Inspiration
Globally, as of 10:33am CEST, 17 October 2020, there have been 39,023,292 confirmed cases of COVID-19, including 1,099,586 deaths, reported to WHO. [1]. According to data published by JAMA Oncology, a subsidiary of the The Journal of the American Medical Association, there were 24.5 million new cancer cases and 9.6 million cancer deaths globally in 2017[2]. Meanwhile, a report released by the World Health Organization on 1 June shows that noncommunicable disease prevention and treatment services have been severely disrupted since the start of the COVID-19 pandemic. Of the 155 countries surveyed, 42 percent had partial or complete disruption of cancer treatment. Because malignancies and anticancer treatments such as chemotherapy or surgery can lead to systemic immunosuppression, cancer patients are more likely than non-cancer patients to be infected by epidemic diseases[3]. Therefore, cancer patients may be more susceptible to COVID-19 and have a poor prognosis.The treatment status of cancer patients with COVID-19 in China shows that compared with patients without cancer, cancer patients are at higher risk of serious events and their disease deteriorates faster[4].
Figure 1. WHO Coronavirus Disease (COVID-19) Dashboard[1]
Under these conditions, it is difficult for cancer patients to go to the hospital for treatment.So we thought about whether there could be a way of giving drugs in the body for a long time so that cancer patients could be treated without having to go to the hospital. And it would improve on existing therapies.
After discussion with Professor Chen Xi and Postdoctor Fu Zheng, we proposed our ExosomeBomb SiRNA therapy, designed a combinable and programmable genetic circuit, and used liver as a tissue chassis to guide the self-assembly of exogenous siRNAs into exosomes, and promote the targeted delivery of self-assembled siRNAs in vivo. At the same time, in the interview and communication with professors and doctors, our project was constantly improved and the final design was formed.
Our Solution
As we mentioned before, cancer is a complex group of diseases with many possible causes, and discovered many genes as targets for cancer treatment. After communication with Postdoctor Fu Zheng, we learned that the drawback of current cancer therapy is targeting, siRNAs offer an opportunity to specifically target mRNAs and modulate the expression of therapeutic targets before their biogenesis
However, siRNA is difficult to be absorbed by the body, so he suggested that we could use the method of exosome packaging siRNA to efficiently deliver the siRNA to targeted cells, and degrade the targeted mRNA to inhibit the proliferation of cancer cells. Because exosomes are difficult to isolate and purify in vitro and yield is very low, it is difficult to effectively pack enough siRNA. This seems a bit tricky.
1. Groundbreaking idea
Professor Chen Xi proposed a ground-breaking idea: designed composable and programmable genetic circuits that used the liver as a tissue chassis to direct the self-assembly of exogenous siRNAs into secretory exosomes. It can ensure the efficient delivery of siRNA in vivo and achieve long-term treatment.
2. Selection of therapeutic targets
According to the Suggestions of Professor Chen Xi and Professor Yan Chao, we selected KRAS, CD47 and PD-L1 as therapeutic targets. By targeting oncogenic drivers KRAS, innate immune checkpoint CD47 and acquired immune checkpoint PD-L1, the immune system can be activated to complete the elimination of tumor cells while inhibiting tumor proliferation.
3. Safety
In the interview with Dr. Liu Rui, Dr. Wang Rui and Professor Huang Zhaohui, we learned the deficiency of the project (To Hp), so we combined the Tet-on system with Cre-lox2272-loxP system to ensure safety and specificity [4].At the same time, components promoting exosome release were designed to ensure the sustainability of treatment [5]. In continuous Suggestions and improvements, we have completed the final design of the project.
The Infinite Possibilities of Our Project
Our project cleverly uses its own tissue as the chassis to produce therapeutic exosomes. The strategy provided a controllable, multifunctional, efficient and convenient cancer treatment which is highly flexible with switchable siRNA sequences and plug-and-play parts. In future prospective, our project may even provide a personalized treatment strategy that can address a broad range of problems in biomedicine.
Reference
[1] https://covid19.who.int/
[2] Torre, Bray, et al. Global cancer statistics, 2012. CA: A Cancer Journal for Clinicians, 2015, 65: 87-108.
[3] Longbottom ER, et al. Features of postoperative immune suppression are reversible with interferon gamma and independent of interleukin-6 pathways. Ann Surg. 2016, 264:370–377.
[4] Hasan, et al. A Fear Memory Engram and Its Plasticity in the Hypothalamic Oxytocin System. Neuron. 2019, 103:133-146.
[5] Lin Song, et al. KIBRA controls exosome secretion via inhibiting the proteasomal degradation of Rab27a. Nat Commun, 2019, 10:1639.