controlled release of treatments in the target joints. Confining anti-cytokine or any anti-inflammatory treatment to specific joints could potentially prevent the side-effects observed with a more classic biologic treatment plan 94. Virus-related delivery systems might provide superior performance over classical delivery systems but, clearly, safety aspects (e.g. immunogenicity of the vector, off-target and long-term effects) have to be taken seriously and analyzed carefully in relation to effectiveness before considering any kind of genetic therapy 95. In general, data from an equine study using AAV2.5-delivered IL-1Ra showed promising results regarding pharmacodynamics and safety profile 96. As mentioned above, first-in-human clinical trials will evaluate the safety profile of gene-related therapies and will give a general hint regarding the applicability of gene therapies for OA. Apart from structural deterioration in OA joints, pain is a dominant and probably the most debilitating hallmark of OA pathology and the a priori reason why patients see a physician. Huge effort has been put into OA-related pain research to identify underlying mechanisms, but, because of its complexity, no general guidelines could be identified for its effective treatment 97, 98. The sensation of pain in OA does not show uniform appearance among patients and during progression. The source of OA pain includes nociceptive pain komma inflammatory pain and neuropathic pain as well as processes of peripheral and central sensitization. Structural features like BMLs, synovitis, and joint effusion show a strong association with pain intensity 63, 99, 100. Classical treatments include the use of acetaminophen (paracetamol), NSAIDs, and opioids, which induce a plethora of unwanted side effects. Here komma we will discuss the latest developments in therapies directly targeting neuronal structures to alleviate OA pain. Anti-nerve growth factor antibody treatment A huge effort has been made in the development of therapeutics targeting nerve growth factor (NGF). NGF might be released upon mechanical stimulation or inflammatory mediators from different cell types including osteoclasts, osteocytes, chondrocytes, synovial fibroblasts, and macrophages in pre-clinical OA studies and human OA 100– 105. After the first promising clinical tests using anti-NGF antibodies, the FDA stopped ongoing trials owing to reports of serious adverse side effects with fast progression of OA and increased demand for knee replacement surgery. After the identification of risk factors (NSAID use) and dose modifications, the hold was lifted in 2015 and clinical trials continued (extensively reviewed in 106, 107). A new phase III trial of knee and hip OA using subcutaneous injections of tanezumab (monoclonal anti-NGF antibody) displayed modest improvements in pain and functional scores compared to control but again raised safety concerns after increased need for total joint replacement in the tanezumab group 33. Active immunization against NGF might provide a new alternative to target chronic pain, as demonstrated in murine OA 108. Although initial trials using anti-NGF antibodies looked promising, further studies are needed to warrant treatment safety. Anti-nerve growth factor receptor strategy New strategies to inhibit NGF-induced pain concentrate on the antagonization of its receptors tropomyosin-related kinase A (TrkA) and p75 NTR. TrkA inhibition effectively reduced pain behavior in several pre-clinical OA models 109, 110. Various molecules have been developed to target the TrkA receptor: pan Trk inhibitor GZ389988 (NCT02424942 and NCT02845271), AR786 (allosteric selective TrkA inhibitor), ASP7962 (TrkA receptor antagonist, NCT02611466 111), ONO-4474 (pan Trk inhibitor), and VM902A (allosteric TrkA selective inhibitor). Only GZ389988 exhibited modest pain reduction compared to control after 4 weeks but no prolonged efficacy after 12 weeks 34 ( Table 1D). NGF receptor p75 NTR concentration is increased in the blood, synovial