Advances and Answers in Pediatric Health
But that didn ’ t make it an easy sell .
“ Fetal therapy is already a foreign concept ,” Dr . Zaretsky says . “ Gene therapy takes it to a whole new level . It ’ s never been done . If you want data on this , there isn ’ t any . There ’ s nothing to go by .
“ The first time I pitched it ,” he adds , laughing . “ It just drew a complete blank .”
MORE COMPLICATED
Molecular biologist Sean McGrath , PhD , an instructor at the University of Colorado School of Medicine who was at the time managing the Stem Cell Biobank and Disease Modeling Core at the Gates Center for Regenerative Medicine , was one of the first to join the team . Dr . Zaretsky reached out to Dr . McGrath after learning of his experience with CRISPR .
Three years later , despite humble beginnings , Dr . Zaretsky has succeeded in assembling basic scientists from Children ’ s Colorado , the University of Colorado School of Medicine , Colorado State University and National Jewish Health . It ’ s a team Dr . Zaretsky is excited and honored to work with .
Of course , his work set the project in motion and has been critical in the success it has had so far . Already the team has created a CRISPR construct that targets f508del , the most common mutation of the CFTR gene , shared by nearly 90 % of individuals with cystic fibrosis . They ’ ve lab-tested it to make sure it modifies the genome where it ’ s supposed to . They ’ ve packaged the construct into an adeno-associated viral delivery system . And they ’ ve tested it in a large animal model at mid-gestation , delivering the therapy through the umbilical vein . They ’ re now awaiting results .
“ The thing is ,” Dr . McGrath says , “ it ’ s actually pretty easy to make a system that will modify the CFTR locus . Those tools are well established . Moving away from the lab bench and editing within a living animal is far more complicated .”
WHICH VEHICLE IS BEST
CFTR mutations only affect a handful of cell types , but the gene is present in every cell of the body . How gene editing will affect those other cells and systems remains to be answered . Is the treatment safe ? Does it introduce unwanted artifacts ? How do you deliver the treatment to the right cells , and can it fix enough of them to correct the phenotype ? And will the fix last ?
“ Right now , they ’ re looking at a viral-based vector ,” says Dr . Sagel . “ We know that viruses infect respiratory cells . That ’ s what makes them attractive for lung disease . But the body also mounts an immune reaction , so you have to account for that . There are other
ways to get things into cells . We just don ’ t know yet which vehicle is best .”
Still there ’ s encouraging evidence that the idea is fundamentally viable . In one proof-of-concept study , researchers delivered CRISPR gene-editing reagents to the amniotic fluid of a small
animal model and were able to successfully modulate otherwisefatal genetic interstitial lung disease ( 1 ).
“ It was able to correct enough lung disease to have survivors ,” says Dr . Zaretsky . “ If you ’ re able to correct enough cells , you probably don ’ t need to get to 100 %. You can still ameliorate the disease .”
And what works for cystic fibrosis could have implications for any single-gene mutation that affects the lungs or digestive system . But it ’ s a long road ahead .
“ I think the ultimate goal is to cure ,” says Dr . Sagel . “ What Dr . Zaretsky and his group are doing will get us closer .”
“ It ’ s a dream , and we have the potential tools to make it a reality ,” Dr . Zaretsky says . “ It ’ s going to take a long time , but it has to start somewhere .” •
1 . Alapati D , Zacharias WJ , Hartman HA , Rossidis AC , Stratigis JD , Ahn NJ , Coons B , Zhou S , Li H , Singh K , Katzen J , Tomer Y , Chadwick AC , Musunuru K , Beers MF , Morrisey EE , Peranteau WH . In utero gene editing for monogenic lung disease . Sci Transl Med . 2019 Apr 17 ; 11 ( 488 ): eaav8375 .
SEAN MCGRATH , PHD
Instructor , Department of Pediatrics , Section of Developmental Biology
Manager , Organoid and Tissue Modeling Shared Resource , University of Colorado School of Medicine
SCOTT SAGEL , MD , PHD
Director of the Mike McMorris Cystic Fibrosis Research and Care Center , Children ’ s Hospital Colorado
Professor of Pediatrics , University of Colorado School of Medicine
MICHAEL ZARETSKY , MD
Co-Medical Director , Colorado Fetal Care Center , Children ’ s Hospital Colorado
Associate professor , Ob / Gyn-Maternal Fetal Medicine , University of Colorado School of Medicine
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