Gene Therapy for Lysosomal Storage Disorders: Ongoing Studies and Clinical Development.

Giulia Massaro,Amy F Geard,Oliver Coombe-Tennant,Ahad A Rahim,Paul Gissen,Julien Baruteau,Simon N Waddington,Wenfei Liu

doi:10.3390/biom11040611

Abstract

Rare monogenic disorders such as lysosomal diseases have been at the forefront in the development of novel treatments where therapeutic options are either limited or unavailable. The increasing number of successful pre-clinical and clinical studies in the last decade demonstrates that gene therapy represents a feasible option to address the unmet medical need of these patients. This article provides a comprehensive overview of the current state of the field, reviewing the most used viral gene delivery vectors in the context of lysosomal storage disorders, a selection of relevant pre-clinical studies and ongoing clinical trials within recent years.

Highlights

Lysosomal storage disorders (LSDs) form a group of genetic errors of metabolism, comprising more than 70 different diseases [1]
This study showed that bipolar cells could be a therapeutic target for several Batten disorders, transduction efficiency of the AAV7m8 vector in human bipolar cells has not yet been assessed
Lysosomal diseases have proven to be fertile ground for the development of gene therapy. This is understandable given the number of conditions, knowledge of the defective gene, the availability of animal models for pre-clinical studies and the frequent absence of effective treatments

Summary

Introduction

Lysosomal storage disorders (LSDs) form a group of genetic errors of metabolism, comprising more than 70 different diseases [1]. These monogenic disorders result from defects in proteins crucial for lysosomal function, such as lysosomal hydrolases, as well as transporters, integral membrane proteins, co-factors and enzyme modifiers or activators [2]. Mutations in non-lysosomal proteins that play a role in lysosome-related processes can cause LSDs. The lysosome is a complex organelle, involved in several cellular processes such as autophagy, signalling cascades, lipid and calcium homeostasis, exocytosis, membrane repair and cell viability [3,4]. Typical LSDs involve accumulation of undegraded substrates in the lysosome due to defective hydrolase enzymes, and classification of the disorder can be based on the nature of the accumulated substrate. LSDs are individually considered rare diseases, some populations have a higher carrier frequency, and the collective prevalence as a group is relatively common, with an estimated incidence of 1 in 5000 live births [1]

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