Westley Reeves

Recombinant Adeno-Associated Virus (rAAV) Vector Expressing Serine Proteinase Inhibitor 1 for Inhibiting Multiple Targets in the Inflammatory Cascade

This recombinant AAV vector encoding a serine proteinase inhibitor (Serp-1) downregulates inflammation by targeting and inhibiting human serine proteinase enzymes. Inflammatory disorders, including lupus, diffuse alveolar hemorrhage, macular degeneration, transplant vasculitis, uveitis, hemorrhagic vascular disease, lung ischemia reperfusion, and inflammatory vasculitis, permeate a vast range of tissue and organ systems. An unusual complication of lupus, diffuse alveolar hemorrhage characterized by lung blood vessel inflammation, occurs in about 3 percent of diagnosed patients and ultimately results in about a 50 percent mortality rate. Additionally, inflammation of the retina is a contributing factor in several of the leading causes of vision loss, such as diabetic retinopathy, age-related macular degeneration, and recurrent uveitis. Due to the complexity of these and other inflammatory diseases, few treatment options are available. Cellular inflammatory responses are promoted by signaling molecules such as serine proteinases. Consequently, the dysregulation of serine proteinases is associated with inflammatory disorders.

Researchers at the University of Florida have created a recombinant AAV-vector encoding a serine proteinase inhibitor (Serp-1), which downregulates inflammation by targeting and inhibiting human serine proteinase enzymes. The potent anti-inflammatory action of Serp-1 encoded in the rAAV renders this therapeutic an effective treatment for inflammatory disorders across several body systems. The capacity for localized or systemic delivery of this rAAV makes it a highly scalable gene therapy.

Application

Recombinant adeno-associated virus vector expressing Serp-1 for the treatment of inflammatory disorders

Advantages

• Non-invasive gene therapy for inflammation that provides lifetime therapeutic effect after one treatment, eliminating the need for recurrent and long-term treatments such as injections and pills
• Multiple possible routes of administration (intranasal, topical, intraocular injection, intravenous injection), improving therapeutic bioavailability and reliable dosage
• Inhibition of multiple members of the inflammatory cascade, resulting in decreased frequency and severity of inflammatory disease signs and symptoms

Technology

This recombinant adeno-associated virus (rAAV) vector encodes and delivers a serine proteinase inhibitor (Serp-1) delivery to target sites, which serves as an effective treatment for inflammatory disorders for which there are currently no effective treatment options. Here, an expression cassette engineered to express serp-1 is packaged into a rAAV vector, which is delivered to the target tissue (for example, eye, lung, heart, liver, transplant site) where Serp-1 is expressed to reduce inflammation by targeting several members of inflammation cascade. Preliminary results in a uveitis mouse model indicate a significant reduction in inflammation. Additional results in a systemic lupus mouse model of diffuse alveolar hemorrhage show increased animal survival and reduced lung hemorrhage in response to treatment. Finally, results from tests in the persistence-induced lupus mouse model demonstrated improved survival and reduced lung hemorrhage with treatment. In a Phase II clinical trial, serp-1 therapy proved safe at 7 trial sites in the US and Canada and reduced markers of heart damage in trial participants.