetic and inflammatory disorders. The Proteostasis Network is the cellular machinery responsible for protein folding, trafficking and clearance, and it can become imbalanced by the cumulative effects of aging, disease and genetics. PTI was founded by leading scientists who discovered a pioneering approach for treating disease by restoring protein network homeostasis. www.proteostasis.com Contacts: Media:
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