Poseida Therapeutics’ gene therapy for hereditary angioedema (HAE) reduced kallikrein protein activity in a mouse model of the disease and edited a gene in the livers of nonhuman primates, the company said in an Oct. 24 release.
The data are set to be presented on Oct. 26 at the American College of Allergy, Asthma & Immunology annual meeting in Boston.
HAE can be caused by mutations in genes that lead to increased production of a protein called bradykinin, which causes swelling attacks. Poseida’s therapy is meant to permanently disrupt a gene that makes a precursor to the protein kallikrein, which helps make bradykinin. This precursor protein, prekallikrein, is made in the liver by the KLKB1 gene.
The gene therapy, called P-KLKB1-101, edited KLKB1 to therapeutic levels in mice with just a single dose, the company said in the release. At the minimally effective dose of 0.125 milligrams per kilogram, kallikrein levels were reduced in the mouse model by 58% for at least 180 days. The levels of gene editing seen in the nonhuman primate model approached therapeutic levels, Poseida added.
P-KLKB1-101 is delivered using lipid nanoparticles, and the gene edits are done using an enzyme called a Cas-CLOVER nuclease. This system is highly specific and can potentially home in on targets 25 times more reliably than the CRISPR-Cas9 approach, according to a 2022 study.
“These tools could potentially enable therapeutic gene editing in other liver-relevant targets, considering the high fidelity editing of Cas-CLOVER and the promising delivery efficiency we are seeing with our proprietary lipid and LNP in pre-clinical studies," Poseida's chief scientific officer of gene therapy, Blair Madison, Ph.D., said in the release.
Poseida is not alone in going after the KLKB1 gene. Intellia also reported today that its in vivo CRISPR gene therapy targeting the same gene reduced monthly attacks in HAE patients by 81% compared to placebo in a phase 2 trial.