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A new approach to treating cystic fibrosis
Modern medicine has turned cystic fibrosis from an immediate death sentence into a disease that can be lived with for years. But it is still debilitating and life-threatening, and researchers have made little progress in fixing the root problem.
Cystic fibrosis is a problem of protein-folding management. The most common form of the disease is caused by a missing amino acid residue, which most current treatments counterbalance by using chemical molecules.
But a new paradigm has been emerging in research in recent years, focusing on the larger picture of a cell's protein-folding system.
"We now appreciate that there is an extensive protein-folding management program in the cell – referred to as 'protein homeostasis' or 'proteostasis,'" said Scripps Research Professor William Balch. "This ensures that most proteins are either folded properly to generate function(s) or removed when unneeded to avoid a buildup of non-functional proteins that could interfere with normal physiology."
This new line of research suggests that the problem of biological protein-folding management could be the missing link in understanding – and treating – cystic fibrosis.
Whereas protein manufacture had previously been seen as a simple, linear process, the new research suggests that each cell type and tissue in fact adjusts the protein fold to facilitate the healthy function of the organism and how it responds to inherited and environmental stresses as well as pathogens. Proteostasis constantly massages the various shapes and molecular properties of proteins in each individual cell type to promote survival and fitness.
But in the case of diseases like cystic fibrosis, the network doesn't work the way it should. The proteostasis machinery with the missing amino acid residue is "out-of-synch" with the folding requirements," said Dr. Balch.
"We now need to tap these normal pathways for correction and management of a human protein-folding disease such as cystic fibrosis," he said.
His lab, working with the lab of Scripps Research Professor John Yates III, has discovered molecular techniques that can correct the deficiency associated with cystic fibrosis in the proteostasis program. This suggests the disease's folding problem could be corrected, possibly using small molecules to readjust the signaling pathways that govern the make up of the proteostasis network in cells associated with cystic fibrosis in order to create a functional protein.
Now, Dr. Balch's lab is working with the company PTI, a company he co-founded, to develop new therapeutics that regulate protein homeostasis to better treat patients with neurodegenerative and orphan diseases, including cystic fibrosis. Using high-throughput screening technologies to identify small molecules that modulate the composition and function of the proteostasis network, PTI and Dr. Balch's lab have identified small molecules that can manipulate the proteostasis program to correct for the effects of the missing amino acid residue.
The company recently announced a new collaboration with the therapeutic arm of the Cystic Fibrosis Foundation, Therapeutics Incorporated, and Dr. Balch's lab to research, develop and commercialize therapies to treat patients with the most common cystic fibrosis mutation.
The new collaboration will focus on identifying small-molecule modulators of proteostasis to correct the folding, trafficking and functioning of the most common variant of the disease. The team will use an integrated platform of scientific tools to essentially generate "signatures" reflecting the necessary changes in the proteostasis network of the cell to provide a correction.
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