Implantable intelligent cell therapy, realizing immediate response drug delivery, can be used for a variety of chronic diseases

　　Controllable gene logic circuits based on synthetic biology are gradually being used in cell therapy.
　　Recently, the team of Farshid Guilak, co-director of the Center for Regenerative Medicine at Washington University School of Medicine in St. Louis, published an article on Science Advances, introducing an implantable genetically engineered cell complex designed by synthetic biology, which can be secreted by inflammatory factors. Anti-cytokine drugs to treat inflammatory arthritis.
　　Guilak said on social media that this article combines synthetic biology and tissue engineering techniques to develop an implant system that can sense inflammation and deliver drugs on demand.
　　The Farshid Guilak team has long focused on 3 areas: obesity, inflammation and osteoarthritis; the mechanobiology and mechanism of mechanical signal transduction in cartilage; and stem cell therapy for osteoarthritis.

research paper
01Automatic induction drug delivery

　　Rheumatoid arthritis is a chronic, symmetric, and progressive autoimmune inflammatory disease that mainly involves peripheral joints. Epidemiological surveys show that 0.5% to 1% of the world’s population suffers from RA. The incidence rate in my country About 0.42%.
　　With the improvement of the treatment level, more and more RA treatment drugs appear, mainly including non-steroidal anti-inflammatory drugs, disease-improving anti-rheumatic drugs, glucocorticoids and biological agents. Although these drugs have certain effects in anti-inflammatory and delaying disease progression, their adverse reactions are still a problem that cannot be ignored.
　　As mentioned in the article, biologic drugs for the treatment of RA usually aim to target a variety of inflammatory cytokines and pathways, including interleukin-1 (IL-1), IL-6 and tumor necrosis factor-α (TNF-α) . However, about 40% of patients do not respond to medications, and medications can also suppress the patient’s immune system and increase the risk of infection.
　　Guilak said: “Doctors often treat patients with rheumatoid arthritis by injection or infusion of anti-inflammatory biological drugs, but these drugs are administered for a long time and in high doses, which can cause serious side effects while producing beneficial effects. Some studies have It was found that IL-1 receptor antagonist (IL-1Ra) can reduce RA joint damage, but due to its short half-life, it has not become a conventional drug for the treatment of RA. ”
　　At the same time, different routes of administration will also bring corresponding problems. For example, long-term oral administration of glucocorticoids may bring adverse reactions such as infection and increased risk of cancer; however, frequent local administration (intra-articular injection) may cause persistent pain and other problems. Therefore, how to improve the effect of RA drug treatment and reduce its adverse reactions has become a research hotspot.
　　The Guilak team used synthetic biology methods to design a gene circuit in induced pluripotent stem cells (iPSC) (as shown in the figure below). When interleukin-1 binds to the IL-1 receptor on the cell membrane, it will pass through NF. -MγB signaling pathway, activates the chemokine Cc12 promoter, starts the downstream IL-1Ra gene, secretes 3..31L-1Ra and releases it outside the cell to compete with IL-1 to bind to the IL-1 receptor, and ultimately reduce the cellular immune response .
　　In the cell implantation stage, in order to better colonize the cells, the team developed a 3D braided scaffold, implanted with chondrocytes to form a simulated cartilage tissue, and finally inoculated the engineered cells into this tissue. After being implanted in an animal, the cells can survive for several months or longer and continue to play a therapeutic role.
　　”These programmed cells can stay under the skin or in the joints for several months, and when they feel an inflammatory stimulus, they release biological drugs.” Guilak said.
　　The article stated that the implanted engineered cells can be activated when inflammation occurs in the body, which solves the problem of the short half-life of IL-1Ra injection in the body. It can be used as a long-term drug delivery method and has important clinical research value.

Gene line and 3D braid scaffold
02Can be applied to a variety of chronic diseases

research paper

　　The experimental subjects of the study selected a mouse model of inflammatory arthritis. After implanting the engineered cell complex, the inflammatory index of the mouse was reduced by about 40%, and the erosion of the bone by the inflammatory factor was also reduced.
　　The researchers also found that the IL-1Ra released by engineered cells can last for at least 72 hours after a single activation, while some studies have reported that the injected IL-1Ra can only last for a few hours. Researchers speculate that this is because IL-1Ra in cells is produced through transcription and translation, which is a sustainable process, while exogenous IL-1Ra is more of a ready-to-use protein drug.
　　The article pointed out that one of the shortcomings of this research is that it only did 40 days of research and did not conduct longer research. The team is looking for biomaterials that can encapsulate cells at a higher density and longer-term survival rate, and plans to continue experimenting with CRISPR-Cas9 and stem cells to create an engineered cell that can respond to different inflammatory triggers and release corresponding biologic drugs. .
　　”The advantage of stem cells is that they can flexibly differentiate into various types of cells, and can design gene circuits based on known drug targets to synthesize cells that can treat various chronic diseases.” Guilak said.
　　One of the major advantages of synthetic biology’s gene circuit is engineering and modularity. In an interview, Professor Ye Haifeng from East China Normal University also proposed a similar concept-a “smart drug factory”, through the design of artificial gene circuits and Programming guides the chassis cells to output a variety of protein drug molecules, such as enzymes, antibodies, hormones, etc., through different instructions, the cells can be controlled to release multiple drugs for combined therapy.
　　More and more research on cell therapy has begun to develop gene circuits that can sense and dynamically respond to disease markers, and provide systems that can accurately control and deliver drugs over time. Can engineered cell-based therapies become the next frontier of medicine?