The future of gene-targeted therapy for hereditary tyrosinemia type 1 as a lead indication among the inborn errors of metabolism

Abstract

Introduction: Inborn errors of metabolism (IEMs) often result from single-gene mutations and collectively cause liver dysfunction in neonates leading to chronic liver and systemic disease. Current treatments for many IEMs are limited to maintenance therapies that may still require orthotropic liver transplantation. Gene therapies offer a potentially superior approach by correcting or replacing defective genes with functional isoforms; however, they face unique challenges from complexities presented by individual diseases and their diverse etiology, presentation, and pathophysiology. Furthermore, immune responses, off-target gene disruption, and tumorigenesis are major concerns that need to be addressed before clinical application of gene therapy. Areas covered: The current treatments for IEMs are reviewed as well as the advances in, and barriers to, gene therapy for IEMs. Attention is then given to ex vivo and in vivo gene therapy approaches for hereditary tyrosinemia type 1 (HT1). Of all IEMs, HT1 is particularly amenable to gene therapy because of a selective growth advantage conferred to corrected cells, thereby lowering the initial transduction threshold for phenotypic relevance. Expert opinion: It is proposed that not only is HT1 a safe indication for gene therapy, its unique characteristics position it to be an ideal IEM to develop for clinical investigation.

Use of an adeno‐associated virus serotype Anc80 to provide durable cure of phenylketonuria in a mouse model

“…Based on the similar safety profile and slightly improved efficacy in reducing circulating phenylalanine (particularly in females), these findings favor development of AAV‐Anc80 containing the PAH expression cassette with intron. These data support further development of this and other Anc80‐based AAVs toward consideration of human clinical trials, especially for diseases requiring transduction of a single functional copy of a gene and without localized toxicity at the hepatocyte level 28 …”

“…These data support further development of this and other Anc80-based AAVs toward consideration of human clinical trials, especially for diseases requiring transduction of a single functional copy of a gene and without localized toxicity at the hepatocyte level. 28 F I G U R E 5 Anc80-adeno-associated virus (AAVs) were not associated with changes in cell turnover or apoptosis. A, Percentage of cells that were positive for Ki-67 staining were similarly low in all groups tested, showing no increased cell turnover resulting from transduction with either AAV.…”

Diagnostic and Therapeutic Challenges of Hereditary Tyrosinemia Type 1 in Lebanon: A 12-Year Retrospective Review

“…Given that nitisinone has availability problems and liver transplantation carries risks of surgical complications, there is a need for new, effective, and less expensive treatments, especially for developing countries. Other therapeutic options are currently being explored for this disease, such as the use of molecular chaperones (35) and gene therapy (36).…”

Designer organs: The future of personalized transplantation

“…The use of mesenchymal stem cells (MSCs) has also been explored in SOTs as a method of modulating the inflammatory response and attenuating tissue damage, and their addition to machine perfusate in discarded human and animal models has been tested in lung, kidney, and liver preclinical and clinical trials and is thoroughly reviewed elsewhere 65 . Gene therapy strategies in allotransplantation can also be used to correct genetic deficiencies, inborn errors of metabolism, or clotting disorders in donor organs that are associated with an increased risk of graft loss 66 …”

“…65 Gene therapy strategies in allotransplantation can also be used to correct genetic deficiencies, inborn errors of metabolism, or clotting disorders in donor organs that are associated with an increased risk of graft loss. 66 Gene silencing strategies have also been implemented in organ transplantation to modulate gene expression at the messenger RNA (mRNA) and protein level. Specifically, RNA interference (RNAi) is a powerful, clinically-established therapeutic technology that enables the repression of disease-associated or overexpressed genes by knocking down the level of target mRNA and thus subsequent protein, and its use in the clinical setting is established.…”