Researchers from Penn Medicine and Children’s Hospital of Philadelphia have fixed a lethal mutation in the prenatal mouse models of a rare pulmonary disease. The hope is that the approach of in utero editing described in Science Translational Medicine will work for other congenital lung diseases as well.
I asked one of the corresponding authors, Edward Morrison, scientific director of the Penn’s Institute for Regenerative Medicine, to explain what they have done and what to expect next. See Q&A below.
Why did you choose surfactant protein C deficiency (SFTPC) as a proof of concept? Why not cystic fibrosis (CF)?
EM: The SFTPC I73T mutation was picked for the following reasons: 1) It is the most common SFTPC mutation in humans and causes a spectrum of diseases including neonatal respiratory distress and 2) The SFTPC gene itself is not essential for lung function and thus we could use non-homologous end joining as a way to rescue the disease caused by the mutation. Cystic fibrosis is a disease of the larger airways in humans and mice do not have significant respiratory disease even when they contain CF mutations.
Why is it so hard to succeed with gene therapy when we come to CF?
EM: CF is caused by mutations in the CFTR gene which is important for the function of the large airways. To correct the CF mutations found in humans, the basal cell, which is found embedded deep within the epithelial layer of the large airways, will need to be efficiently targeted. There are many barriers to doing this so it has remained difficult for gene therapy including CRISPR editing to work.
Do you think human fetuses should be routinely screened for lung diseases in the future?
EM: If this technique can be optimized for human use, then it might be clinically relevant to screen for monogenic lung diseases.
Do your results offer any hope for gene therapy in infants?
EM: We are of course hopeful that this will one day lead to a new therapeutic approach, but as this is a proof of principle study there are still many steps before this can happen.
Is in vivo editing the only available option for editing lung diseases in your opinion?
EM: There are efforts to replace damaged or lost cells in the lung with lung cell types generated in a dish from pluripotent stem cells. As with many of these efforts, such studies are still in their infancy and will require much additional work.
What vectors do you expect to work better for lung diseases?
EM: I think everyone in the field hopes that there will be non-viral approaches as the use of viruses is not optimal. However, viral transduction of CRISPR reagents remains the most efficient method to date.