Gene editing for inflammatory disorders

Abstract

Technology for precise and efficient genetic editing is constantly evolving and is now capable of human clinical applications. Autoimmune and inflammatory diseases are chronic, disabling, sometimes life-threatening, conditions that feature heritable components. Both primary genetic lesions and the inflammatory pathobiology underlying these diseases represent fertile soil for new therapies based on the capabilities of gene editing. The ability to orchestrate precise targeted modifications to the genome will likely enable cell-based therapies for inflammatory diseases such as monogenic autoinflammatory disease, acquired autoimmune disease and for regenerative medicine in the setting of an inflammatory environment. Here, we discuss recent advances in genome editing and their evolving applications in immunoinflammatory diseases. Strengths and limitations of older genetic modification tools are compared with CRISPR/Cas9, base editing, RNA editing, targeted activators and repressors of transcription and targeted epigenetic modifiers. Commonly employed delivery vehicles to target cells or tissues of interest with genetic modification machinery, including viral, non-viral and cellular vectors, are described. Finally, applications in animal and human models of inflammatory diseases are discussed. Use of chimeric autoantigen receptor T cells, correction of monogenic diseases with genetically edited haematopoietic stem and progenitor cells, engineering of induced pluripotent stem cells and ex vivo expansion and modification of regulatory T cells for a range of chronic inflammatory diseases are reviewed.

Lung Inflammation in STING-Associated Vasculopathy with Onset in Infancy (SAVI)

“…The identification of a major hematopoietic component to lung pathogenesis would highlight the potential of HSCT as a treatment strategy. Similarly, the development of genome editing technologies is providing new possibilities in medical therapeutics [114], including in inflammatory disorders [115,116], and may be promising for SAVI patients.…”

Microneedle-assisted dual delivery of PUMA gene and celastrol for synergistic therapy of rheumatoid arthritis through restoring synovial homeostasis

“…For instance, the expression of pro-apoptotic gene PUMA (p53 upregulated modulator of apoptosis) is low in RA FLS, which partially accounts for the resistance of RA FLS to apoptosis [ 13 ]. Delivering proapoptotic gene PUMA via viral vectors has been proven to be an effective apoptotic therapy for RA FLS [ 14 , 15 ], but the actual therapeutic efficacy of gene therapy based on viral vectors is restricted by the carcinogenesis, immunogenicity and limited packaging capacity [ [16] , [17] , [18] ]. Our group has developed a reactive oxygen species (ROS) responsive polyethylenimine-based fluorinated polymers ( TK PF) for the delivery of gene drugs and has been used for cancer therapy [ 19 , 20 ], which could overcome the limitations of viral vectors and realized enhanced transfection efficiency and decreased cytotoxicity.…”

Engineered Self-Regulating Macrophages for Targeted Anti-inflammatory Drug Delivery

“…Cell-based therapies have broad potential for use in autoimmune and in ammatory diseases. Recent work in immunoengineering offers a new perspective utilizing cell therapies and genetic engineering approaches where cells can be engineered to express inducible transgenes for dynamic, microenvironment-level control of cell response, eliminating the need for systemic and repeated, highdose therapies [35][36][37][38][39]. Due to their prominent role in the in ammatory cascade and pathology of RA, macrophages represent a potential target for interrupting the perpetuating production of proin ammatory factors.…”