Intrapleural Administration of an AAVrh.10 Vector Coding for Human α1-Antitrypsin for the Treatment of α1-Antitrypsin Deficiency

Abstract

Alpha-1 antitrypsin (α1AT) deficiency is a common autosomal recessive disorder characterized by a marked reduction in serum α1AT levels, lung and liver disease. α1AT is mainly produced and secreted by hepatocytes, with its primary function to protect the lung against the proteolytic activity of neutrophil elastase. Serum α1AT levels <11 μM are associated with progressive destruction of lung parenchyma and early-onset of panacinar emphysema in the age range 35-45. The current approved treatment for α1AT deficiency is a costly protein augmentation therapy requiring weekly intravenous infusion of purified α1AT from pooled human plasma. Gene therapy offers the advantage of a single vector administration, eliminating the burden of the repeated purified protein infusions, with the consequent reduced overall drug cost and improved compliance. We have developed a novel, highly efficient gene therapy approach for α1AT deficiency based on the administration of AAVrh.10hα1AT, an adeno-associated viral vector serotype rh.10 coding for normal M-type human α1AT via the intrapleural route. On the basis of prior murine studies, this approach provides sustained α1AT proximal to the lung with a highly efficient vector. In support of a clinical trial for this approach, we carried out a study to assess the safety of intrapleural administration of AAVrh.10hα1AT to 280 mice and 36 nonhuman primates. The data demonstrate that this approach is safe, with no toxicity issues. Importantly, there was persistent expression of the human α1AT mRNA in chest cavity cells for the duration of the study (6 months in mice and 1 year in nonhuman primates). Together, these data support the initiation of a clinical trial of intrapleural human AAVrh.10hα1AT for the treatment of α1AT deficiency.

Gene Therapy for Alpha-1 Antitrypsin Deficiency Lung Disease

“…Importantly, similar levels were achieved in serum lung ELF, demonstrating "biochemical efficacy." In a safety and toxicology study, the AAVrh.10 delivered by the intrapleural route was shown to be safe in studies with 280 mice and 36 nonhuman primates (149). The intrapleural vector transfer resulted in high levels of human AAT messenger RNA localized to the proximity of the lung that persisted for at least 6 months in mice (149) and for at least 1 year after a single vector administration in nonhuman primates (149), the entire length of the study ( Figure 6).…”

“…In the case of parietal pleura, the lymphatic system connects directly to the pleural space through stomata, a mechanism for systemic distribution of the gene therapy vector to primarily the liver after intrapleural delivery ( Figure 4A) (138,139,148). Another advantage of targeting the pleura for gene therapy is the low risk of adverse effects of any inflammation induced by the gene therapy vector, as demonstrated in a safety and toxicology study (149).…”

Challenges and Prospects for Alpha-1 Antitrypsin Deficiency Gene Therapy

“…Other modifications have focused on the promoter, method, and optimal application site to supply a high level of transgene expression. 66,67,[70][71][72][73][74][75][76][77] Efficiency of AAT expression at the rAAV application site. The first study using rAAVs in AATD was conducted in 1998.…”

“…76 The preclinical study demonstrated that intrapleural administration of the carrier allowed for the detection of AAT mRNA for 6 months in 280 mice and 1 year in 36 nonhuman primates, with no side effects. 77 AAVs in AATD experimental treatment: summary. Numerous studies have demonstrated that the therapeutic effect depends on multiple factors, such as AAV serotype, prior exposure to virus, and administration site.…”

Progress with Recombinant Adeno-Associated Virus Vectors for Gene Therapy of Alpha-1 Antitrypsin Deficiency

“…Another strategy to decrease the immune response might be to select or create a capsid type with lower preexisting immunity or immune profile in humans. 39,40,41 Expression could be potentially increased through codon optimization of the AAT gene or through the use of selfcomplimentary AAV vectors.…”