Abstract
A decade of progress in sequencing and in CRISPR/Cas technologies has created a situation without precedent in the history of medicine. Starting with an individual patient, next-generation sequencing can diagnose, in less than 24 h, the genetic basis of a Mendelian disorder. 1 Owen M.J. Niemi A.-K. Dimmock D.P. Speziale M. Nespeca M. Chau K.K. Van Der Kraan L. Wright M.S. Hansen C. Veeraraghavan N. et al. Rapid sequencing-based diagnosis of thiamine metabolism dysfunction syndrome. N. Engl. J. Med. 2021; 384: 2159-2161 Crossref PubMed Scopus (25) Google Scholar Once the causative mutation is found, CRISPR/Cas, in principle, represents a targeted therapy, a first-pass iteration of which can be designed in silico within minutes thanks to straightforward principles of target locus recognition by Cas9. 2 Jinek M. Chylinski K. Fonfara I. Hauer M. Doudna J.A. Charpentier E. A programmable dual-RNA-guided DNA endonuclease in adaptive bacterial immunity. Science. 2012; 337: 816-821 Crossref PubMed Scopus (8856) Google Scholar The juxtaposition of the two to yield a treatment is not a hypothetical. For Mendelian disorders of hematopoiesis and those that can be treated by editing genes in the liver or the eye, a charted path exists to (1) engineer a CRISPR/Cas-based therapeutic, (2) complete IND-enabling preclinical safety, efficacy, and manufacturing studies, and (3) perform a phase 1/2 clinical trial. Three ongoing such trials have reduced all of this to practice, 3 Frangoul H. Altshuler D. Cappellini M.D. Chen Y.-S. Domm J. Eustace B.K. Foell J. de la Fuente J. Grupp S. Handgretinger R. et al. CRISPR-Cas9 gene editing for sickle cell disease and β-thalassemia. N. Engl. J. Med. 2021; 384: 252-260 Crossref PubMed Scopus (363) Google Scholar ,4 Gillmore J.D. Gane E. Taubel J. Kao J. Fontana M. Maitland M.L. Seitzer J. O’Connell D. Walsh K.R. Wood K. et al. CRISPR-Cas9 in vivo gene editing for transthyretin amyloidosis. N. Engl. J. Med. 2021; 385: 493-502 Crossref PubMed Scopus (255) Google Scholar with a good safety record in ∼22 (sickle cell disease and transfusion-dependent β-thalassemia), 6 (TTR amyloidosis), and 6 (Leber's congenital amauropathy) subjects dosed to date; in the first case, all subjects for whom data are publicly available have experienced a resolution of major disease symptoms.
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