Therapeutics: Gene Therapy for Alpha-1 Antitrypsin Deficiency

Abstract

This review seeks to give an overview of alpha-1 antitrypsin deficiency, including the different disease phenotypes that it encompasses. We then describe the different therapeutic endeavors that have been undertaken to address these different phenotypes. Lastly we discuss future potential therapeutics, such as genome editing, and how they may play a role in treating alpha-1 antitrypsin deficiency.

Delivery of mRNA Therapeutics for the Treatment of Hepatic Diseases

“…Therefore, many alternative options are being investigated, such as autophagy-enhancing drugs; 87 induced pluripotent stem cell (iPSC)-genome editing based on zinc-finger nucleases, 88 transcription activator-like effector nucleases (TALENs), 89 and the CRISPR/ Cas9 system; 90,91 gene replacement therapy based on viral 92 and non-viral 4,93 mediators; microRNA (miRNA) for gene silencing; and mRNA as a transcript therapy. [94][95][96] In a recent study by Connolly et al, 96 transfection of patient fibroblasts and hepatocytes with AATencoding mRNA resulted in significant secretion of AAT protein in the cell culture supernatant. An i.v.…”

Alpha-1 antitrypsin deficiency: outstanding questions and future directions

“…AAT augmentation therapy requires regular intravenous infusion of plasma-purified AAT, which is costly and dependent on the availability of the protein. Therefore, alternative strategies are currently being investigated, including new delivery strategies, the use of gene therapy or iPSCs, non-augmentation strategies to prevent AAT polymerisation inside hepatocytes, the use of autophagy-enhancing drugs and silencing RNA strategies [ 123 , 124 ].…”

Is More Better? Promising Biological Effects of Double-Dose Alpha 1-Antitrypsin Therapy

“…This report and the recent advances in experimental gene therapy (13–15) and in the discovery of novel therapeutic targets in AATD (16), highlight the concerted effort of the medical and research community to provide much needed relief for individuals affected with AATD.…”