Ex vivo gene therapy for lysosomal storage disorders: future perspectives

ABSTRACT

Introduction

Lysosomal storage disorders (LSD) are a group of monogenic rare diseases caused by pathogenic variants in genes that encode proteins related to lysosomal function. These disorders are good candidates for gene therapy for different reasons: they are monogenic, most of lysosomal proteins are enzymes that can be secreted and cross-correct neighboring cells, and small quantities of these proteins are able to produce clinical benefits in many cases. Ex vivo gene therapy allows for autologous transplant of modified cells from different sources, including stem cells and hematopoietic precursors.

Areas covered

Here, we summarize the main gene therapy and genome editing strategies that are currently being used as ex vivo gene therapy approaches for lysosomal disorders, highlighting important characteristics, such as vectors used, strategies, types of cells that are modified and main results in different disorders.

Expert opinion

Clinical trials are already ongoing, and soon approved therapies for LSD based on ex vivo gene therapy approaches should reach the market.

KEYWORDS:

• Lysosomal storage disorders
• adeno-associated vectors
• lentiviral vectors
• ex vivo gene therapy
• hematopoietic stem cells
• Genome editing

Article highlights

• Lysosomal storage disorders are good candidates for gene therapy protocols

• Different vectors, such as AAV and lentiviruses, can be used for ex vivo gene therapy

• Genome editing is recently being tested as a new ex vivo gene therapy platform

• Ex vivo gene therapy protocols include promising studies for mucopolysaccharidoses, sphingolipidoses, glycogen storage disorders, and even disorders involving lysosomal membrane proteins

Reviewer disclosures

Peer reviewers in this manuscript have no relevant financial or other relationships to disclose.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This paper was funded by grants from the National Research Council (CNPq 442545/2020-7 GB), State Agency of Research (FAPERGS - 22/2551-0000385-0), Fundo de Incentivo a Pesquisa (FIPE/HCPA) and Proadi-SUS (25000.003071/2021-28).