Alpha1-Antitrypsin (AAT) is a plasma glycoprotein and was first named by its ability of inhibiting trypsin. As a protease inhibitor, it protects tissues from enzyme especially neutrophil elastase, which destroys bacteria and host tissues during inflammation.
When there is inadequate AAT or functionally defective AAT in the blood (AAT deficiency), neutrophil elastase disrupts elastin and degrades elasticity of lung, resulting in respiratory complications such as pulmonary emphysema in adults. Defective AAT often fails to enter systemic circulation but stays in liver, which causes cirrhosis in both adults and children.
AAT deficiency, caused by a mutation in the SERPINA1 gene encoding the protein, is one of the most common genetic diseases in US. The only available specific therapy for AAT deficiency is weekly or biweekly intravenous injection of enriched AAT. Prolastin, Zemaira, Glassia, and Aralast are tradenames of purified AAT products from human plasma approved by FDA to treat AAT deficiency. Unfortunately, long-term therapy currently is not available.
When AAT deficiency patients experience shortness of breath, wheezing or liver failure, they may not know these symptoms are mostly caused by one single base pair substitution (Glu342Lys) of SERPINA1 in their genome. If this single point mutation is corrected, AAT level in blood will be restored, providing long-term therapeutic benefits to patients.
A recent study reported that AAT level was partially restored in an AAT deficiency mouse model using CRISPR mediated genome editing technology. CRISPR (clustered regularly interspaced short palindromic repeats) as a powerful genome editing tool contains two components: single guide RNA (sgRNA) and Cas9 endonuclease. SgRNA guides Cas9 to the specific genomic locus, in this case, SERPINA1 exon 5, then Cas9 works as a molecular scissor and makes a cut. In the presence of a repair template containing the correct sequence, Lys at position 342 is converted to Glu precisely. This research group delivered sgRNA/Cas9/repair template in dual viral vector into AAT deficient mice and observed restoration of 8-12% of suggested therapeutic threshold serum AAT level. This study provides proof of principle for AAT deficiency gene therapy and sheds a light on long-term treatment of patients.
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