Discovery opens the door to a new class of therapies.
A team led by Prof William Balch, department of cell biology and chemical physiology at Scripps Research, and colleagues have restored partial function to lung cells from patients with cystic fibrosis.
The new study, published online ahead of print in the journal Nature Chemical Biology on December 6, performed in collaboration with a large number of cystic fibrosis investigators across the United States and Canada, showed that a compound called suberoylanilide hydroxamic acid (SAHA)—currently approved by the FDA for the treatment of lymphoma—can restore approximately 28% of normal function to lung surface cells with the most common, yet severe, cystic fibrosis mutation that results in complete loss of function in homozygous patients.
Bach drew upon his work in network biology, in which he challenged current thinking and practices of the pharmaceutical industry that focuses on drugging single targets. “This traditional view limits our ability to tackle pharmacologically many complex loss-of-function sporadic and inherited diseases, which are really systems disorders,” Bach said in an announcement about the research. “These diseases have multiple steps in the biological network that must be adjusted to regain a more normal function of the compromised protein and tissue.”
In the case of the current study, Bach suspected that the endoplasmic reticulum—a compartment in the cell responsible for the synthesis of CFTR, which works to protect the body by degrading potentially dangerous abnormal proteins—could be doing its job too efficiently, eliminating mutant CFTR proteins that could still provide some function to the cell and tissue.
Rather than attempting to directly target or replace the mutant CFTR proteins present in CF patients—an approach that has so far failed—Bach and colleagues sought to adjust the cell folding to make a new environment that would work with the mutant CFTR proteins.
“By rebalancing the proteostasis program to provide a more supportive cellular environment,” said Bach, “the cells appear to treat the mutation more like a polymorphism rather than something dangerous needing to be completely eliminated.”
Bach said there is much work to do before this therapy becomes a reality, but “the results are very promising. The added degree of function conveyed by SAHA … could make a tremendous difference to patients with acute disease.”