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Organoid Technology for Basic Science and Biomedical Research
Published in Hyun Jung Kim, Biomimetic Microengineering, 2020
Szu-Hsien (Sam) Wu, Jihoon Kim, Bon-Kyoung Koo
Alpha 1-antitrypsin (A1AT) is a secreted protein encoded by the SERPINA1 gene, produced by hepatocytes and transported to the lungs in the circulation in order to protect the lungs from the proteolytic activity of elastase produced by neutrophils. A1AT deficiency leads to respiratory complications, whilst an accumulation of misfolded A1AT in hepatocytes causes cirrhosis and increases the risk of pulmonary emphysema and hepatic disease (Fairbanks and Tavill 2008; Lawless et al. 2008). The most common disease-causing mutation detected is a single copy of the autosomal co-dominant Z allele (Glu342Lys) of SERPINA1 (ZZ mutant). Huch et al. established liver organoids from patients with the ZZ mutant genotype, and whilst expansion in the bipotent state appeared normal in terms of organoid morphology, growth rate and functionality, upon differentiation into hepatocytes, misfolded A1AT aggregates rapidly accumulated in the patient-derived organoids (Huch et al. 2015).
Genome Editing for Genetic Lung Diseases
Published in Anthony J. Hickey, Sandro R.P. da Rocha, Pharmaceutical Inhalation Aerosol Technology, 2019
Alpha-1 antitrypsin (AAT) deficiency causes progressive lung diseases due to the loss of AAT function and results in significant liver injury due to toxic gain-of-function mutations of AAT.114,115 Injection of two AAVs, one for Cas9 and the other for AAT guide RNA plus HDR template, partially restored the right form of AAT protein expression in hepatocytes, suggesting an effective approach for the clinical applications.114,115 The CRISPR/Cas9 approach was used to correct the mutated CFTR gene via HDR in the cultured intestinal stem cells from CF patients.116 The corrected allele expressed the fully functional CFTR protein in clonally expanded organoids and provided the proof-of-concept support for HDR-mediated gene correction in adult stem cells from patients with hereditary defects.116 In another study, induced pluripotent stem cells (iPSCs) were generated from CF patients with the deltaF508 mutation genotype in the CFTR gene.117 Using CRISPR, mutated CFTR is corrected in iPSCs, and the edited iPSCs are able to differentiate into airway epithelial cells with restored function of CFTR protein.117
The roadmap towards cure of chronic hepatitis B virus infection
Published in Journal of the Royal Society of New Zealand, 2022
Translation inhibitors can silence production of disease-associated proteins and enzymes by intervening at the transcript level (mRNA) (Figure 3). Target diseases include both inherited conditions associated with unwanted gene products including hypercholesteraemia, familial amyloid polyneuropathy, PNH, acute intermittent porphyria and alpha-1-antitrypsin deficiency and acquired diseases such as chronic bacterial or viral infections.