Gene therapy for alpha-1 antitrypsin deficiency: an update

ABSTRACT

Introduction

Altering the human genetic code has been explored since the early 1990s as a definitive answer for the treatment of monogenic and acquired diseases which do not respond to conventional therapies. In Alpha-1 antitrypsin deficiency (AATD) the proper synthesis and secretion of alpha-1 antitrypsin (AAT) protein is impaired, leading to its toxic hepatic accumulation along with its pulmonary insufficiency, which is associated with parenchymal proteolytic destruction. Because AATD is caused by mutations in a single gene whose correction alone would normalize the mutant phenotype, it has become a popular target for both augmentation gene therapy and gene editing. Although gene therapy products are already a reality for the treatment of some pathologies, such as inherited retinal dystrophy and spinal muscular atrophy, AATD-related pulmonary and, especially, liver diseases still lack effective therapeutic options.

Areas covered

Here, we review the course, challenges, and achievements of AATD gene therapy as well as update on new strategies being developed.

Expert opinion

Reaching safe and clinically effective expression of the AAT is currently the greatest challenge for AATD gene therapy. The improvement and emergence of technologies that use gene introduction, silencing and correction hold promise for the treatment of AATD.

KEYWORDS:

• Alpha-1 antitrypsin deficiency
• AAV vectors
• CRISPR-Cas9
• editing guide RNA gene therapy

Article highlights

• Alpha-1 antitrypsin deficiency is characterized by progressive lung and liver disease.

• AATD has historically been treated by augmentation therapy, but this is inadequate for patients.

• Preclinical and clinical studies have investigated several approaches, and gene therapy is the most promising so far.

• Clinical studies to date have not achieved long-lasting expression of the M-AAT protein at endogenous levels, but have markedly reduced levels of the pathogenic Z-AAT protein.

• Current strategies are employing CRISPR technology to simultaneously express the M-AAT allele and silence the Z-AAT allele.

• As technology advances in the gene therapy field and across all areas of biomedicine, there is great reason for optimism in achieving a curative treatment for AATD.

This box summarizes key points contained in the article.

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.

Reviewer disclosures

A reviewer on this manuscript has disclosed that they have consulted for Grifols, CSL, Takeda and Inhibrx and have run trials for Grifols, Arrowhead, Mereo BioPharma, Shire/Baxter/Takeda and Adverum. A reviewer on this manuscript has disclosed that they were an investigator for Adverum in a previous gene therapy study for AATD that ended in 2022. They participate and consult for the companies involved in the gene silencing studies for AAT liver disease. A reviewer on this manuscript has disclosed receipt of consulting fees from Takeda. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

Additional information

Funding

This paper was not funded.