The small molecule approach can be a very powerful way to impact CFTR function, but still represents a temporary fix for a permanent problem. For patients like Brady, Kalydeco might be considered a "one day cure." As long as he maintains sufficient levels of Ivacaftor pumping through his veins, his body doesn't really realize it has CF..., BUT, if he were to stop swallowing those expensive little blue darlings, his CF symptoms would return quickly. Because of the temporary nature of the effects, small molecules don't really fit the bill as a true cure. While the CFF has millions of dollars invested in the development of new small molecules, they are also looking even further toward the future. Ultimately, we would all love to see a LIFETIME cure, rather than a ONE DAY cure. True to the "venture philanthropy" model that The CF Foundation has made famous, they are poised to make considerable investments in new exciting fields of research that could yield that lifetime cure that we all dream of, for each and every person with cystic fibrosis--regardless of their genetic mutations. I was disappointed that the UK Gene Therapy Trial results were not presented at this meeting as scheduled, but there are plenty of other new technologies to get REALLY excited about.
Symposium Session 8: Gene Editing Strategies for Therapy and Research
In this session, two technologies were described to manipulate genes such as CFTR. What makes these techniques so attractive is that they have the potential to be tailored to treat diverse cystic fibrosis mutations. These techniques can be thought of as "mutation agnostic," and could provide functional results for the multitudes of CF mutations, no matter how rare or complex the dysfunction.
1) Genome editing by the CRISPR/Cas9 system
2) RNA editing--where mutations in messenger RNA are corrected without modification of the genomic DNA
Functional Repair of CFTR by CRISPR/Cas9 in Intestinal Stem Cell Organoids of CF Patients
To perform this study, adult intestinal stem cells were obtained from rectal biopsies of adults with CF. Just to be perfectly clear--embryonic stem cells were not required in this research. The tissue samples obtained from the rectal biopsies were then taken into the lab, where they were manipulated to create intestinal organoids for experimentation. Most people have heard a lot about changes in sweat chloride levels as a measure of CFTR function. Over the last several years, I've seen more and more evidence that, while correlated with CFTR function, sweat chloride levels may not paint the most accurate picture of how much functional CFTR is being rescued. A better way to directly measure CFTR channel function is to examine intestinal organoid swelling.
|This slide details the methods used to grow organoids from adult stem cells.|
CFTR function can be directly measured via the amount of swelling that intestinal organoid cells exhibit. The amount of swelling can be directly correlated to CFTR function. This has been found to be a much more accurate measure of CFTR channel activity than sweat chloride measurements.
Using this method, researchers were able to restore functional swelling of the organoids in homozygous DF508, indicating restored CFTR function.
This work is very preliminary...but extremely exciting. This experiment serves as proof-of-concept for "regenerative medicine" approaches of CF using gene-corrected adult stem cells. In addition, this study shows that intestinal organoid swelling can be an effective mode of measuring CFTR function for future studies. At this point, researchers will need to work on improving the efficiency of correction, which is still very low. They seem confident that refinement of technique can produce much higher efficiency in future studies.
Correction of Genetic Mutations By Site-Directed RNA Editing
|I've never actually visited The Cayman Islands before...but it seems like a really nice place.|