I have the most amazing good luck. 8 years ago, my world came crashing down when my newborn baby was diagnosed with the genetic disease cystic fibrosis. Today, we feel like the most fortunate family in the world because we have Kalydeco! Now my goal is to work toward more personalized research, to help bring the most effective treatment to each and every person living with CF!
Gene editing and mRNA editing have been discussed at NACFC for a few years now. Here is the link to last year's blog and conference slides. Researchers have been working hard to overcome obstacles to delivery and expression of genetic treatments over the course of the last year...and they are getting somewhere. I spent Friday afternoon, as well as Saturday morning listening to talks about gene editing. Check out this animation illustrating what gene editing might look like in cystic fibrosis.
As seen in the video, nucleases can be engineered to create site specific, double strand breaks at desired locations in the genome. Antisense Oligonucleotides can be thought of as our "molecular scissors" that guide the gene editing process.
A First-In-Human, Phase 1B, Dose Escalation Study of QR-010, A Novel Antisense Oligonucleotide Administered in Subjects with Cystic Fibrosis Homozygous for the F508Del CFTR Mutation. Elborn, S.
Pro-QR is one of the companies really leading the way with gene editing technologies in cystic fibrosis, and this was a highly anticipated discussion, as this is an early gene editing trial in HUMANS WITH CYSTIC FIBROSIS.
Pro-QR's treatment is called "QR-010"
An "antisense oligonucleotide" is a synthesized strand of nucleic acid that is complementary to the gene's messenger RNA. Pro-QR's treatment was administered to the lungs via nebulizer.
Goals are to establish safety and tolerability, as well as assess maximum tolerated dose (MTD).
Quality of life improvements were patient reported using the Cystic Fibrosis Questionnaire-Revised (CFQ-R), and the Respiratory Symptom Score (RSS)
Wow! Just Wow!!!!!!
Antisense Oligonucleotide-Mediated Upregulation of CFTR via Steric Block of Post-Transcriptional Control Elements: A Novel Approach for Cystic Fibrosis Therapeutics. Sasaki, S.
Antisense oligonucleotides function as our "molecular scissors."
Antisense oligonucleotides are programmed to target a specific site.
Could this type of treatment be successful for gene transfer in CF lungs?
ASOs = antisense oligonucleotides (our molecular scissors).
In Utero Nanoparticle Delivery for Site-Specific Genome Editing. Ricciardi, A.
In 2015, researchers from Yale published a study in Nature Magazine where the F508del mutation was corrected in a living mouse using their specially engineered "peptide nucleic acid" (PNA) to edit the genetic defect.
“What the PNA does is clamp to the DNA close to the mutation, triggering DNA repair and recombination pathways in cells,” Egan explained.
Perhaps even more importantly, the Yale group has developed a unique way to deliver their genetic treatment using nanoparticles--particles less that a billionth of a meter in diameter--designed to penetrate targeted cells. Encouraged by their success in living mice, the research group decided to try to deliver their treatment to a developing mouse embryo with cystic fibrosis. Imagine a world where cystic fibrosis could be cured before a child is even born...
The CFF registry has confirmed that early diagnosis and intervention leads to better health outcomes.
We have the ability to detect CF in developing fetuses.
The fetus is deeply affected by cystic fibrosis--even prenatally.
Could in utero gene editing PREVENT cystic fibrosis altogether?!?!
Stay with me here! Remember, PNA is our pair of "molecular scissors," programmed to make the cut at a specific target.
One of the most important things about this research is the FORMULATION of their genetic product. They do this special "nanoparticle" thing--where they cram all the genetic info onto these itty bitty spheres.
The PNA/DNA nanoparticles work to correct the F508del mutation in living mice.
So they decided to test their treatment on a developing CF mouse embryo...
Holy crap, is that a mouse uterus?!
Researchers have to use specially made glass pipettes to inject their nanoparticles into this particular vein in the uterus.
So cool. This is the actual injection of the nanoparticles into the uterine vein.
Researchers were able to show uptake and expression of desired genetic information in fetal organs!!!
In conclusion...holy shit. This talk left my jaw hanging open!
Manipulating Vector Interactome to Enhance Gene Delivery. Siefert, M.
As previously noted, perfecting the "vector" to enhance gene delivery was a hot topic because it has proven to be so challenging over the years.
Researchers have encountered multiple obstacles to success gene transfer.
Another example of nanoparticle delivery. Could this be the way forward?
Safe, but not perfect.
How do we improve efficacy?
Penetrating mucus is a formidable barrier in CF.
Manipulation of other cellular interactions can enhance gene transfer.
It is worth taking a closer look at how to achieve maximal benefit from manipulation of these cellular interactions.
Researchers were able to show improved efficacy of their gene product by manipulation of cellular interactome.
What an amazing world we live in. Cure Cystic Fibrosis.
This is my 7th year attending the NACFC...and after 3 days of Workshops, Symposia, and Plenary Sessions--I am more optimistic than ever. At the NACFC, I try to take every opportunity I can to soak in the science and connect with the researchers. This year was the largest NACFC ever--with close to 5000 in attendance from all over the world. I skip the gym, sleep, and regular meals to that no opportunities escape me. This entry will touch on exciting news from the first Plenary Session. 2020 is going to be a BIG year for treating Cystic Fibrosis
The first Plenary Session always features the most exciting progess from the previous year. I've been watching and writing about the development of the "second generation" 3 drug combinations of CFTR modulators at NACFC for several years. The lab data has been nothing short of THRILLING. Finally, researchers are confident enough in the combounds that they've put a real timeline on moving these breakthroughs from the lab to your medicine cabinet. The second generation combos will be available for those with either one or two copies of F508del, which means that 90% of the CF population will be eligible for treatment in 2020!
CFTR response for homozygous F508del--INCREDIBLE!
CFTR Response to next gen combos for heterozygotes with one F508 del mutation. Treating one mutation alone offers a clinical response almost as good as Kalydeco for G551D.
Studies focused on selection of the best of the Vertex corrector in development (the 3rd ingredient in our cocktail) to add to the next gen combo.
The CFF is leaving no stone unturned to effectively treat nonsense mutations.
Gene editing or mRNA editing represents a true opportunity for a one time cure for people with ANY of the thousands of cystic fibrosis mutations.
FDA Accepts Lab Data as Legitimate Path Toward Drug Approval for Rare CF Mutations.
There are over 1000 mutations of cystic fibrosis worldwide that are only carried by a very small number of individuals. The potential to perform a traditional large scale human trial does not exist. As treatments for those with cystic fibrosis evolve, so must the FDA's approval criteria. I am so encouraged by this step forward. We now have the capability to test drug responses in cell lines in the lab, and truly personalize medicine for people with rare mutations. There are many that may even be responsive to existing drugs like Kalydeco, and now we have the opportunity to make sure responders are not getting missed!
The FDA is an integral part of getting drugs to patients. This evolution of the drug approval process is a huge step forward!
It would be horrible to be missing out on an existing treatment if your mutation would benefit.
Testing drugs on cell lines in the lab in a way to bypass large scale clinical trials for those with rare CF mutations.
There is an effort underway to evaluate rare mutations to better predict drug response.
Techniques to address the mutations not eligible for small molecule modulators.
