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Teknologi
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Genom grundlig forskning på hästleder har SGPTH upptäckt biomarkörer som frigörs när en inflammation börjar i brosket. Biomarkören mäts genom ett enkelt blodprov och ger en indikation på hur allvarlig inflammationen är. Produkten har patent över hela världen både för människor och djur och har patentsökt för behandling av artrose.
Schematisk ritning som illustrerar det etablerade tvärvetenskapliga samarbetet mellan SLU, GU, Sahlgrenska Universitetssjukhuset och Chalmers. Det övergripande syftet är att dechiffrera de mekanismer som ligger bakom initieringen av artros, en process som bevaras mellan människa och häst, reda ut sjukdomens fortskridande och belysa nya strategier för diagnos och farmakologisk intervention.
En schematisk representation av den longitudinella utvecklingen av OA.
Artros sjukdomsprogression sträcker sig över dagar till år. Den biokemiska nedbrytningen som initieras av inflammation i den tidiga händelsen är inte möjlig att fastställa med dagens diagnostiska metoder. Denna process i brosket är fortfarande reversibel. När hästen blir kliniskt halt har utvecklingen av sjukdomen avancerat och blir irreversibel. De olika avbildningstekniker som finns tillgängliga idag kan bara utvärdera de irreversibla morfologiska förändringarna och inte de tidiga kataboliska biokemiska processerna. COMP-fragmentering i ledbrosk är ett tidigt svar på inflammation, vi har upptäckt en neo-epitop av COMP som frisätts i akuta och tidiga stadier av artros.
Precision diagnosis and a novel treatment for osteoarthritis in horses
Osteoarthritis (OA) is a chronic low-grade inflammatory disease, with subtle progression, including tissue destruction before clinical gait asymmetries become apparent. The need to prevent, diagnose and treat OA, while the disease is still reversible, relies on early detection of molecular changes (biomarkers) before the onset of chronic OA. The present costly imaging techniques (radiographs, MR, CT) can only detect late structural changes. Gait asymmetries and clinical lameness are detected when OA progresses from reversible to the irreversible stage.
Regulatory bodies, European Medicines Agency, Food and Drug Administration and OA international research organizations, all recognize the importance of biomarkers, since early identification using biomarkers allow for timely, targeted disease modifying osteoarthritic drugs (DMOAD), potentially preventing joint pain and irreversible damage. We have identified novel soluble neo-epitopes reflecting ongoing extracellular matrix degradation in osteoarthritic cartilage and bone that can be quantified in body fluids (synovial fluid, blood, saliva). Development of validated customized ELISAs for detecting superficial cartilage damage (COMP156) and bone changes (BGN262), as well as deeper cartilage degradation (COMP644) in OA has been achieved. These biomarkers can monitor destruction of articular cartilage and subchondral bone during training programs (prevention), diagnose and post-intervention (treatment efficacy and side effect) and during rehabilitation (post-treatment). Using these biomarkers for diagnosis also enables an understanding of molecular mechanisms (endotypes) and distinguishing progressive from non-progressive cases. The biomarkers can identify bone-driven and cartilage-driven endotypes. Defining the specific endotypes, helps categorise the horses into biomarker assisted sub-groups for tailored treatments, improving clinical trial outcome. Monitoring the levels of the different biomarkers can aid in evaluating the efficacy of treatment and the effect of different rehabilitation regimes.
Currently registered pharmacological OA treatments only improve pain/symptoms and are frequently associated with side effects. There are no approved DMOADs on the market. A DMOAD must show improvement in joint structure, and slow down the progression of tissue destruction of cartilage and bone, with or without an efficacy on joint pain. A new drug that fulfill these criteria has been developed by the group and together with the biomarker have been validated in a double-blind randomised clinical trial in racehorses. The introduction of the drug on the market in Sweden has improved OA treatment by promoting joint tissue healing, slowing disease progression and elimination of joint pain without causing side effects. The biomarkers are in use for measuring the efficacy and/or side-effects after treatment.
References:
1) Salivary biglycan-neo-epitope-BGN262: A novel surrogate biomarker for equine osteoarthritic sub-chondral bone sclerosis and to monitor the effect of short-term training and surface arena. Adepu S, Lord M, Hugoh Z, Nyström S, Mattsson-Hulten L, Abrahamsson-Aurell K,Lützelschwab C, Skiöldebrand E. Osteoarthritis and Cartilage Open 5 (2023) 100354
2) Biglycan Neo-epitope (BGN262),a Novel biomarker for screening early changes in equine osteoarthritic subchondral bone. Adepu S, Ekman S, Leth J, Johansson U, Lindaahl A, Skiöldebrand E. Osteoarthritis Cartilage. 2022 Oct; 30(10):1328-1336.
3) A randomized, triple-blinded controlled clinical study with a novel disease-modifying drug combination in equine lameness-associated osteoarthritis. Skiöldebrand E, Adepu S, Lützelschwab C, Nyström S, Lindahl A, Abrahamsson-Aurell K, Hansson E. Osteoarthritis and Cartilage Open. 2023 Jun 16;5(3):100381.
4) Effect of circadian rhythm, age, training, and acute lameness on serum concentrations of cartilage oligomeric matrix protein (COMP) neo-epitope in horses. Stina Ekman, Anders Lindahl, Ulla Rüetschi, Anna Jansson, Kristina Björkman, Kristin Abrahamsson – Aurell, Sigríður Björnsdóttir, Maria Löfgren, Lillemor Mattsson Hultén and Eva Skiöldebrand. Equine Vet J. 2019 Sep;51(5):674-680. doi: 10.1111/evj.13082. Epub 2019 Mar 6.
5) Cartilage oligomeric matrix protein neoepitope in the synovial fluid of horses with acute lameness: A new biomarker for the early stages of osteoarthritis. Skiöldebrand E, Ekman S, Mattsson Hultén L, Svala E, Björkman K, Lindahl A, Lundqvist A, Önnerfjord P, Sihlbom C, Rüetschi U. Equine Vet J. 2017 Sep;49(5):662-667.
6) An inflammatory equine model demonstrates dynamic changes of immune response and cartilage matrix molecule degradation in vitro. Svala E, Löfgren M, Sihlbom C, Rüetschi U, Lindahl A, Ekman S, Skiöldebrand E. Connect Tissue Res. 2015;56(4):315-25.
7) A novel treatment combination of sildenafil, mepivacaine, and glucose with disease modifying properties, in a pony with lameness associated osteoarthritis – a case report. Skiöldebrand E, Abrahamsson Aurell K, Adepu S, Lindahl A, Hansson E. J Clin Case Reports, 2023, Volume 13:06.