Purvi Desai

Background: Rheumatoid arthritis (RA) affects around 1 % of the global population and causes chronic inflammation in joints, eventually leading to bone and cartilage damage. Early symptoms include joint swelling, tenderness, and fatigue, while overall systemic inflammation can damage various organs [1,2]. Inflammation is mediated by cytokines which include IL-1, IL-6 and TNF-a [3]. While disease modifying anti-rheumatic drugs (DMARDs) have revolutionized treatment, their high doses lead to significant adverse effects. Additionally, 40% of patients fail to respond to treatment [4]. This study explores localized treatments, such as genome-engineered stem cells [5,6,7] and encapsulation of adipose derived stem cells (ADSCs) in an ECM inspired hydrogel [8].

Methods: PubMed searches were conducted including terms: “molecular targets for RA”, “gene therapy for RA”, “RA treatment.”

Results: Chemokine ligand 2 (Ccl2) gene product is responsible for immune cell trafficking and is potently stimulated by TNF-a and IL-1. Thus, resolving inflammation results in a decay of Ccl2 expression. Researchers used CRISPR-Cas9 to edit pluripotent stem cells, adding the IL-1Ra gene near the Ccl2 promoter to create a self-regulating circuit in response to inflammation [5,6,7]. These were seeded onto 3D woven scaffolds and implanted into the K/BxN murine model of arthritis. The Ccl2-IL-1Ra constructs produced IL-Ra in a feedback-controlled manner and demonstrated a significant decrease in arthritis severity. Additionally, when compared to Anakinra, a current IL-1 inhibitor, the constructs showed improved cytokine inhibition [6]. A follow-up study investigated a simplified implantation by injecting these cells in agarose hydrogel constructs subcutaneously. The constructs showed significantly mitigated arthritis and mechanical allodynia. Thus, this demonstrates a minimally invasive approach for autoregulated therapy delivery [7].  Another study investigated using ADSCs for RA therapy. ADSCs release bioactive molecules to promote regenerative pathways in RA, but their effectiveness is limited by short-term retention and poor distribution at the target site. To address this, researchers developed an ECM-inspired G3K/OHA hydrogel to encapsulate ADSCs. This approach demonstrated maintained bioactivity and immunomodulatory effects of ADSCs. These constructs alleviated RA symptoms and significantly reduced mRNA levels of TNF-a and IL-6 while increasing expression of Arg-1 and IL-10, indicating a shift from a pro-inflammatory (M1) to anti-inflammatory (M2) macrophage phenotype [8].

Conclusions: In summary, localized delivery of stem cell treatment for RA is able to mitigate inflammation. Further studies will need to be done to determine if these treatment options can prevent the systemic side effects seen with current RA treatment.

Works Cited:

1. Lin YJ, Anzaghe M, Schülke S. Update on the Pathomechanism, Diagnosis, and Treatment Options for Rheumatoid Arthritis. Cells. 2020;9(4):880. doi:https://doi.org/10.3390/cells9040880
2. Zhao J, Guo S, Schrodi SJ, He D. Molecular and Cellular Heterogeneity in Rheumatoid Arthritis: Mechanisms and Clinical Implications. Frontiers in Immunology. 2021;12:790122. doi:https://doi.org/10.3389/fimmu.2021.790122
3. Ding Q, Hu W, Wang R, et al. Signaling pathways in rheumatoid arthritis: implications for targeted therapy. Signal Transduction and Targeted Therapy. 2023;8(1):1-24. doi:https://doi.org/10.1038/s41392-023-01331-9
4. Choi, Yun-Rak et al. “A genome-engineered bioartificial implant for autoregulated anticytokine drug delivery.” Science advances vol. 7,36 (2021): eabj1414. doi:10.1126/sciadv.abj1414
5. Brunger, Jonathan M et al. “Genome Engineering of Stem Cells for Autonomously Regulated, Closed-Loop Delivery of Biologic Drugs.” Stem cell reports vol. 8,5 (2017): 1202-1213. doi:10.1016/j.stemcr.2017.03.022
6. Choi, Yun-Rak et al. “A genome-engineered bioartificial implant for autoregulated anticytokine drug delivery.” Science advances vol. 7,36 (2021): eabj1414. doi:10.1126/sciadv.abj1414
7. Collins, Kelsey H et al. “Hydrogel Encapsulation of Genome-Engineered Stem Cells for Long-Term Self-Regulating Anti-Cytokine Therapy.” Gels (Basel, Switzerland) vol. 9,2 169. 20 Feb. 2023, doi:10.3390/gels9020169
8. Zhu, Haofang et al. “ECM-Inspired Hydrogels with ADSCs Encapsulation for Rheumatoid Arthritis Treatment.” Advanced science (Weinheim, Baden-Wurttemberg, Germany) vol. 10,9 (2023): e2206253. doi:10.1002/advs.202206253