CRISPR/Cas9-Mediated Gene Correction in Newborn Rabbits with Hereditary Tyrosinemia Type I

Modern therapeutic approaches to liver-related disorders

“…1 Integration can be achieved by using (i) an integrative vector such as an optimised lentivirus 27 or (ii) an integrative transgene dependent on a nuclease (such as CRISPR), a transposase, or a nuclease-free DNA template that integrates into the endogenous Albumin locus through homologous recombination. 1,28,29 The integrative transgene has been successfully delivered to the liver using rAAVs or LNP in preclinical studies [28][29][30][31] ; however, studies in humans are limited. Although promising, the use of viral vectors carries certain risks, as discussed below.…”

“…However, this method could be of interest for the treatment of children, particularly if the corrected cells have a selective advantage, as has been demonstrated for some liver diseases in preclinical studies. 30 Finally, the major caveats are potential genotoxicity, possible off-target effects, and large-scale chromosomal deletions. 89,90 Safety data are scarce in human patients, and toxicity will need to be monitored closely.…”

CRISPR/Cas9 application in cancer therapy: a pioneering genome editing tool

“…Engineered nucleases accompanied with the correct sequence of the target gene can be injected directly into the patient for systemic or targeted tissue (such as the eye, brain, or muscle) in vivo [ 74 , 75 ]. During the recent decade, CRISPR/Cas9 has exhibited promising preliminary capability to treat β-thalassemia [ 76 – 78 ], tyrosinemia [ 79 ], Duchenne muscular dystrophy (DMD) [ 80 , 81 ], hemophilia [ 82 , 83 ], cystic fibrosis [ 84 ], central nervous system (CNS)-associated diseases [ 85 , 86 ], Tay–Sachs diseases (TSD) [ 87 ], and fragile X syndrome disorders (FXS) [ 88 , 89 ]. Indeed, this technology has enabled the correction of the multiple mutated genes associated with responding genetic disorders, including the DMD gene in DMD, CFTR gene in CF, factor IX gene in hemophilia B, hemoglobin beta-chain gene in β-thalassemia, presenilin 1 and 2 (PSEN1 and PSEN2) and apolipoprotein E4 (apoE4) genes in AD, HTT gene in HD, leucine-rich repeat kinase 2 (LRRKK2) gene in PD, fumarylacetoacetate hydrolase (FAH) in tyrosinemia, Hex gene in TSD, fragile X mental retardation 1 (FMR1) gene in FXS, etc.…”

Applications and challenges of CRISPR-Cas gene-editing to disease treatment in clinics

“…Monogenic diseases, which are associated with more than 75 000 genetic variants, affect a large population of patients, and sadly the majority of them remain difficult to treat. 35 The CRISPR-Cas tools are being widely used to correct genetic variants with the hope of treating many human genetic diseases, such as inherited blood disorders (sickle cell disease, β-thalassemia, and hemophilia), 36–38 inherited eye diseases (Leber congenital amaurosis and inherited retinal degeneration), 39–41 muscular genetic disease (Duchenne muscular dystrophy), 42–44 genetic liver diseases (α-1 antitrypsin deficiency and hereditary tyrosinemia type 1), 45–47 congenital genetic lung disease (inherited surfactant protein syndromes and cystic fibrosis), 48–50 neurological disorders (Parkinson's disease, Alzheimer's disease, and Huntington's disease), 51–53 genetic deafness, 54 , 55 etc.…”