Gene Editing Corrects CF Mutation in Multiple Organs All at Once
Yale researchers share results of novel mouse study
A novel gene-editing treatment platform corrected the mutation that causes cystic fibrosis (CF) in multiple tissues throughout the bodies of mice, according to results of a first-of-its-kind study.
“This is the first study looking at treating multiple organs affected by CF with a single gene editing treatment administered intravenously,” Alexandra Piotrowski-Daspit, PhD, a postdoctoral fellow at Yale University and co-author of the study, said in a Yale School of Medicine press release.
The study, “In vivo correction of cystic fibrosis mediated by PNA nanoparticles,” was published in Science Advances.
CF is caused by mutations in the CFTR gene, leading to symptoms such as lung disease and digestive problems. The basic concept behind gene-editing therapy for CF is to “correct” the disease-causing mutation, restoring the functionality of the CFTR gene.
“The power of gene editing is that you can correct the underlying cause, so that you’re not necessarily looking at lifelong treatments. If you can optimize the delivery to the specific organs, you’re looking at a one-time cure,” Piotrowski-Daspit said.
A notable obstacle in developing this type of therapy is that it is difficult to use one therapy to simultaneously deliver gene-editing material to all the different organs that are affected by CF.
A team of scientists at Yale previously had created a gene-editing platform that uses nanoparticles composed of poly(lactic-co-glycolic acid), or PLGA, to deliver molecules called peptide nucleic acids (PNAs) to cells in the body. Very simplistically, PNAs can form structures with the cell’s DNA at specific sites and prompt the cell’s normal DNA-repairing machinery to “fix” a given mutation.
“The therapeutic approach for CF described here combines non–nuclease-based PNA gene editing technology with systemic delivery of biocompatible polymeric [nanoparticles] to achieve gene correction in multiple tissue types,” the scientists wrote.
Now, researchers tested whether this nanoparticle-based platform could correct the F508del mutation in CFTR in a mouse model. F508del is the most common CF-causing mutation, found in roughly 90% of patients.
In an initial set of experiments, the researchers confirmed that their PLGA nanoparticle platform could enter the lung, digestive tract, and many other organs throughout the body when administered intravenously (into the bloodstream) without causing any notable toxicity.
“While we observed widespread [nanoparticle] biodistribution to multiple tissues apart from airway and [digestive tract cells], we did not observe any pathology in tissues with particularly high [nanoparticle] accumulation, including the liver and spleen,” the researchers wrote.
F508del mutation in CFTR
Genetic testing revealed correction of the CFTR gene in the tissue of mice with the F508del mutation, though the number of affected cells was limited and there was marked variation from mouse to mouse. Assessments of CFTR protein function, namely through nasal potential difference and a related measure called rectal potential difference, broadly suggested an increase in CFTR function after treatment, though again there was notable variation in response.
These results were confirmed in vitro in relevant cells grown in a laboratory setting, including airway epithelial cells.
“In summary, these data suggest that PLGA-based [nanoparticles] are able to reach target organs and cell types relevant to CF treatment after intravenous delivery,” and that “systemic gene editing is possible, and more specifically that intravenous delivery of PNA [nanoparticles] designed to correct CF-causing mutations is a viable option to ameliorate CF in multiple affected organs,” the researchers wrote.
“Even modest levels of editing can result in partial restoration” of CFTR function, the researchers added, though they noted a need for further research to improve the potency and consistency of results.
According to the team, another area where further investigation is needed is the longevity of the effect. Researchers noted that, in mice who responded to the gene-editing treatment, the effect tended to wane over time; however, mice that responded once tended to respond again when re-treated.
“The longevity of treatment response is also an important consideration for translation of gene editing therapeutics. We observed an attenuation in treatment response over time that was reversed upon additional treatment rounds,” the researchers wrote. “Optimization of the delivery to target stem cells will be key to obtaining a one-time cure.”
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