Thread by @yaireinhorn

1/@BeamTx has recently reported new preclinical data demonstrating the ability of its in vivo drug candidate $BEAM-302 to directly correct the PiZ mutation - the primary disease-causing mutation associated with severe alpha-1 antitrypsin deficiency (AATD). #BioTech #CRISPR $XBI

2/Alpha-1 antitrypsin deficiency (AATD) is the lack of a protein made by the patient’s liver. AATD is a genetic disease that can affect both the patient’s liver or the lung. Lung problems typically begin at the age of 20-50 and can include shortness of breath, wheezing, or an increased risk of lung infections.

3/Each individual carries 2 copies of his DNA code - one from each of his parents. AAT deficiency is caused when there is an error or abnormality in the SERPINA1 gene in one of the genes. A person who carries two copies of the Z allele (ZZ) in each cell has a high risk of developing lung disease (such as emphysema) and liver disease associated with alpha-1 antitrypsin deficiency

4 $BEAM-302 is a liver-targeting lipid-nanoparticle (LNP) formulation of base editing reagents designed to precisely perform a one-time A-to-G correction of the PiZ mutation, a single-letter genetic error which is the primary cause for severe alpha-1 antitrypsin deficiency (AATD)

5/At first @beamtx’s scientific team used an NSG-PiZ mouse model of AATD which carried >10 copies of the human PiZ allele. But since humans have only 2 copies of the gene - the mouse model wasn’t enough and a more suitable model was needed in order to measure the exact outcomes.

@BeamTx 6/In order to imitate the human physical conditions needed to test $BEAM-302’s efficacy - @BeamTx’s scientists have created a novel PiZ rat model by knocking out wild type PiM alleles and inserting mutant PiZ alleles thus creating a humanized PiZ rat model with only 2 PiZ copies.

7/When compared to pre-dose values - #GeneEditing with $BEAM-302 yielded two-times higher levels of total serum AAT and a 70% decrease in serum Z-AAT in rats. In addition four-times higher levels of total serum AAT & a 90% decrease in serum Z-AAT were observed in mice.

8/Another encouraging outcome which demonstrates $BEAM-302’s potential as a one and done treatment for severe alpha-1 antitrypsin deficiency (AATD) is the reduction that was observed after the use of $BEAM-302 in toxic liver aggregates - also referred to as liver polymers.

9/Another important find was that when compared to pre-dose values, #GeneEditing with $BEAM-302 yielded two-and three-times higher functional AAT in rats and mice, respectively, as indicated by the increased capacity of serum samples to inhibit human neutrophil elastase.

10/The recent readout supports the potential of $BEAM-302 to efficiently correct the disease-causal PiZ mutation after a single dose thus addressing both liver & lung diseases associated with AATD. @BeamTx intends to submit an IND & initiate BEAM-302 clinical trial in 1Q of ‘24

Please feel free to #share, #retweet or #Bookmark this 🧵 so that those on @X - who are interested in #GeneEditing, #CRISPR, #BioTech & #Genomics will be able to access this resource and as always I would be more than happy to read your thoughts.

https://twitter.com/yaireinhorn/status/1703459066318598244