CRISPR/Cas-Based Gene Editing Strategies for DOCK8 Immunodeficiency Syndrome

Abstract

Defects in the DOCK8 gene causes combined immunodeficiency termed DOCK8 immunodeficiency syndrome (DIDS). DIDS previously belonged to the disease category of autosomal recessive hyper IgE syndrome (AR-HIES) but is now classified as a combined immunodeficiency (CID). This genetic disorder induces early onset of susceptibility to severe recurrent viral and bacterial infections, atopic diseases and malignancy resulting in high morbidity and mortality. This pathological state arises from impairment of actin polymerization and cytoskeletal rearrangement, which induces improper immune cell migration-, survival-, and effector functions. Owing to the severity of the disease, early allogenic hematopoietic stem cell transplantation is recommended even though it is associated with risk of unintended adverse effects, the need for compatible donors, and high expenses. So far, no alternative therapies have been developed, but the monogenic recessive nature of the disease suggests that gene therapy may be applied. The advent of the CRISPR/Cas gene editing system heralds a new era of possibilities in precision gene therapy, and positive results from clinical trials have already suggested that the tool may provide definitive cures for several genetic disorders. Here, we discuss the potential application of different CRISPR/Cas-mediated genetic therapies to correct the DOCK8 gene. Our findings encourage the pursuit of CRISPR/Cas-based gene editing approaches, which may constitute more precise, affordable, and low-risk definitive treatment options for DOCK8 deficiency.

Deciphering the role of DOCK8 in tumorigenesis by regulating immunity and the application of nanotechnology in DOCK8 deficiency therapy

“…Importantly, the allogenic hematopoietic stem cell transplantation (HSCT) is now the only reported therapeutic strategy for the treatment of DOCK8 deficiency related diseases. However, the need of compatible donors, the adequate number of cells, unpredictable adverse effects, immune rejection and GVHD are common problems typically associated with HSCT ( Ravendran et al, 2022 ). Therefore, to achieve better therapeutic effect, many strategies were investigated to solve or reduce these limitations during HSCT.…”

“…Furthermore, because DIDS is a disease caused by a single gene defect, correcting the disease-driving mutation in the cells of DIDS patient by genetic therapies to restore the function of DOCK8 might be an alternative treatment for DOCK8 deficiency ( Ravendran et al, 2022 ). Recently, CRISPR/Cas9 and other related technologies are wided used to achieve genetic edition and make huge progress.…”

“…Recently, CRISPR/Cas9 and other related technologies are wided used to achieve genetic edition and make huge progress. Importantly, several CRISPR/Cas-based gene editing strategies have been proposed to be used in DIDS, providing a more accurate, lower-risk treatment option for the patients with DIDS ( Ravendran et al, 2022 ). However, many concerns for the genetic editing technologies warrant further in deep investigation before they are applied in the clinical trials for the treatment of DOCK8 deficient patients.…”

“…However, allogenic hematopoietic stem cell transplantation (HSCT) is the current therapeutic strategy to efficiently treat DOCK8 deficiency related diseases. But the wide application of HSCT is limited by the need of compatible donors, the adequate number of cells, unpredictable adverse effects, immune rejection, graft-versus-host disease (GVHD) and high expenses ( Ravendran et al, 2022 ). Fortunately, nanotechnology was applied in many fields including the pharmaceutical and medical research such as diagnosis (nanodiagnosis), controlled drug delivery (nanotherapy), and regenerative medicine ( Soares et al, 2018 ).…”

“…And further studies have confirmed that HSCT can effectively restore the differentiation and function of lymphocytes in DIDS patients, corresponding to the improvement of clinical symptoms ( Pillay et al, 2019 ). However, other factors such as the need of compatible donors, the adequate number of cells, unpredictable adverse effects, immune rejection, graft-versus-host disease and high expenses limited the wide therapeutic application of HSCT ( Ravendran et al, 2022 ).…”