Therapeutic CRISPR/Cas9 Genome Editing in a Humanized Mouse Model Ameliorates α1-antitrypsin Deficiency Phenotype | Chapter 2 | Research Perspectives of Microbiology and Biotechnology Vol. 9

The aim of the study is to evaluate the role of CRISPR/Cas9 Genome Editing in improving α1-Antitrypsin Deficiency Symptoms. α1-antitrypsin (AAT) is a circulating serine protease inhibitor secreted from the liver and important in preventing proteolytic neutrophil elastase associated tissue damage, primarily in lungs. In humans, AAT is encoded by the SERPINA1 (hSERPINA1) gene in which a point mutation (commonly referred to as PiZ) causes aggregation of the miss-folded protein in hepatocytes resulting in subsequent liver damage. Targeting a defective gene in order to cure inherited human disease is an attractive therapeutic option and the stable disruption of SERPINA1 variants in vivo, at the genomic or mRNA level, is a promising strategy to reduce levels of miss-folded AAT protein and ameliorate pathological findings in the liver. In an attempt to rescue the pathologic liver phenotype of a mouse model of human AAT deficiency (AATD), we used adenovirus to deliver Cas9 and a guide-RNA (gRNA) molecule targeting hSERPINA1. Our single dose therapeutic gene editing approach completely reverted the phenotype associated with the PiZ mutation, including circulating transaminase and human AAT (hAAT) protein levels, liver fibrosis and protein aggregation. Furthermore, liver histology was significantly improved regarding inflammation and overall morphology in hSERPINA1 gene edited PiZ mice, which expresses the human SERPINA1 variant. Genomic analysis confirmed significant disruption to the hSERPINA1 transgene resulting in a reduction of hAAT protein levels and quantitative mRNA analysis showed a reduction in fibrosis and hepatocyte proliferation as a result of editing. Currently, available treatment options for patients with AATD are limited and include protein replacement therapy using plasma-derived AAT in lung disease and, in the case of advanced cirrhosis, liver transplantation. Our findings indicate that therapeutic gene editing in hepatocytes is possible in an AATD mouse model.

 

Author (s) Details

 

Mikael Bjursell
Discovery Sciences, IMED Biotech Unit, AstraZeneca, Gothenburg, Sweden.

 

Michelle J. Porritt
Discovery Sciences, IMED Biotech Unit, AstraZeneca, Gothenburg, Sweden.

 

Elke Ericson
Discovery Sciences, IMED Biotech Unit, AstraZeneca, Gothenburg, Sweden.

 

Amir Taheri-Ghahfarokhi
Discovery Sciences, IMED Biotech Unit, AstraZeneca, Gothenburg, Sweden.

 

Maryam Clausen
Discovery Sciences, IMED Biotech Unit, AstraZeneca, Gothenburg, Sweden.

 

Lisa Magnusson|
Discovery Sciences, IMED Biotech Unit, AstraZeneca, Gothenburg, Sweden.

 

Therese AdmyreA
Discovery Sciences, IMED Biotech Unit, AstraZeneca, Gothenburg, Sweden.

 

Roberto Nitsch
Discovery Sciences, IMED Biotech Unit, AstraZeneca, Gothenburg, Sweden.

 

Lorenz Mayr
Discovery Sciences, IMED Biotech Unit, AstraZeneca, Gothenburg, Sweden.

 

Leif AasehaugA
Drug Safety and Metabolism, IMED Biotech Unit, AstraZeneca, Gothenburg, Sweden.

 

Frank Seeliger
Drug Safety and Metabolism, IMED Biotech Unit, AstraZeneca, Gothenburg, Sweden.

 

Marcello Maresca
Discovery Sciences, IMED Biotech Unit, AstraZeneca, Gothenburg, Sweden.

 

Mohammad Bohlooly-Y
Discovery Sciences, IMED Biotech Unit, AstraZeneca, Gothenburg, Sweden.

 

John Wiseman
Discovery Sciences, IMED Biotech Unit, AstraZeneca, Gothenburg, Sweden.

 

Please see the book here:- https://doi.org/10.9734/bpi/rpmab/v9/3611

A Novel Role of Candesartan and Ramipril in Attenuation of Liver Fibrosis in Patients with Chronic Hepatitis C Viral Infection | Chapter 7 | New Horizons in Medicine and Medical Research Vol. 11

 This research looked at how Candesartan and Ramipril affected individuals with chronic hepatitis C's liver fibrosis.

This randomised controlled prospective study included 64 participants with chronic hepatitis C and liver fibrosis. The participants were divided into three groups according to randomization: group I (control group; n=21), which got only conventional therapy; group 2 (Ramipril group; n=21); and group 3 (Candesartan group; n=22); which received just traditional therapy plus 8 mg/day oral Candesartan.

At the beginning, the demographic and laboratory data for the three research groups were statistically identical. In comparison to baseline data, the three research groups' post-treatment liver stiffness, HA and TGF-1 blood levels, and indicators of liver fibrosis all significantly decreased (p 0.001). When compared to the control group six months after therapy, patients taking Ramipril and Candesartan showed a substantial improvement in all analysed parameters. Additionally, the Candesartan group showed a significantly lower level of liver stiffness, biomarkers, and fibrosis indices when compared to the Ramipril group.

Patients with chronic hepatitis C who had liver fibrosis responded well to be successfully treated with ramipril and candesartan. A safe and effective therapy for liver fibrosis in people with chronic liver disease may be candesartan, an AT1-R antagonist that maintained anti-fibrotic action better than Ramipril.

Author(s) Details:

Tarek M. Mostafa,
Department of Clinical Pharmacy, Faculty of Pharmacy, Tanta University, Tanta, Egypt.

Gamal A. El-azab,
Department of Clinical Pharmacy, Faculty of Pharmacy, Tanta University, Tanta, Egypt.

Gamal A. Badra,
National Liver Institute, Faculty of Medicine, Menoufia University, Shebin El-kom, Egypt.

Alyaa S. Abdelwahed,
National Liver Institute, Faculty of Medicine, Menoufia University, Shebin El-kom, Egypt.

Abeer A. Elsayed,
Department of Clinical Pharmacy, Faculty of Pharmacy, Sinai University, Al-Arish, Egypt.

Please see the link here: https://stm.bookpi.org/NHMMR-V11/article/view/7142