Project: Research project

Project Details


Background: Interleukin-1 (IL-1) is an important intra-articular mediator of the pathophysiology of osteoarthritis (OA) and thus a promising therapeutic target. The IL-1 receptor antagonist (IL-1Ra) is a naturally occurring inhibitor of IL-1 and thus a potential therapeutic agent for treating OA. It is also safe. However, because of the pharmacokinetics of joints, IL-1Ra is impossible to deliver to joints at sustained therapeutic concentrations. Local gene delivery to the joint promises to overcome this barrier by enabling sustained, endogenous synthesis of IL-1Ra. Preclinical studies have developed a recombinant adeno-associated virus (AAV) vector for delivering IL-1Ra cDNA to the joint by intra-articular injection. This vector (sc-rAAV2.5IL-1Ra) has proved safe in rigorous pharmacology/toxicology/biodistribution studies in rats under Good Laboratory Practices conditions; confirmatory experiments have been conducted in horses. The vector has also shown efficacy in rat and horse models of OA. This study seeks to perform a Phase I, safety study in human subjects.Rationale: IL-1 is a mediator of pathophysiology in joints with OA. Its naturally occurring inhibitor IL-1Ra thus holds therapeutic promise but is impossible to deliver to joints at sustained therapeutic concentrations because its intra-articular half-life is only a few hours. Transfer of IL-1Ra cDNA to cells within the joint promises to solve this delivery problem. We have developed a vector (scrAAV2.5IL-1Ra) that, when injected into the knee joint of experimental animals, results in the sustained, local synthesis of IL-1Ra by resident cells. It also proved safe. We now wish to confirm safety and synthesis of IL-1Ra after intra-articular injection of sc-rAAV2.5IL-1Ra.Specific Aims and Objectives: (1) To obtain regulatory permission to conduct a Phase I study in the gene therapy of osteoarthritis. This includes approval from the Food and Drug Administration (Investigational New Drug), Recombinant DNA Advisory Committee, and Institutional Review Board. (2) To inject the vector sc-rAAV2.5IL-1Ra into one knee joint of nine subjects with moderate OA at low (three subjects), medium (three subjects), and high (three subjects) dose. (3) To follow each subject for 1 year to assess safety, immune reaction to the vector, transgene expression, possible anti-inflammatory effects, and disease activity.Study Design: This study is an open-label, uncontrolled, Phase I trial of the safety and tolerability of scrAAV2.5IL-1Ra when introduced by intra-articular injection into human knee joints with moderate OA. Subjects will be screened at the Mayo Clinic. Once consent has been obtained, baseline values will be established and qualifying subjects will receive a single, intra-articular injection of sc-rAAV2.5IL-1Ra into the index knee joint. Subjects will undergo periodic clinical evaluation for 12 months. Subjects will be evaluated for safety, IL-1Ra expression, immune responses to the vector, presence of vector genomes in blood, changes in inflammatory mediators, clinical symptoms (Western Ontario McMaster Universities OA Index; Visual Analog Scale), and radiologic changes (X-ray; magnetic resonance imaging).Clinical Impact: Over 27 million Americans have OA, a disease whose prevalence is higher in military personnel. It is incurable, very difficult to treat, and a leading cause of disability; it costs the economy over $100 billion per year. If sc-rAAV2.5IL-1Ra is therapeutic in even a subset of patients, it will dramatically improve the quality of life of large numbers of civilian and military personnel and help alleviate a major medico-economic problem.Relevance to Fiscal Year 2015 Peer Reviewed Medical Research Program Topic Areas Osteoarthritis and Post-Traumatic Osteoarthritis: This study will evaluate a novel therapeutic for OA, both idiopathic and post-traumatic, in a Phase I clinical trial.

Effective start/end date9/1/168/31/20


  • Congressionally Directed Medical Research Programs: $4,889,678.00


Explore the research topics touched on by this project. These labels are generated based on the underlying awards/grants. Together they form a unique fingerprint.