Retinoic acid metabolism blocking agents (RAMBAs) to treat hand osteoarthritis

视黄酸代谢阻断剂（RAMBA）治疗手部骨关节炎

• 批准号: MR/S035664/1
• 负责人: Tonia Vincent
• 金额: $ 111.19万
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2020
• 资助国家: 英国
• 起止时间: 2020 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FS035664%2F1
• 关键词: Retinoic; acid; metabolism; blocking; agents

Hand osteoarthritis (OA) is a debilitating condition affecting over 2 million people in the UK that causes pain and swelling in the base of the thumb and small joints of the hands. The condition can affect people's independence, quality of life and ultimately, for some, the ability to work. Currently there is no cure available. The only available drugs used in hand OA are standard pain killers and steroid injections. What causes osteoarthritis remains poorly understood. However, we know that excessive loading of joints (through injury, or over loading), being female and having a family history of the condition are all strong risk factors for developing the disease. The condition arises when pathways typically associated with inflammation are switched on in joint tissues including the articular cartilage of the joint, the smooth lining on the ends of the bones, leading to tissue damage and pain. A gene has recently been linked to hand osteoarthritis which controls the production of retinoic acid (vitamin A) levels in tissues in the body. We have shown that joint injury causes levels of retinoic acid activity to fall in cartilage, and that the drug talarozole, a retinoic acid metabolism blocking agent (RAMBA) prevents that drop. We already knew that joint injury to cartilage in the laboratory switches on inflammation in the tissue, but have shown that the presence of a RAMBA at the time of cartilage injury prevents this increase in inflammation. In patients undergoing hand surgery who donated their waste tissue samples, we have shown that having at least one copy of this gene variant is quite common in hand OA (~75% of those with the condition) and that this variant is associated with lower levels of retinoic acid pathway activity and higher levels of inflammation in joint cartilage compared to those without this gene variant, further supporting an important role for this pathway in the disease. The drug used in our laboratory studies, talarozole has been used in clinical trials of psoriasis and appears safe and well tolerated, but has not made it to the clinic for other conditions. In this experimental medicine study we want to test in patients with hand OA whether talarozole when given by mouth can:1. get into OA joint cartilage 2. normalise levels of retinoic acid and its family members in joint cartilage3. reduce inflammation levels in joint cartilage 4. have any effect on levels of hand pain over a short duration To do this we will ask 44 patients who are undergoing base of thumb surgery for hand OA (an operation that removes the small bone at the base of the thumb, which is usually discarded) to take a drug before their surgery and then donate their surgical tissue sample so that we can measure the drug's effects. Those who agree to take part will be asked to take either talarozole for 14 days before their surgery or a sugar tablet that looks like talarozole, but does not contain active drug (placebo). Our main outcome will be to see if there is a difference in the gene message level of a key retinoic acid family member between those taking the active drug and those taking placebo. (We have identified this readout as reliable from our earlier studies). We will also look at a defined panel of inflammation genes and whether these are lower in those on the active drug. On the day of starting the drug, during the 14 days and on the day of surgery, we will also collect questionnaire information on hand pain and function. The study will run at a single hospital for 3 years, managed by doctors and researchers with a strong track record of research linking the clinic with the laboratory. It is hoped that if this study is successful, that a larger, longer trial testing whether a RAMBA could help pain and disease progression in hand OA could then be undertaken.

手骨关节炎（OA）是一种使人衰弱的疾病，影响英国超过200万人，导致拇指根部和手部小关节疼痛和肿胀。这种情况会影响人们的独立性、生活质量，并最终影响一些人的工作能力。目前没有治愈方法。手部OA唯一可用的药物是标准止痛药和类固醇注射剂。什么原因导致骨关节炎仍然知之甚少。然而，我们知道关节过度负荷（通过损伤或过度负荷），女性和有家族病史的条件都是发展这种疾病的强有力的危险因素。当通常与炎症相关的途径在关节组织中打开时，就会出现这种情况，包括关节的关节软骨，骨骼末端的光滑衬里，导致组织损伤和疼痛。最近，一种基因与手骨关节炎有关，该基因控制着体内组织中维甲酸（维生素A）水平的产生。我们已经证明，关节损伤导致软骨中维甲酸活性水平下降，而药物他拉罗唑（一种维甲酸代谢阻断剂（RAMBA））可以防止这种下降。我们已经知道实验室中软骨的关节损伤会引发组织中的炎症，但已经证明在软骨损伤时RAMBA的存在可以防止炎症的增加。在接受手部手术并捐献了废弃组织样本的患者中，我们发现至少有一个这种基因变异的拷贝在手部OA中是很常见的。（约75%的患有这种疾病的人），并且与没有这种基因变体的人相比，这种变体与关节软骨中较低水平的视黄酸途径活性和较高水平的炎症有关，进一步支持该途径在疾病中的重要作用。在我们的实验室研究中使用的药物，他拉罗唑已被用于银屑病的临床试验，似乎是安全和耐受性良好的，但还没有使其用于临床其他条件。在这项实验性医学研究中，我们想测试手OA患者口服他拉罗唑是否可以：1。进入OA关节软骨2.使关节软骨中维甲酸及其家族成员的水平正常化3.减少关节软骨的炎症水平4.为了做到这一点，我们将要求44名正在接受拇指根部手术治疗手部OA（一种切除拇指根部小骨头的手术，通常被丢弃）的患者在手术前服用药物，然后捐赠他们的手术组织样本，以便我们可以测量药物的效果。那些同意参加的人将被要求在手术前服用他拉罗唑14天，或者服用看起来像他拉罗唑但不含活性药物的糖片（安慰剂）。我们的主要结果将是看看是否有一个关键的维甲酸家族成员的基因信息水平之间的差异，服用活性药物和服用安慰剂。(We已经从我们早期的研究中确定了这一读数是可靠的）。我们还将研究一组确定的炎症基因，以及这些基因在活性药物中是否较低。在开始给药当天、14天期间和手术当天，我们还将收集关于手部疼痛和功能的问卷信息。这项研究将在一家医院进行3年，由医生和研究人员管理，他们在临床和实验室之间有着良好的研究记录。希望如果这项研究成功，那么可以进行更大，更长的试验来测试RAMBA是否可以帮助手部OA的疼痛和疾病进展。