Cell-Based Implant as a Stable System for Biological Therapy Delivery
A team of scientists from Washington University in St. Louis focused on the possibility of delivering biological inhibitors for the treatment of rheumatoid arthritis using modified induced pluripotent stem cells. To verify the effectiveness of the therapy, they used a mouse model of rheumatoid arthritis, and their results represent progress in the development of rheumatoid arthritis treatment.
Current Treatment of Rheumatoid Arthritis
The treatment of autoimmune diseases has significantly changed with the availability of biological therapy. However, approximately 40% of patients suffering from rheumatoid arthritis (RA) do not respond to this treatment. Long-term use of biological therapy affects the immune system and may increase the risk of infection in patients. Biological therapy is administered in constant doses regardless of the current severity of RA. Therefore, the authors of a recently published work focused on creating a system capable of dosing the biological drug based on the current state of the disease.
Self-Regulating Dosing System
The authors used CRISPR-Cas9 technology and created a self-regulating synthetic circular gene construct, which they inserted into induced pluripotent stem cells (iPSC). These cells were then delivered to a bioartificial implant, where their ability to produce biological substances inhibiting cytokines in response to inflammatory signals such as interleukin 1 (IL-1) and tumor necrosis factor alpha (TNF-α) was verified in vitro and in vivo. This system is regulated by feedback, ensuring the production of inhibitors only in the presence of inflammatory signals.
Verification of System Function in a Mouse Model
To verify whether this system can be used in disease therapy, an implant with differentiated iPSC (chondrocyte-like cells with high production of proteoglycan-rich matrix) was inserted subcutaneously into a mouse model of inflammatory arthritis, which is dependent on the presence of IL-1. The implants proved to be a long-term (up to 5 weeks) and stable drug delivery system in vivo, capable of reactivation (even after 30 days without an activation signal) and deactivation.
Is Treatment with Implants Effective?
Implants were inserted into the dorsal side of the mice, and the effectiveness of the therapy was measured after complete recovery from the procedure. In the mouse model of rheumatoid arthritis, the implant therapy showed improvement in measurable indicators of RA severity, such as joint pain, structural damage, and systemic and local inflammation. The therapy proved superior to the deployment of disease-modifying antirheumatic drugs (DMARDs). Therapeutic implants completely prevented bone erosion and increased sensitivity to pain. These results are not achievable with standard treatment using DMARDs or biologic drugs.
Summary and Conclusion
Implants are made from modified iPSC differentiated into cartilage tissue. Modified iPSC contain a construct created by CRISPR-Cas9 technology, from which the expression of the inhibitor (IL-1Ra) occurs only in the presence of pro-inflammatory signals. This drug delivery system has proven effective in a mouse model of RA, and in some respects, surpasses currently used drugs.
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Source: Choi Y. R., Collins K. H., Springer L. E. et al. A genome-engineered bioartificial implant for autoregulated anticytokine drug delivery. Sci Adv 2021; 7 (36): eabj1414, doi: 10.1126/sciadv.abj1414.
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