Alliance Forges New Approaches to Human Lung Disease

While considerable progress has been made in increasing the average lifespan of cystic fibrosis patients—now 38 years compared to the five years before modern medicine—the inherited disease is still debilitating and life-threatening. And little progress has been made in correcting the root cause of the disease—a faulty ion channel that leads to pancreatic, intestine, and lung malfunction.

But now, thanks to new funding by the Cystic Fibrosis Foundation, The Scripps Research Institute laboratory of Professor William Balch is working with Proteostasis Therapeutics Incorporated (PTI) in a focused effort to find ways to correct an important biological trigger of the disease.

Addressing a Critical Problem in Cystic Fibrosis

Cystic fibrosis is an inherited disorder caused by mutations affecting the function of the cystic fibrosis transmembrane conductance regulator (CFTR), a chloride channel that regulates the hydration of the epithelial surfaces found in multiple tissues, including the pancreas, intestine, and lung. The most common form of cystic fibrosis is caused by the deletion of the amino acid residue Phe 508 (dF508-CFTR), found in the normal (wild-type) protein sequence.

“The dF508-CFTR variant affects more than 90 percent of cystic fibrosis patients in the cystic fibrosis registry and thus is an important target in the clinic,” said Balch. "Cystic fibrosis is a problem of protein-folding management. While wild-type CFTR is normally efficiently synthesized by the cell, both the assembly and stability of the dF508-CFTR variant are severely impaired, resulting in its rapid removal by degradative pathways. This leads to loss of function in tissues such as the lung—a major hallmark of disease progression and one that currently limits patient lifespan."  

Recently, patients have benefited from a therapy of molecules that augment CFTR stability or function—chemical molecules called “correctors” and “potentiators.” Not only is this immediate good news for patient health, the development has offered new clues to the nature of the disease that could lead to further progress.

"We now appreciate that there is an extensive protein-folding management program in the cell—referred to as 'protein homeostasis' or 'proteostasis,' ” said 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."

A Unifying Paradigm

The concept of proteostasis has recently emerged as a unifying paradigm for a rapidly growing area of research. Following the concept formulated by Balch, Andrew Dillin of Salk Institute, Richard Morimoto of Northwestern University, and Jeffery Kelly of Scripps Research in a 2008 Science paper (319: 916), this new line of research frames the problem of biological protein-folding management as the missing link in the central dogma (which describes the process of protein manufacture in a simple, linear fashion: DNA to RNA to protein).

The proteostasis network of folding chaperones instead defines how each cell type and tissue adjusts the protein fold to facilitate healthy function of the organism, and, importantly, how it manages responses to numerous inherited and environmental stresses and pathological challenges utilizing signaling pathways including the “unfolded protein response,” the “heat shock response,” and the “oxidative stress response”. Proteostasis constantly massages the various shapes and molecular properties of proteins encoded by the genome in each individual cell type to promote survival and fitness.

However, in the case of diseases such as cystic fibrosis, this network fails to work as it should. "The proteostasis machinery in cells expressing the variant CFTR protein is 'out-of-sync' with the unanticipated folding requirements imposed by the dF508-CFTR variant,” Balch said. “In simplest terms, dF508 poses a kinetic and/or thermodynamic barrier to the native proteostasis folding machinery that would normally assemble and manage the wild-type protein.”

"We now need to tap these normal pathways for correction and management of a human protein-folding disease such as cystic fibrosis," he said.

Building Bridges

The Balch lab, along with the laboratory of Scripps Research Professor John Yates III, has been studying the protein interactions that direct normal and mutant CFTR folding and function. The scientists have discovered that many interactions directing folding through the proteostasis program, when adjusted using molecular techniques, can correct the deficiency associated with cystic fibrosis and restore many interactions to those observed for the wild-type protein.

These findings suggested it might be possible to correct the cystic fibrosis folding problem by direct manipulation of the dF508-CFTR folding environment. How? One approach would be to use small molecules to readjust the signaling pathways that govern the composition of the proteostasis network in cystic fibrosis-sensitive cells to generate a functional protein.

To achieve this goal, the Balch laboratory is working closely with PTI, a company founded by Kelly, Morimoto, and Dillin. The company is developing novel therapeutics that regulate protein homeostasis to improve outcomes for patients with neurodegenerative and orphan diseases, including cystic fibrosis, through the efforts of  Balch, a co-founder of the company. Using high-throughput-screening technologies to identify small molecules that modulate the composition and function of the proteostasis network, PTI and the Balch group have identified small molecules that can manipulate the proteostasis program to correct dF508-CFTR function.

Accelerating Solutions

To build on this promising work, PTI recently announced a new collaboration with the therapeutic branch of the Cystic Fibrosis Foundation, Therapeutics Incorporated (CFFT), and the Balch laboratory to research, develop, and commercialize therapies to treat patients with the most common cystic fibrosis mutation, dF508.

“CFFT has funded some of the most innovative and successful research in the field and we believe this collaboration validates PTI’s potential to develop and commercialize novel disease-modifying therapies that will complement existing approaches to managing this devastating disease,” said PTI Chief Executive Office Mark Enyedy.

Robert J. Beall, president and CEO of the Cystic Fibrosis Foundation, added, “PTI has a unique technology to help identify new compounds to treat the most common defect in cystic fibrosis and this new collaboration is part of our strategy to find effective therapies for all people with this devastating disease.”

The new collaboration will focus on identifying new small-molecule modulators of proteostasis to correct the folding, trafficking, and function of dF508 CFTR. The team will apply an integrated platform comprising genomics, proteomics, functional assays, and medicinal chemistry to identify promising compounds—in essence, generating “signatures” reflecting the necessary changes in the proteostasis network of the cell to affect dF508-CFTR correction.

For more information on the Balch laboratory, see http://www.scripps.edu/research/faculty/balch and http://www.scripps.edu/balch/. For more information about the Cystic Fibrosis Foundation, see www.cff.org. For more information about Proteostasis Therapeutics, see www.proteostasis.com.

Contribute to this Effort

To help this pioneering effort to prevent and manage cystic fibrosis and its challenging lifestyle and healthspan issues, please contact William Burfit at (858) 784-2037 or burfitt@scripps.edu.

Send comments to: press[at]scripps.edu