Current status of gene therapy for α-1 antitrypsin deficiency

Abstract

Introduction: As a common monogenic disease, α-1 antitrypsin (AAT) deficiency has undergone thorough investigation for the development of gene therapy. The most common pathology associated with AAT deficiency occurs in the lung, where the loss of function due to impaired secretion of mutant AAT prevents the inhibition of neutrophil elastase and leads to loss of elastin content from the alveolar interstitium.

Areas covered: Current treatment in the USA consists of recurrent intravenous protein replacement therapy to augment serum AAT levels. In an attempt to replace recurring treatments with a single dose of gene therapy, recombinant adenovirus, plasmid, and recombinant adeno-associated virus (rAAV) vectors have been investigated as vectors for transgene delivery.

Expert opinion: Large strides in gene therapy for AAT deficiency lung disease have led to the development of rAAV1-AAT capable of producing sustained serum AAT levels in clinical trials after intramuscular administration in humans at 3% of the target level. Further increases in levels are anticipated as limb perfusion targets greater muscle mass. The future roles of intrapleural and airway delivery, miRNA-expressing vectors, iPS cell platforms, and genome editing are anticipated.

Keywords:

• adeno-associated virus
• α-1 antitrypsin
• emphysema
• gene therapy
• liver disease
• vectors

Declaration of interest

T Flotte was a founder of Applied Genetic Technologies Corporation (NASDAQ:AGTC) but donated founder equity to the Alpha One Foundation, who subsequently transferred it to AlphaNet. He also serves as a Scientific Advisor to Dimension Therapeutics (in which he holds equity) and Editas Medicine, and may be entitled to royalties as an inventor of some technology described here. 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.

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