scholarly journals Treatment of a metabolic liver disease by in vivo genome base editing in adult mice

2018 ◽  
Vol 24 (10) ◽  
pp. 1519-1525 ◽  
Author(s):  
Lukas Villiger ◽  
Hiu Man Grisch-Chan ◽  
Helen Lindsay ◽  
Femke Ringnalda ◽  
Chiara B. Pogliano ◽  
...  
Keyword(s):  
Liver Disease ◽  
Base Editing ◽  
Adult Mice ◽  
Metabolic Liver Disease

scholarly journals Amelioration of an Inherited Metabolic Liver Disease through Creation of a De Novo Start Codon by Cytidine Base Editing

2020 ◽  
Vol 28 (7) ◽  
pp. 1673-1683 ◽  
Author(s):  
Lei Yang ◽  
Liren Wang ◽  
Yanan Huo ◽  
Xi Chen ◽  
Shuming Yin ◽  
...  
Keyword(s):  
Liver Disease ◽  
De Novo ◽  
Start Codon ◽  
Base Editing ◽  
Metabolic Liver Disease

scholarly journals 804. In Vivo Correction of a Metabolic Liver Disease by AAV8-Mediated Homologous Recombination

2006 ◽  
Vol 13 ◽  
pp. S311-S312
Author(s):  
Karsten Wursthorn ◽  
Terry Storm ◽  
Mark A. Kay ◽  
Milton Finegold ◽  
Markus Grompe
Keyword(s):  
Liver Disease ◽  
Homologous Recombination ◽  
Metabolic Liver Disease

scholarly journals Efficient precise in vivo base editing in adult dystrophic mice

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Li Xu ◽  
Chen Zhang ◽  
Haiwen Li ◽  
Peipei Wang ◽  
Yandi Gao ◽  
...  
Keyword(s):  
High Efficiency ◽  
Functional Improvement ◽  
Systemic Delivery ◽  
Mutation Site ◽  
Base Editing ◽  
Adult Mice ◽  
Exciting Opportunity ◽  
Protospacer Adjacent Motif ◽  
Monogenic Diseases

AbstractRecent advances in base editing have created an exciting opportunity to precisely correct disease-causing mutations. However, the large size of base editors and their inherited off-target activities pose challenges for in vivo base editing. Moreover, the requirement of a protospacer adjacent motif (PAM) nearby the mutation site further limits the targeting feasibility. Here we modify the NG-targeting adenine base editor (iABE-NGA) to overcome these challenges and demonstrate the high efficiency to precisely edit a Duchenne muscular dystrophy (DMD) mutation in adult mice. Systemic delivery of AAV9-iABE-NGA results in dystrophin restoration and functional improvement. At 10 months after AAV9-iABE-NGA treatment, a near complete rescue of dystrophin is measured in mdx4cv mouse hearts with up to 15% rescue in skeletal muscle fibers. The off-target activities remains low and no obvious toxicity is detected. This study highlights the promise of permanent base editing using iABE-NGA for the treatment of monogenic diseases.

scholarly journals Treatment of a metabolic liver disease by in vivo prime editing in mice

2021 ◽  
Author(s):  
Desiree Boeck ◽  
Tanja Rothgangl ◽  
Lukas Villiger ◽  
Lukas Schmidheini ◽  
Nicolas Mathis ◽  
...  
Keyword(s):  
Liver Disease ◽  
Phenylalanine Hydroxylase ◽  
Proof Of Concept ◽  
Adeno Associated Virus ◽  
Average Efficiency ◽  
Metabolic Liver Disease ◽  
Somatic Tissues ◽  
Transversion Mutation ◽  
Metabolic Liver Diseases

Prime editing is a highly versatile CRISPR-based genome editing technology with the potential to correct the vast majority of pathogenic mutations. However, correction of a disease phenotype in vivo in somatic tissues has not been demonstrated thus far. Here, we establish proof-of-concept for in vivo prime editing and repair the metabolic liver disease phenylketonuria (PKU) in mice. We first developed a size-reduced SpCas9 prime editor (PE) lacking the RNaseH domain of the reverse transcriptase (PE2-deltaRnH), and a linker- and NLS-optimized intein-split PE construct (PE2 p.1153) for delivery by adeno-associated virus (AAV) vectors. Systemic dual AAV-mediated delivery of this variant into the liver of neonatal mice enabled installation of a transversion mutation at the Dnmt1 locus with an average efficiency of 15%, and delivery of unsplit PE2-deltaRnH using human adenoviral vector 5 (AdV5) further increased editing rates to 58%. PE2-deltaRnH-encoding AdV5 was also used to correct the disease-causing mutation of the phenylalanine hydroxylase (Pah)enu2 allele in phenylketonuria (PKU) mice with an average efficiency of 8% (up to 17.3%), leading to therapeutic reduction of blood phenylalanine (L-Phe) levels. Our study demonstrates in vivo prime editing in the liver with high precision and editing rates sufficient to treat a number of metabolic liver diseases, emphasizing the potential of prime editing for future therapeutic applications.

Altered phosphoethanolamine levels in alcoholic liver disease assessed by in vivo proton-decoupled 31P MR spectroscopic imaging

2001 ◽  
Vol 120 (5) ◽  
pp. A116-A116
Author(s):  
H SCHLEMMER ◽  
T SAWATZKI ◽  
I DORNACHER ◽  
S SAMMET ◽  
M HELLENSCHMIDT ◽  
...  
Keyword(s):  
Liver Disease ◽  
Alcoholic Liver Disease ◽  
Spectroscopic Imaging ◽  
Mr Spectroscopic Imaging

scholarly journals Lentiviral Vectors for Delivery of Gene-Editing Systems Based on CRISPR/Cas: Current State and Perspectives

Viruses ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1288
Author(s):  
Wendy Dong ◽  
Boris Kantor
Keyword(s):  
Large Scale ◽  
Lentiviral Vector ◽  
Clinical Applications ◽  
Scale Production ◽  
Base Editing ◽  
Epigenome Editing ◽  
Vector Systems ◽  
Dividing Cells

CRISPR/Cas technology has revolutionized the fields of the genome- and epigenome-editing by supplying unparalleled control over genomic sequences and expression. Lentiviral vector (LV) systems are one of the main delivery vehicles for the CRISPR/Cas systems due to (i) its ability to carry bulky and complex transgenes and (ii) sustain robust and long-term expression in a broad range of dividing and non-dividing cells in vitro and in vivo. It is thus reasonable that substantial effort has been allocated towards the development of the improved and optimized LV systems for effective and accurate gene-to-cell transfer of CRISPR/Cas tools. The main effort on that end has been put towards the improvement and optimization of the vector’s expression, development of integrase-deficient lentiviral vector (IDLV), aiming to minimize the risk of oncogenicity, toxicity, and pathogenicity, and enhancing manufacturing protocols for clinical applications required large-scale production. In this review, we will devote attention to (i) the basic biology of lentiviruses, and (ii) recent advances in the development of safer and more efficient CRISPR/Cas vector systems towards their use in preclinical and clinical applications. In addition, we will discuss in detail the recent progress in the repurposing of CRISPR/Cas systems related to base-editing and prime-editing applications.

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