Alpha-1 antitrypsin deficiency: current therapy and emerging targets

ABSTRACT

Introduction

Alpha1 antitrypsin deficiency (AATD), a common hereditary disorder affecting mainly lungs, liver and skin has been the focus of some of the most exciting therapeutic approaches in medicine in the past 5 years. In this review, we discuss the therapies presently available for the different manifestations of AATD and new therapies in the pipeline.

Areas covered

We review therapeutic options for the individual lung, liver and skin manifestations of AATD along with approaches which aim to treat all three. Along with this renewed interest in treating AATD come challenges. How is AAT best delivered to the lung? What is the desired level of AAT in the circulation and lungs which therapeutics should aim to provide? Will treating the liver disease increase the potential for lung disease? Are there treatments to target the underlying genetic defect with the potential to prevent all aspects of AATDrelated disease?

Expert opinion

With a relatively small population able to participate in clinical studies, increased awareness and diagnosis of AATD is urgently needed. Better, more sensitive clinical parameters will assist in the generation of acceptable and robust evidence of therapeutic effect for current and emerging treatments.

KEYWORDS:

• Alpha1 antitrypsin deficiency
• emphysema
• COPD
• cirrhosis
• panniculitis
• gene therapy
• siRNA
• gene editing
• protein folding

Article highlights

• Alpha-1 antitrypsin deficiency is a genetic condition caused by mutations in the SERPINA1 gene.

• We discuss the lung, liver, and skin manifestations of this under-diagnosed condition and highlight improvements in detection and diagnosis.

• Treatment options have been historically limited for the lung, liver and skin manifestations, with lung and liver transplantation a common outcome.

• Current treatments for AATD-related lung disease are similar to treatments for non-AATD lung disease, with the notable exception of augmentation therapy.

• We discuss new and innovative therapies in development, including some that tackle the underlying genetic defect, and discuss future challenges for newer treatment approaches.

Acknowledgments

The authors are grateful to Alpha-1 Foundation Ireland and the Irish Alpha-1 patient community for their constant support and encouragement.

Declaration of Interests

NG McElvaney has received funding for investigator-initiated studies from CSL Behring, Grifols, pH Pharma, Chiesi, funding to carry out pharmaceutical-company initiated studies from Vertex, Kamada, CSL Behring, and participated on advisory boards organized by Vertex, Inhibrx, Intellia, Dicerna. 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 or other relationships to disclose.

Additional information

Funding

This paper was not funded.