Combined Cell and Gene Therapy Towards the Prevention of Osteoarthritis

Osteoarthritis (OA) ranks as the 11th highest contributor among 291 diseases, causing global disability and emerging as the predominant cause of chronic disability in the elderly population. OA has a profound impact on joint function and quality of life and represents a significant socio-economic burden. Presently, OA remains incurable and no approved medications, biological therapy, or procedure cures or prevents the progressive destruction of the joint. Present treatment options primarily offer symptomatic relief rather than preventative or regenerative results. There is an urgent call to innovate, validate, and explore new biological therapeutics. Among these, cell-based therapies involving the injection of mesenchymal stromal cells (MSCs) to the osteoarthritic knee joint have surfaced as a promising solution to address this clinical challenge. In this study, we addressed this by using isogenic mouse derived MSCs, combined with a novel and engineered biologic IL-1β sticky trap to prevent OA in the destabilization of the medial meniscus (DMM) mouse OA knee model. Our hypothesis is that intraarticular injection of local acting IL-1β sticky trap expression MSCs could reduce the inflammation and attenuate the progression of OA. For that purpose, firstly, we set up a MSC cell line from the C57BL/6J mouse compact bone. We explored how long MSCs could survive in the knee joint of these mice using an enhanced luciferase tracking system. Injected MSCs stayed in the joint for up to 10 weeks. We then generated a novel IL-1β sticky trap (stkIL1R2) by using the extracellular domain of the IL-1 receptor 2 (IL1R2) plus the sticky trap technology developed in our lab. This stkIL1R2 expression vector was transfected into MSCs and was found to be localized on the surface of the plasma membrane of MSCs. Finally, MSCs expressing stkIL1R2 were injected into the knees one week after DMM surgery. Histological analysis showed that stkIL1R2 expressing MSCs reduced synovitis and attenuated OA in the DMM OA knee model. Therefore, IL-1β sticky trap expressing MSCs may be a potential therapeutic option to prevent or slow down the progression of OA.

Department dc:contributor.department

Medical Science

Year dc:date.issued

2024

Author dc:creator

• Kim, Christopher Kwangil

Advisor dc:contributor.advisor

• Nagy, Andras

Handle dc:identifier.uri

http://hdl.handle.net/1807/140102

OAI identifier oai:identifier

oai:utoronto.scholaris.ca:1807/140102