CAMBRIDGE, Mass.—Cystic fibrosis (CF), a genetic disorder affecting the lungs, pancreas, liver and intestine, afflicts more than 50,000 people worldwide, concentrated primarily in Europe and the United States. About 1,000 new cases are diagnosed every year. While people who have the disease are living longer, researchers are seeking to improve their quality of life.
Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene result in misfolded protein. Absence of functional CFTR protein, and thus cell surface chloride channel activity, causes dysfunctional ion flow and reduced airway surface hydration. The most common mutation is a deletion of phenylalanine 508 (ΔF508) on CFTR.
Proteostasis Therapeutics Inc., a Massachusetts-based company that develops therapeutics for various diseases based on the idea of modulating protein homeostasis, has identified multiple chemical series that regulate protein homeostasis to promote ΔF508 CFTR folding and trafficking in patient-derived human bronchoepithelial cells. These compounds demonstrate single-agent activity as well as significant synergies with agents currently in development, according to the company.
Recently, the company announced an extension of its funded collaboration with Cystic Fibrosis Foundation Therapeutics Inc. (CFFT), the nonprofit drug discovery and development affiliate of the Bethesda, Md.-based Cystic Fibrosis Foundation. The purpose of the collaboration, which began in 2012, is to research, develop and commercialize therapeutic candidates to treat people with CF who have the ΔF508 mutation. This extension will focus on moving the company’s lead compounds toward a development candidate this year and a goal of filing an Investigational New Drug Application with the U.S. Food and Drug Administration in 2015.
The collaboration has focused on identifying small-molecule modulators of protein homeostasis to correct the folding, trafficking and function of ΔF508. Recent research demonstrates that CF is a disease characterized by improper folding and inadequate trafficking of the CFTR protein. Working closely with collaborators from the laboratory of Dr. William Balch of The Scripps Research Institute (TRSI), Proteostasis Therapeutics scientists have used an integrated platform including genomics, proteomics, functional assays and medicinal chemistry to identify compounds that regulate key folding and trafficking pathways in the cell. These Proteostasis Regulators have demonstrated significant efficacy in CF-specific cellular models, according to the company.
The collaboration was designed to build upon these observations to discover and develop Proteostasis Regulators that correct ΔF508 CFTR function both alone and in combination with agents currently in development and to expand the company’s existing CF biology relationship with TSRI. It will continue to focus on the development of small-molecule proteostasis regulators that modulate protein homeostasis pathways within the cell to correct the folding, trafficking and functional activity of the CFTR.
Preclinical research by Proteostasis Therapeutics, including data presented at the North American Cystic Fibrosis Conference in October 2013, has shown that the lead corrector series identified by the company is can significantly increase functional activity in ΔF508 patient-derived human bronchial epithelial cells. Additionally, the company’s lead candidates have shown significant synergistic properties with existing clinical-stage corrector candidates, more than doubling maximal activity and providing a strong foundation for the potential of combination therapies.
“We are excited to continue our collaboration with CFFT, which has supported some of the most innovative and successful research in the field,” says Dr. Markus Haeberlein, chief scientific officer at Proteostasis Therapeutics. “This extension represents an endorsement of our novel approach to correcting CFTR activity and of the preclinical results that we have generated during the past 18 months.”
He added that the maintenance of protein homeostasis is essential to human health. When working properly, the proteostasis network (PN) ensures that every protein within a cell will reach its final destination correctly folded with appropriate function or be degraded and cleared to prevent damage.
“Proteostasis is developing novel therapeutics designed to pharmacologically control the proteostasis network, either by restoring its normal state or enhancing the capacity of the compromised PN to create a therapeutic state sufficient to control or delay progression of disease,” Haeberlein concludes. “This approach of rebalancing the PN offers a broader application to genetic diseases than protein replacement therapy by providing access to many cell types, organelles and tissues where recombinant proteins cannot be delivered.”
