Systemic modified messenger RNA for replacement therapy in alpha 1-antitrypsin deficiency

Area of Science:

• Genetics and Molecular Biology
• Hepatology
• Pulmonology

Background:

• Alpha 1-antitrypsin (AAT) deficiency is an inherited disorder caused by SERPINA1 gene mutations.
• AAT deficiency leads to liver damage and lung emphysema due to uninhibited elastolytic activity.
• Current treatments are limited, with AAT augmentation reserved for advanced lung disease.

Purpose of the Study:

• To evaluate modified mRNA encoding human AAT as a potential therapeutic strategy.
• To assess AAT expression and functional activity in vitro and in vivo.
• To investigate the systemic delivery and efficacy of mRNA-based AAT therapy.

Main Methods:

• Modified mRNA encoding human AAT was tested in primary human hepatocytes (including those from AAT-deficient patients).
• AAT expression and secretion were quantified using ELISA and Western blot.
• Functional activity was assessed via elastase activity assays.
• mRNA formulated in lipid nanoparticles was delivered systemically to wild-type and AAT-deficient mouse models.

Main Results:

• mRNA treatment significantly increased secreted AAT protein levels in cultured human hepatocytes (1.14 to 3.43 µg/ml).
• The translated AAT protein demonstrated protease inhibitory function.
• Systemic intravenous delivery of mRNA in mice resulted in hepatic uptake and functional protein production.

Conclusions:

• Modified mRNA therapy can successfully produce functional AAT protein in human hepatocytes and in vivo.
• Systemic mRNA delivery demonstrates potential for treating Alpha 1-antitrypsin deficiency.
• This approach offers a promising new therapeutic avenue for AAT deficiency patients.