Gene therapy for Fabry disease: Progress, challenges, and outlooks on gene-editing

Mol Genet Metab Sep-Oct 2021;134(1-2):117-131. doi: 10.1016/j.ymgme.2021.07.006. Epub 2021 Jul 21.

PMID: 34340879

Jakob M Domm, Sarah K Wootton, Jeffrey A Medin, Michael L West

Highlights: This review focuses on the current state of gene therapy as it is being developed for Fabry disease, including progresses and challenges as well as an overview of gene-editing and how it may be applied to correct Fabry disease-causing mutations in the future.

Abstract

Background: The transfer of a therapeutic gene for endogenous cellular expression with the purpose of rescuing a disease phenotype is referred to as gene therapy. It's being utilized to treat a growing number of human diseases, with many approaches proving to be safe and effective in clinical trials. Gene delivery may be viral or non-viral, performed in vivo or ex vivo, and relies on gene integration or transient expression; all of these approaches have been used to treat Fabry disease. Fabry disease is a genetic disorder affecting the α-galactosidase A gene (GLA), which results in an accumulation of glycosphingolipids in cells, causing damage to the heart, kidneys, and brain, as well as death. There are currently no curative treatments available, and those that are accessible have substantial downsides. Because of these issues, gene treatments for Fabry disease have become available. The first Fabry patients to receive gene therapy had their hematopoietic stem/progenitor cells targeted by a recombinant lentivirus. Treatments of adeno-associated virus have also begun. Gene editing, on the other hand, is a very new and quickly expanding field. Repairing disease-causing mutations or inserting genes into cellular DNA have both been accomplished using gene editing. If the issues about gene-editing technologies, such as safety and efficiency, are resolved, these approaches have the potential to be used to treat Fabry disease.

Objective: This study focuses on the current state of gene therapy for Fabry disease, covering advancements and problems, as well as a look at gene editing and how it might be used to correct Fabry disease-causing mutations in the future.

Keywords: Fabry disease, Gene editing, Gene therapy, Lysosomal storage disease