Gout is a prevalent inflammatory arthritic disease that affects 8.3 million people in the US. As current treat- ments are often inadequate, the impact of gout on the economy is a substantial burden. Gout develops when excessive levels of uric acid accumulate in tissue and form crystalline deposits in various joints, causing excru- ciating pain and inflammation. Without treatment, the disease can lead to more frequent and protracted poly- arthritis attacks that eventually result in permanent joint damage. Gout flares are typically treated via NSAIDs, colchicine, or corticosteroids, but >60% of gout patients suffer co-morbidities or drug contraindications that pre- clude use of these first line therapies. Interleukin-1 (IL-1) is a pro-inflammatory cytokine indicated as a key player in mediating gout. Current IL-1 receptor inhibitors (like anakinra), do not share the same contraindica- tions with first line therapies and offer an alternative treatment strategy to reduce inflammation and joint dam- age caused by gout. However, while anakinra treatment shows favorable results in otherwise recalcitrant gout flares, its utility is limited as a subcutaneous and intra-articular injectable due to its short half-life (20 min-4hrs), rapid clearance, and high concentrations required (100 mg/day). A method to effectively deliver anakinra, to reduce the severity of gout flares and prevent further attacks would significantly reduce the rate of outpatient visits, hospital admissions, and overall economic burden resulting from this disease. To overcome the limitations of current delivery platforms, Dianomi Therapeutics (Madison, WI) has devel- oped a mineral coated microparticle (MCM) for sustained protein delivery that maintains protein activity, stabi- lizes protein structure, and has a high protein loading capacity, which will increase efficacy, decrease cost of treatment, improve patient satisfaction and compliance, improve safety, and reduce side effects through sus- tained delivery. In this Phase I STTR, we will demonstrate the feasibility of our approach by (1) engineering MCMs to release active anakinra in synovial fluid and demonstrate sustained delivery of a therapeutic dose following a single intra-articular injection of rats, and (2) explore the traditional dose requirements of anakinra used to ameliorate symptoms and reduce occurrences of arthritic gout flares. Successful completion will lead to Phase II trials using our protein delivery platform. The proposed studies will also suggest that approved ther- apeutics for treatment of inflammatory pathologies, extending beyond anakinra and gout, can be more effec- tively delivered using Dianomi TherapeuticsÂ’ MCM delivery method.
Public Health Relevance Statement: Narrative The overall goal of this Phase I STTR project is to demonstrate the in vivo feasibility to deliver anakinra by mineral coated microparticles in order to reduce symptoms and prevent recurrences of gout flares. Development of mineral coated microparticles to augment anakinra delivery will lead to improved dosing regimens, reduced patient side-effects, and increased efficacy, that overall enhances patient experience and treatment outcomes.
Project Terms: Adrenal Cortex Hormones; Affect; Aftercare; alternative treatment; anakinra; Anti-Inflammatory Agents; Antibodies; Arthritis; Biological Products; Cells; Chronic; Client satisfaction; Colchicine; comorbidity; compliance behavior; cost effectiveness; crystallinity; Custom; cytokine; Data; Deposition; Development; Disease; Dose; Economic Burden; efficacy testing; Employee; Engineering; Environment; experience; FDA approved; Flare; Future; Goals; Gout; Half-Life; Hospitalization; immunogenic; immunogenicity; improved; In Vitro; in vivo; Inflammation; Inflammatory; Inflammatory Arthritis; inhibitor/antagonist; Injectable; Injections; Interleukin-1; Interleukin-1 Receptors; Interleukin-6; Intra-Articular Injections; joint inflammation; joint injury; Joints; Kinetics; Knee; Lead; macrophage; Measurement; Mediating; Methods; microsphere encapsulation; Minerals; Modeling; neutrophil; Non-Steroidal Anti-Inflammatory Agents; Outpatients; Pain; Pathology; patient population; Patients; Pharmaceutical Preparations; Phase; phase II trial; Polyarthritides; Polymers; prevent; Prevention; prophylactic; protein aggregation; Protein Conformation; protein structure; Proteins; Rattus; Recurrence; reduce symptoms; Regimen; Rodent Model; Safety; Scientist; Senior Scientist; Serum; Severities; side effect; Small Business Technology Transfer Research; standard of care; Structure; subcutaneous; Symptoms; Synovial Fluid; System; T-Lymphocyte; Technology; Testing; Therapeutic; Therapeutic Effect; therapeutic protein; Therapeutic Uses; Time; Tissues; TNF gene; Treatment Cost; Treatment Efficacy; Treatment outcome; treatment response; treatment strategy; Universities; Urate; Uric Acid; Visit; Wisconsin; Work
