Researchers at Cold Spring Harbor Laboratory have successfully improved the activity of a protein compromised by the CFTR-W1282X mutation, which causes cystic fibrosis (CF), in human bronchial epithelial cells.

CF occurs when the CFTR-W1282X mutation instructs a cell to stop making the protein CFTR too soon. CFTR plays a key role in mobilizing mucus from the lungs and absorbing nutrition. With little to no functioning CFTR, CF patients experience frequent infections, progressive lung damage, and respiratory failure.

Cold Spring Harbor Laboratory Professor Adrian Krainer and his former graduate student Young Jin Kim, an M.D.-Ph.D. student at Stony Brook University, inserted two antisense oligonucleotides (ASOs), one on either side of the segment containing the CFTR-W1282X mutation, in human bronchial cells. The ASOs forced the protein-making machinery to skip over this “stop sign” mutation, allowing a functional version of the protein to be made.

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Krainer and Kim hope their findings could lead to an RNA therapeutic that helps address CF caused by the CFTR-W1282X mutation. “There is a significant unmet therapeutic need for patients with this type of mutation,” says Kim. “Many mutations in the CFTR gene are not responsive to drugs used to treat CF.”

The technique does not need to work all the time in every cell, nor does the CFTR need to be a perfect protein. “We can show that this version of the protein has some activity,” says Krainer. “In cystic fibrosis, there’s been a lot of work, and so there were many reasons to believe that you don’t need to go to a hundred percent of the normal protein level, that somewhere between 10% and 30% would be substantially beneficial.”

The researchers plan to refine the ASO technique for CF and progress toward clinical studies, following a path similar to the one that led to the first FDA-approved treatment for the genetic disorder spinal muscular atrophy.

The findings were published in Proceedings of the National Academy of Sciences.