Liver-directed gene-based therapies for inborn errors of metabolism

ABSTRACT

Introduction

Inborn errors of metabolism include several genetic disorders due to disruption of cellular biochemical reactions. Although individually rare, collectively they are a large and heterogenous group of diseases affecting a significant proportion of patients. Available treatments are often unsatisfactory. Liver-directed gene therapy has potential for treatment of several inborn errors of metabolism. While lentiviral vectors and lipid nanoparticle-mRNA have shown attractive features in preclinical studies and still have to be investigated in humans, adeno-associated virus (AAV) vectors have shown clinical success in both preclinical and clinical trials for in vivo liver-directed gene therapy.

Areas covered

In this review, we discussed the most relevant clinical applications and the challenges of liver-directed gene-based approaches for therapy of inborn errors of metabolism.

Expert Opinion

Challenges and prospects of clinical gene therapy trials and preclinical studies that are believed to have the greatest potential for clinical translation are presented.

KEYWORDS:

• Liver-directed gene therapy
• gene therapy
• clinical trials
• inborn errors of metabolism
• biochemical genetics
• adeno-associated virus

Article Highlights

• Inborn errors of metabolism include a large number of disorders that are typically due to enzyme deficiency. Available treatments are often unsatisfactory.

• Liver-directed gene therapy has potential for long-term treatment of several inborn errors of metabolism.

• AAV, lentiviral vectors and RNA replacement are among the most attractive therapeutic modalities for inborn errors of metabolism.

• Preclinical studies and clinical success in hemophilia clinical gene therapy justifies applications of gene-based therapies in inborn errors of metabolism.

• Several challenges from long-term safety to immune responses, higher efficiency and commercialization remain to be addressed. Multiple solutions addressing these issues are going to be investigated in the next years.

Reviewer disclosures

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

Declaration of interest

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.

Additional information

Funding

N Brunetti-Pierri and P Piccolo are supported by Telethon Foundation, Italy.