Researchers at Beam Therapeutics developed base editing reagents that lead to better genetic correction in a mouse model with alpha-1 antitrypsin deficiency (AATD) and presented their findings at the 25th Annual Meeting of the American Society of Gene & Cell Therapy. 

The most common genetic polymorphism leading to AATD is a G-to-A transition in the SERPINA1 gene, which codes for the alpha-1 antitrypsin (AAT) protein, a neutrophil elastase inhibitor that is essential for lung health. This polymorphism leads to a substitution of lysine with glutamic acid at position 342 of the AAT protein and causes the protein to misfold and aggregate inside the liver where it is mostly produced causing liver fibrosis and cirrhosis.

This G-to-A transition is amenable to adenine base editor correction, a gene-editing construct that is able to perform A-to-G base conversions in the DNA.


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In the present study, a team of researchers led by Francine M. Gregoire, PhD, the senior vice president and head of in vivo programs at Beam Therapeutics improved the gene-editing reagents through protein engineering of the base editor itself, mRNA codon optimization, and chemical modification of the guide RNA.

The team reported that these modifications led to a more than a 2-fold increase in the potency of the resulting lipid nanoparticles. They also resulted in therapeutically meaningful increases in circulating AAT in a mouse model of AATD. Similar efficacy and durability were also seen in older mice in which liver fibrosis has already occurred, a situation similar to what is likely to be seen in the clinic in patients with the disease.

“These results go beyond previous proof-of-concept studies in demonstrating both therapeutic relevance and technical feasibility of base editing as a potential treatment for [AATD],” the researchers concluded. 

Reference

Packer MS, Leboeuf D, Cheng LI, et al. Optimized base editing reagents yield more potent genetic correction in a mouse model of alpha-1 antitrypsin deficiency. Poster presented at: 25th Annual Meeting of the American Society of Gene & Cell Therapy. May 16-19, 2022; Washington DC.