Abstract
Monogenic metabolic disorders of hepatic origin number in the hundreds, and for many, liver transplantation remains the only cure. Liver-targeted gene therapy is an attractive treatment modality for many of these conditions, and there have been significant advances at both the preclinical and clinical stages. Viral vectors, including retroviruses, lentiviruses, adenovirus-based vectors, adeno-associated viruses and simian virus 40, have differing safety, efficacy and immunogenic profiles, and several of these have been used in clinical trials with variable success. In this review, we profile viral vectors and non-viral vectors, together with various payloads, including emerging therapies based on RNA, that are entering clinical trials. Genome editing technologies are explored, from earlier to more recent novel approaches that are more efficient, specific and safe in reaching their target sites. The various curative approaches for the multitude of monogenic hepatic metabolic disorders currently at the clinical development stage portend a favorable outlook for this class of genetic disorders.
Highlights
The liver is the principal organ in the body involved in the metabolism and detoxification of numerous agents; and multiple disorders of metabolism are of hepatic origin
An additional study found that hepatitis C virus (HCV) entry into Huh-7.5 cells was significantly impaired in a claudin-1-dependent manner when diacylglycerol acyltransferase-1 expression was silenced using Transcription activator-like effector nucleases (TALENs) [161]
Given the multitude of monogenic metabolic disorders that have been clinically and mechanistically described, the feasibility that Liver-targeted gene therapy (LTGT) could provide a cure to such disorders is potentially in reach
Summary
The liver is the principal organ in the body involved in the metabolism and detoxification of numerous agents; and multiple disorders of metabolism are of hepatic origin. There are as many as 400 inherited and acquired metabolic disorders caused by a single gene mutation, and for many of these, orthotopic liver transplantation is the only known curative therapy. Liver-targeted gene therapy (LTGT) has been successfully applied in preclinical models of various disorders, including hemophilia A and B, urea cycle disorders and familial hypercholesterolemia, with varying degrees of success. Given the monogenic nature of many of these disorders, a gene therapy approach appears naturally suited for therapeutic benefit. Viral vector-based approaches have overcome significant hurdles, with progress made on inherent viral protein immunogenicity, toxicity, specificity of target site delivery and methods of delivery. Non-viral approaches, including genome editing, have made significant advances in improving the safety and efficacy profile of these novel technologies to gene therapy. We present in this review the evolution and current status of the various technologies available for LTGT as well as the challenges that still exist
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