Base editing for Precise and Specific Elimination of Lipoprotein(a)

Lipoprotein(a) (Lp(a)) is a causal risk factor for cardiovascular disease (CVD), and currenttherapeutic options are limited. Commercial efforts are currently underway to develop one-timegene editing interventions aimed at permanent inactivation of the LPA gene in the livers of highrisk patients. In our previous work, we demonstrated that adeno-associated virus (AAV) deliveryof CRISPR/Cas9 could reduce liver and plasma apolipoprotein(a) (apo(a)) to undetectablelevels in an LPA transgenic mouse model. However, due to the highly repetitive nature of thetargeted genomic region, we observed frequent chromosomal rearrangements in the treatedanimals - including large deletions, inversions, and AAV genome insertions. Consequently, wehypothesized that cytosine base editing (CBE) could be used to more precisely introducepremature stop codons in LPA to decrease Lp(a) levels, while circumventing double-strand DNAbreaks and the associated deleterious chromosomal rearrangements.