Negulescu's research focuses on the therapy of
cystic fibrosis. Cystic fibrosis can be caused by any of the thousands of identified
mutations in the
CFTR protein, an
ion channel that allows
chloride ions to pass through. These mutations have been classified into Class I to V, with Class III mutations causing defective channel gates in CFTR despite normal expression of the protein. Via
high-throughput screening, his team at
Vertex Pharmaceuticals discovered
ivacaftor, a
small-molecule potentiator that increases the probability that mutated CFTR gates will open. Ivacaftor was approved by the
Food and Drug Administration (FDA) for cystic fibrosis patients with one specific Class III mutation in 2012, and has since been approved for mutation classes as well. Of note, the expanded approval in 2017 was based solely on
in vitro data, due to the small number of patients carrying those rare mutations making
clinical trials impossible. Negulescu also led the discovery of another cystic fibrosis drug,
lumacaftor, which is known as a "corrector" as it acts as a
chaperone to help the CFTR protein fold correctly. Thus, it can be used in patients with Class II mutations, which create
misfolded CFTR protein that cannot reaching the
cell surface. Again with high-throughput screening, Negulescu and his team found that lumacaftor can correct F508del-mutated CFTR protein. It was later found that the drug was not effective enough when administered on its own, but was so when administered together with ivacaftor. The FDA approved this drug combination in 2015. Further research led to the discovery of
tezacaftor and
elexacaftor, 2 other correctors of the CFTR protein. The triple combination
elexacaftor/tezacaftor/ivacaftor was approved by the FDA in 2019. == Honors and awards ==