Peptide-siRNA conjugates: A novel targeted therapeutic approach for the treatment of chronic inflammation and pain in osteoarthritic joints

Osteoarthritis (OA) is a disease occurring in the joints of the body. It is a leading cause of disability, causing pain and loss of movement to over 500 million people worldwide. To date, there are no approved treatments that slow or stop the disease. Current treatments focus on relieving pain, but for many people they are not very effective and often have side effects. As a result, many people continue to experience chronic pain, which may eventually require joint replacement surgery. OA was once thought to be caused by natural “wear and tear” on the joints. However, it is now understood to involve significant inflammation within the joints, particularly in the joint lining. Inflammation is normally beneficial to the body acting over the short term to fight infections or promote healing, but in OA it persists long term and becomes damaging, contributing to cartilage breakdown and joint pain. Our research has found that certain cells in the joint lining, called synovial fibroblasts, are key drivers of this inflammation. These cells become highly active in people with OA, especially those who are obese, producing inflammatory substances that lead to increased pain and joint damage. We have discovered that specific molecules (called COX2, NRN1 and MALAT1) within the joint lining cells trigger joint inflammation and are associated with OA joint pain. We believe that blocking the activity of these molecules will reduce joint inflammation and pain in OA. To achieve this, we propose a new treatment strategy using small interfering RNAs (siRNAs), which are short strands of genetic material designed to switch off specific disease-causing genes. Although siRNAs have been successful in treating other diseases, delivering them to the right cells remains a challenge – something that is critical for ensuring the treatment is safe and effective for OA. To overcome this, we will attach siRNAs to peptides, which are short chains of amino acids. These peptides will guide the siRNA to joint cells by binding to a receptor on the cell surface, thereby minimising the risk of side-effects. Critically, we have identified a receptor, termed receptor X, that is found in large amounts on the surface of synovial fibroblasts and cartilage cells, especially during inflammation. We will develop and test “Receptor X homing” molecules (called conjugates), consisting of peptides that bind Receptor X and siRNAs targeting the inflammation-related molecules COX2, MALAT1 and NRN1. The ability of the conjugates to reduce inflammation and pain markers will first be tested using OA patient cells and tissue samples. The most promising conjugate will be tested in animal models of arthritis to evaluate its effectiveness in reducing pain behaviour and joint inflammation. Our goal is to create a targeted therapy that can be delivered directly to the joint, providing long-lasting pain relief and slowing OA progression without side-effects. This innovative approach could also provide a gateway for the development of new treatments for other inflammatory joint diseases, significantly improving the quality of life for millions of people living with OA and other forms of arthritis.