Optimized Gene Therapy for Hereditary Angioedema

Background & Unmet Need

• Hereditary Angioedema (HAE) is a genetic disorder in which patients experience acute episodic swelling, often in the face, limbs, GI tract, or airway
• HAE is caused by mutations in the SERPING1 gene, leading to a deficiency in C1 esterase inhibitor (C1EI) or inactive forms of this protein
• Complications of HAE include asphyxiation or death due to swelling of the airway, as well as pain, nausea, vomiting, or unnecessary surgery
• Current treatment for HAE are prophylactic, including infusions of replacement C1EI or related vasodilation inhibitors
• Despite prophylactic treatments, there are more than 20 K emergency department visits annually attributable to HAE
• Unmet Need: A one-time treatment eliminating acute swelling episodes from HAE

Technology Overview

• The Technology: A novel AAV vector encoding a functional, human C1EI gene for treatment of HAE
• The Discovery: The team first created and validated a murine model of HAE by inducing CRISPR-mediated deletions in the SERPING1 gene
• An optimized C1EI gene was generated by removing mRNA instability elements, high and low GC regions, splice signals, and in-sequence translation initiation sequences to increase stability of the gene
• An AAVrh.10hC1EI vector encoding the optimized hC1EI gene under a CAG promoter was generated to restore C1EI activity in deficient mice
• PoC Data: Expression of hC1Ei in AAVrh.10hC1EI-treated mice persisted for at least 24 weeks
• Vascular permeability, a hallmark of HAE, was significantly reduced (p<0.05) in rear paws and internal organs of AAVrh.10hC1EI-treated mice at 24 weeks (except for lung and intestines in female mice)

Technology Applications

• One-time gene therapy for Hereditary Angioedema to prevent episodic swelling and resulting complications

Technology Advantages

• Single dose gene therapy improves patient compliance relative to continuous prophylactic regimens
• Quality of life is improved by one-time treatment regimen compared to burdensome chronic treatments