Preclinical studies of HAE gene-editing therapy promising
P-KLKB1-101 is designed to control activation of kallikrein-bradykinin pathway
An investigational gene-editing therapy for hereditary angioedema (HAE) called P-KLKB1-101 showed it could safely work as intended in preclinical studies, according to recent data.
The treatment, developed by Poseida Therapeutics, successfully edited the KLKB1 gene and lowered levels of the kallikrein enzyme across experiments in lab-grown human liver cells, mice, and nonhuman primates. Kallikrein is needed for producing bradykinin, the protein that mediates HAE swelling attacks, so P-KLKB1-101’s mechanism of action should help prevent them.
The findings were presented by Blair Madison, PhD, Posieda’s chief scientific officer of gene therapy, at the American College of Allergy, Asthma & Immunology 2024 Scientific Meeting in Boston. The talk was titled “Highly Specific Non-Viral Gene Editing with P-KLKB1-101 for Hereditary Angioedema.”
“The newest preclinical data for P-KLKB1-101 support our goal to develop a gene editing treatment option for HAE with encouraging early tolerability, safety, and efficacy results,” Madison said in a company press release.
In HAE, recurrent swelling attacks occur in the deep layers of the skin and mucus membranes. The disease is caused by genetic mutations that result in a signaling cascade called the kallikrein-bradykinin pathway becoming overactive.
While each type of HAE has a different genetic underpinning, the end result is always an overproduction of bradykinin, a molecule involved in inflammation and blood pressure control. Bradykinin causes blood vessels to relax and become more permeable. When it’s present at excessive levels, fluid leaks out of blood vessels into surrounding tissues, leading to swelling.
What is P-KLKB1-101?
P-KLKB1-101 is an investigational nonviral gene-editing therapy designed to control the activation of the kallikrein-bradykinin pathway to lower bradykinin production and prevent swelling attacks. It’s designed to deliver Poseida’s Cas-CLOVER gene-editing tool specifically to liver cells, where it edits the KLKB1 gene, which codes for a precursor of kallikrein, in order to suppress its activity.
By making KLKB1 inactive, P-KLKB1-101 should reduce kallikrein levels, stopping the chain of events that leads to bradykinin production and providing sustained prevention of HAE swelling attacks.
In a previous company webcast, Poseida indicated its Cas-CLOVER technology has around 20 times higher fidelity than standard Cas9-based gene-editing tools, meaning it’s less likely to modify sections of DNA it isn’t supposed to, thereby minimizing the risk of off-target safety effects.
Moreover, unlike other gene-editing approaches, P-KLKB1-101 doesn’t rely on a viral carrier to deliver the gene-editing machinery to cells. Instead, the machinery is packaged up into tiny spheres of fatty molecules, called lipid nanoparticles (LNPs). A single dose should have lasting effects, but this approach makes it safer to re-dose if necessary, according to the company.
Reduced kallikrein levels with P-KLKB1-101
The recently presented results showed P-KLKB1-101 led to highly efficient KLKB1 gene editing and kallikrein reduction in lab-grown human liver cells. Off-target gene editing was very low in these cells, occurring at a rate of no more than 0.1%, even with high doses.
In a mouse model engineered to have certain human features, P-KLKB-101 led to dose-dependent reductions in kallikrein levels and enzyme activity. A single dose effectively resulted in the desired level of KLKB1 editing and the minimally effective dose of 0.125 mg/kg resulted in a 58% drop in kallikrein protein levels. As of the last assessment, kallikrein level reductions had remained stable for up to six months.
“We achieved a highly effective, therapeutically relevant reduction of kallikrein in our new humanized preclinical mouse model,” Madison said.
The treatment was also well tolerated and didn’t lead to any signs of liver toxicity.
Poseida has started testing the gene therapy in nonhuman primates, which is an important step for establishing a therapy’s safety and pharmacological properties before human studies are initiated. Interim data shows P-KLKB1-101 was tolerated well and led to gene editing in the liver that was within “the desired therapeutic range,” the company states.
“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 … LNP in preclinical studies,” Madison said.
About the Author
