Immunotherapy using CRISPR-Cas9 systems to treat rheumatoid arthritis with PTPN22 R620W mutations and target PD-1 and CD20

Rheumatoid arthritis (RA) is an inflammatory autoimmune disease that causes joint pain and inflammation. Current treatments for RA leave patients immunocompromised and may have harmful side effects. As part of the mechanism behind RA, overactive T cell signaling to B cells contributes to inflammation. Specific genes, such as PTPN22, can play a role in overactive T cell signaling in RA patients’ immune systems. The protein encoded by tyrosine phosphatase non-receptor 22 (PTPN22), is lymphoid tyrosine phosphatase (LYP), which performs regulatory activities for both T and B cells. In particular, the R620W variant of this protein is associated with RA and may increase the overall sensitivity of an individual’s immune system. This review will discuss the mechanisms of CRISPR/Cas9 to disrupt or express specific genes to combat inflammation in RA patients. First, CRISPR/Cas9 can be used to disrupt PTPN22 in T cells to restore homeostasis. Second, CRISPR/Cas9 can be used to knock in PDCD1, which encodes for the PD-1 protein that inhibits cytokine production and T cell proliferation, which may downregulate T cells. T cells play a role in RA by producing proinflammatory cytokines and interacting with synovial fibroblasts and macrophages. Third, CRISPR/Cas9 can be used to target MS4A1, the gene that encodes for CD20 on B cells, in order to deplete B cells without affecting T cells. Using CRISPR/Cas9 to either knock out PTPN22 in T cells or knock in PDCD1 in T cells and MS4A1 in B cells could potentially treat and even reverse the symptoms of rheumatoid arthritis for patients affected by the R620W variant of the PTPN22 protein.