Transient modulation of the immune system with CRISPR-Cas 9 technology

-Anwita Sarkar, Team bioXone

The current scenario of the devastating global pandemic of COVID-19 clearly depicts the importance of our immune system for our survival. The vast network of cells and tissues of the immune system are constantly searching for foreign particles and are eliciting immune responses by modulating their genome. Thus, regulation of the immune system is vital for maintaining the immune homeostasis in vivo.  With the advent of CRISPR-Cas9 gene editing technique scientists are able to temporarily modify the genes of the immune system.

A CRISPR based transcriptional repressor system consisting of heterochromatin protein1 (HP1a) and Kruppel-associated box (KRAB) transcriptional repressors, when fused with MS2  coat protein and followed by the guide RNA (gRNA) aptamer recruitment and binding to a nuclease competent CRISPR complex, (containing truncated gRNAs) reported a transcriptional down-regulation of Myeloid differentiation primary response 88 (Myd88) gene in the lung, bone marrow and, the blood of Cas9 transgenic mice. These transgenic mice are injected with adeno-associated virus (AAV) 2/1 carrying truncated gRNA and targeting Myd88 and MS2-HP1a-KRAB cassette. Transcriptional down-regulation of Myd88 is accompanied by changes in the signaling elements such as TNF-α and ICAM-1. A decrease in immunoglobulin G (IgG) production against AAV was reported.  This CRISPR-mediated Myd88 repression can influence the course of scepticaemia. Thus the CRISPR-based repression can act as an effective therapy for AAV, as this mechanism induces the host humoral immunity against AAV serotypes.

Source: Synthetic immunomodulation with a CRISPR super-repressor in vivo. Moghadam, F., LeGraw, R., Velazquez, J.J. et al., Nat Cell Biol 22, 1143–1154 (2020). https://www.nature.com/articles/s41556-020-0563-3