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

Lead Research Organisation: University of Oxford
Department Name: Kennedy Institute

Abstract

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 cartilage
3. 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.

Technical Summary

Pathogenesis of osteoarthritis (OA) remains poorly understood, but there is a general consensus that mechanical load and inflammatory signalling drives tissue catabolism. Hand OA has strong genetic heritability. A recent GWAS identified common polymorphic variants in ALDH1A2 in individuals with severe hand OA. ALDH1A2 codes for the enzyme that is responsible for synthesising retinoic acid. We have shown experimentally that retinoic acid levels drop dramatically in response to mechanical injury of cartilage and maintaining levels of retinoic acid in the chondrocyte at the time of injury with talarozole, a retinoic acid metabolism blocking agent (RAMBA), prevents the up-regulation of injury-driven inflammatory response genes. We have also confirmed this reciprocal relationship in patient tissues by showing that the articular cartilage (removed at time of hand surgery) of individuals homozygous for the high-risk variants had significantly lower levels of ALDH1A2 mRNA and other retinoic acid-dependent genes, whereas key inflammatory genes were increased in these individuals.
In this project we hypothesise that talarozole, by blocking breakdown of retinoic acid, will enhance retinoic acid-responsive genes and suppress OA chondrocyte inflammatory genes in hand OA. We will conduct a randomised, placebo controlled study of talarozole in 44 patients immediately prior to planned surgery for base of thumb OA. Primary outcome will be mRNA levels for a panel of retinoic acid and inflammatory response genes. This study will (i) provide evidence as to whether systemic administration of this class of drug is able to penetrate the joint and modify the retinoic acid pathway in human chondrocytes in vivo; (ii) establish whether augmenting retinoic acid can suppress chondrocyte inflammatory gene regulation in hand OA as a pre-requisite for suppressing pain and degeneration; (iii) provide preliminary data that will be used to design a full clinical trial of a RAMBA in hand OA.

Planned Impact

Patients tell us that they want new drug therapies to manage the pain of hand osteoarthritis (OA) and slow down the progression of disease. This project has identified a putative new target in hand OA and will establish whether it is clinically translatable. If so, this not only represents a new targeted therapy in hand OA, but the first disease modifying treatment in OA of any sort.

Given the high prevalence of hand OA and high unmet clinical need, validation of a new molecular target will have substantial societal and economic impact. This is especially the case when one considers the cost of clinical management and work disability associated with this chronic condition.

A number of strategies will be pursued to ensure that our potential beneficiaries have the opportunity to engage with this research to increase the likelihood of impacts being achieved. These are laid out in detail in our "Pathways to Impact" document. Specific areas of delivery include strong public and patient involvement in the work we are planning. This is exemplified by existing activities through the Centre for OA pathogenesis and strong links with Versus Arthritis. Our multidisciplinary team include investigators involved in hand OA management (rheumatology, hand surgery, physiotherapy), those involved in innovative Experimental Medicine trial design, and those at the cutting edge of OA pathogenesis and inflammation research. Collectively we have strong links with our academic, clinical and industry colleagues to be able to deliver real benefit to patients.

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