An update on gene therapy for lysosomal storage disorders

ABSTRACT

Introduction: Gene therapies can be envisioned for many disorders where conventional therapies fall short. Lysosomal Storage Disorders (LSDs) are inherited, mostly monogenic, disorders resulting from deficient lysosomal enzyme or co-factor activity. Existing standard-of-care treatments for LSDs are expensive and can negatively impact quality-of-life. They also may not be sufficiently efficacious. LSDs are particularly amenable to gene therapy as modified cells can secrete functional enzyme that can also correct unmodified cells. Gene therapies may thus be able to provide sustained long-term correction for LSD patients.

Areas covered: We highlight recent advances and discuss advantages/disadvantages of gene therapies with a focus on lentiviral and adeno-associated virus vectors currently in clinical trials for LSDs. We also mention promising strategies that are close to clinical testing. We emphasize protocols using ex vivo hematopoietic stem cell-directed gene therapy, systemic/liver-directed gene therapy, and brain-directed gene therapy. We also discuss next-generation gene therapy approaches and how they may address emerging challenges in the field.

Expert opinion: Gene therapy is still in its infancy with respect to LSDs. However, efficacy and safety has been demonstrated in numerous pre-clinical studies, and promising clinical results suggest that gene therapy treatment for several LSDs is a real possibility.

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KEYWORDS:

• Lysosomal storage disorders
• gene therapy
• lentivirus
• adeno-associated virus
• vectors
• hematopoietic stem cells
• cross-correction
• clinical trials

Article highlights

• LSDs are excellent candidates for gene therapy as transduced cells can secrete lysosomal enzymes that “cross-correct” unmodified “bystander” cells.

• Promising pre-clinical results have warranted the translation of multiple gene therapies for LSDs into the clinic.

• Ex vivo HSC-directed gene therapies are aided by the distribution of the hematopoietic system and may result in systemic correction, including in the CNS.

• In vivo gene therapies may aid in establishing immunotolerance to the transgene product, but also may require repeated administrations.

• CNS-administration of gene therapies may benefit neuronopathic disorders, but may require co-treatment by other administration routes to improve systemic pathology.

• Next-generation approaches are being developed to improve on existing gene therapy strategies, including attempts to reduce vector and transgene immunogenicity, improve blood-brain barrier penetration, and engineer protein/vector for efficient tissue-specific uptake.

This box summarizes key points contained in the article.

Declaration of interest

J Medin has the following financial relationships to disclose: SAB - Rapa Therapeutics. Honoraria - Sanofi Genzyme, Shire. Co-Founder - AVROBIO, Inc. Share Holder - AVROBIO, Inc. The authors have no other 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 apart from those disclosed.

Reviewer Disclosures

Peer reviewers on this manuscript have no relevant financial relationships or otherwise to disclose.

Additional information

Funding

Funding for this article came from the Midwest Athletes Against Childhood Cancer, Inc. (MACC Fund).