Efficacy of Recombinant Equine Lubricin for OA
Principal Investigator: Heidi Reesink
DESCRIPTION (provided by applicant):
Lameness is the leading cause of retirement across all horse breeds and disciplines. More specifically, lameness due to osteoarthritis (OA) is responsible for more than 60% of all equine lameness (Caron 2003), and it is the second leading cause of premature race horse retirement. OA begins with a pre-radiographic stage, where the inflammatory cascade is initiated within the joint and initial, reversible cartilage injury becomes evident. As OA progresses, cartilage lesions become irreversible, and radiographic changes such as osteophytosis, joint space collapse, and subchondral bone sclerosis develop.
Corticosteroids and hyaluronic acid (HA) viscosupplementation have been the mainstays of intra-articular therapy in horses for more than two decades. Orthobiologics are also frequently used for management of OA, but most require processing or more extended culture or incubation times. Systemic non-steroidal anti-inflammatory drugs provide treatment of the whole animal, but adverse effects can occur, and they require daily, long term administration. Lubricin is a highly sugar-coated glycoprotein, which confers its properties as the primary boundary lubricating molecule of articular cartilage surfaces. Lubricin has demonstrated promise in rodent and mini-pig models of joint instability. In addition, because lubricin can physically bind to the surface of articular cartilage, its sustained residence time of 28-42 days following a single intraarticular injection suggest that it may have a sustained effect. However, progress with lubricin therapy has been hampered by significant challenges with the large-scale production and purification of recombinant lubricin. The field has been slow to translate lubricin therapy to large animals or veterinary clinical trials due to technical challenges associated with producing sufficient quantities of recombinant lubricin. Notably, we have recently developed a novel codon scrambling and custom gene synthesis strategy for production and purification of full-length, highly glycosylated recombinant equine lubricin.
The long-term objective of this proposal is to translate lubricin therapy to equine clinical patients. We hypothesize that equinespecific synthetic recombinant lubricin (rEqLub) can ameliorate osteoarthritis by means of its anti-inflammatory and lubricating properties. In Aim 1, the efficacy of equine-specific recombinant lubricin will be evaluated in an equine carpal osteochondral fragment model of OA. In Aim 2, the molecular mechanisms will be investigated in healthy equine fetlock joints treated with rEqLub through the use of synovial fluid proteomics and synovial membrane and articular cartilage transcriptomics. In addition to a safety study we are currently conducting we expect these studies to provide valuable information into the viability of a future clinical trial in equine patients and begin to understand the mechanisms behind lubricin’s role in joint homeostasis and healing.