Synovial Macrophage Targeting Immunomodulatory Therapies for Post-Traumatic Osteoarthritis
Abstract
Post-traumatic osteoarthritis (PTOA) is one of the leading causes of disability and a medical cause of disability following a joint injury and affects ~12% of ~32.5 million American suffering from osteoarthritis (OA). PTOA develops as soon as 2 years post-trauma to the joint and occurs more frequently in young adults, resulting in detrimental long-term OA-related pain and disability at an early age. Military personnel have a higher risk of developing PTOA than age-matched civilians. Military personnel are at a greater risk to develop PTOA most likely due to intense physical activities or training or combat-related joint trauma such as anterior cruciate ligament (ACL) tears. ACL injuries are a common cause of PTOA development in adolescents and young adults before the age 40. An incidence rate of 87% is reported for PTOA development following ACL injury. Even after ACL reconstruction surgery, which is the last resort to restoring joint stability, the risk of developing PTOA is still 10 times higher in individuals with a previous joint trauma than unaffected individuals. About 75% of young military personnel under the age of 50 undergoing total knee replacement (TKA) suffer from end-stage PTOA. Persistent low-grade inflammation post joint injury is believed to be an important contributor to development of PTOA. The inflammation leads to slow degradation of joint tissue, and over a few years leads to joint dysfunction and disability. Currently, available drug therapies mainly include pain reducing medications such as corticosteroids, which temporarily mitigate the PTOA symptoms but do not prevent disease development or modify long-term disease outcomes. Pain-reducing corticosteroids and other anti-inflammatory medications that non-specifically suppress all inflammation have been largely unsuccessful in promoting repair or halting disease progressing in PTOA. Changing the inflammatory milieu in PTOA may thus require selectively eliminating the responsible subtype of immune cells such as macrophages. Progression of PTOA is positively related with increased presence of macrophages, a type of immune cells. A subset of the macrophages when activated, secrete several pro-inflammatory factors, which lead to cartilage and joint destruction in the long term. Therapeutic approaches that can selectively engage and eliminate only a sub-population of pro-inflammatory activated macrophages can potentially remodel the immune response and promote healing in PTOA. Such an approach, however, is still lacking for PTOA therapy. To fill in this gap in PTOA therapies, this project aims at developing a system that can specifically target the pro-inflammatory activated macrophages in the joint tissue. Recent studies have shown that only a subset of pro-inflammatory activated macrophages express folate receptor-2 (FR-2) in PTOA affected joints. Exclusive expression of FR-2 on activated macrophages can allow selective targeting of drug therapies for PTOA. The primary hypothesis of the project is that direct delivery into the joints of a FR-2 targeting drug carrier loaded with zoledronate (ZA), a bisphosphonate (BP), can selectively eliminate a subset of activated synovial macrophages, modulate joint inflammation, and modify disease outcomes of PTOA. BPs are a class of clinically approved drugs that specifically induce cell death in all types of macrophages and are being tested in clinical trials for OA treatment. Several off-target effects and ubiquitous elimination of all macrophages by BPs have reduced the clinical benefits of BPs for OA treatment. The proposed targeted carrier system for ZA/BPs can increase the target selectivity of BPs only to a subset of macrophages rather than all macrophages in joint and reduce off-target adverse effects of these drugs. Moreover, the proposed drug carrier will also act as a drug depot, allowing sustained drug release in the joint and reduced frequency of drug administration and exposure. The objectives of th
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210020
Entities
People
- Era Jain
Organizations
- Syracuse University
- United States Army