Current Gene Therapy - Volume 19, Issue 2, 2019

Transplantation is the only cure for end-stage organ failure. Current immunosuppressive drugs have two major limitations: 1) non antigen specificity, which increases the risk of cancer and infection diseases, and 2) chronic toxicity. Cell therapy appears to be an innovative and promising strategy to minimize the use of immunosuppression in transplantation and to improve long-term graft survival. Preclinical studies have shown efficacy and safety of using various suppressor cells, such as regulatory T cells, regulatory B cells and tolerogenic dendritic cells. Recent clinical trials using cellbased therapies in solid organ transplantation also hold out the promise of improving efficacy. In this review, we will briefly go over the rejection process, current immunosuppressive drugs, and the potential therapeutic use of regulatory cells in transplantation.

MDSCs play an important role in the induction of immune tolerance. Cytokines and chemokines (GM-CSF, IL-6) contributed to the expansion, accumulation of MDSCs, and MDSCs function through iNOS, arginase and PD-L1. MDSCs are recruited and regulated through JAK/STAT, mTOR and Raf/MEK/ERK signaling pathways. MDSCs’ immunosuppressive functions were realized through Tregs-mediated pathways and their direct suppression of immune cells. All of the above contribute to the MDSC-related immune tolerance in transplantation. MDSCs have huge potential in prolonging graft survival and reducing rejection through different ways and many other factors worthy to be further investigated are also introduced.

Acute Respiratory Distress Syndrome (ARDS) and its complications remain lifethreatening conditions for critically ill patients. The present therapeutic strategies such as prone positioning ventilation strategies, nitric oxide inhalation, restrictive intravenous fluid management, and extracorporeal membrane oxygenation (ECMO) do not contribute much to improving the mortality of ARDS. The advanced understanding of the pathophysiology of acute respiratory distress syndrome suggests that gene-based therapy may be an innovative method for this disease. Many scientists have made beneficial attempts to regulate the immune response genes of ARDS, maintain the normal functions of alveolar epithelial cells and endothelial cells, and inhibit the fibrosis and proliferation of ARDS. Limitations to effective pulmonary gene therapy still exist, including the security of viral vectors and the pulmonary defense mechanisms against inhaled particles. Here, we summarize and review the mechanism of gene therapy for acute respiratory distress syndrome and its application.

High mobility group box 1 (HMGB1) presents in almost all somatic cells as a component of the cell nucleus. It is necessary for transcription regulation during cell development. Recent studies indicate that extracellular HMGB1, coming from necrotic cells or activated immune cells, triggers inflammatory response whereas intracellular HMGB1 controls the balance between autophagy and apoptosis. In addition, reduced HMGB1 can effectively mediate tissue regeneration. HMGB1, therefore, is regarded as a therapeutic target for inflammatory diseases. In this review, we summarized and discussed the immunomodulatory effect of HMGB1.

An autoimmune disease is an inflammatory condition in which the human body’s immune system attacks normal cells, resulting in decreased and abnormal immune function, which eventually leads to tissue damage or organ dysfunction. In the field of medicine, especially in pediatrics, knowledge about autoimmune diseases is still inadequate. Some common juvenile autoimmune diseases such as Henoch–Schonlein purpura, systemic juvenile idiopathic arthritis, mucocutaneous lymph node syndrome, and autoimmune encephalitis cause considerable public concern. Recent studies revealed that heme oxygenase 1 (HO-1), an enzyme that participates in heme degradation, plays a critical role in the pathogenesis and may regulate autoimmunity. Firstly, it may promote the differentiation of T lymphocytes into CD4+CD25+ regulatory T cells and may be associated with changes in the ratios of cytokines (Th1/Th2 and Th17/Treg) as well. Secondly, HO-1 can regulate the immune system through the secretion of proteins such as transforming growth factors and interleukins. Moreover, increasing the expression of HO-1 can improve vascular function by increasing antioxidant levels. Thus, HO-1 may provide a theoretical basis and guidance for therapeutic management of juvenile autoimmune diseases.

Background: Ferroptosis is a newly discovered form of iron-dependent oxidative cell death characterized by lethal accumulation of lipid-based reactive oxygen species (ROS). It is distinct from other forms of cell death including apoptosis, necrosis, and autophagy in terms of morphology, biochemistry and genetics. Discussion: Ferroptosis can be induced by system xc- inhibitors or glutathione peroxidase 4 (GPx4) inhibitors, as well as drugs such as sorafenib, sulfasalazine (SAS), and artesunate (ART). Ferroptosis has been recently shown to be critical in regulating growth of tumors, such as hepatocellular carcinoma (HCC), renal cell carcinoma (RCC), non-small cell lung cancer (NSCLC), ovarian cancer, pancreatic carcinoma, and diffuse large B cell lymphoma (DLBCL). Ferroptosis is also associated with resistance to chemotherapeutic drugs and the anti-tumor efficacy of immunotherapy. Conclusion: This review summarizes the mechanism of ferroptosis and its relationship with different types of tumors, to advance our understanding of cell death and to find a novel approach for clinical cancer management.

Circular RNAs (circRNAs) are a class of non-coding RNAs (ncRNAs) that structurally form closed loops without 5'-end cap and 3'-end poly(A) tail unlike linear RNAs. CircRNAs are widely present in eukaryotic cells with the capabilities of structural stability, high abundance and cell- /tissue-specific expression. A growing body of researches suggest that the dysregulated circRNAs are intimately relevant to the occurrence and development of cancer. In this review, we mainly discuss the differentially expressed circRNAs in cancer tissues, plasma and exosomes, which makes it possible for clinicians to use certain circRNAs as novel biomarkers for cancer diagnosis and prognosis. In particular, we primarily focus on circRNAs as potential therapeutic targets, which will provide promising applications in cancer gene therapy.

Background: During the first few trials of gene therapy for Leber’s hereditary optic neuropathy performed by our group, the visual acuity of the patients increased gradually over several months, or even years. However, in the current round of gene therapy for Leber’s hereditary optic neuropathy, we noted that the visual acuity of three patients increased rapidly, within a few days after treatment. Case presentation: Three patients who were diagnosed with mitochondrial gene 11778 mutation (associated with a G-to-A transition at Mt-11778 in the ND4 subunit gene of complex I of mitochondrial DNA that changes an arginine to histidine at amino acid 340) by genetic diagnosis were followed up three times before gene therapy, which lasted for 1 year, without spontaneous improvement of vision. Visual acuity in one or both eyes of each of the three patients increased rapidly after the initial gene therapy treatment. Conclusion: We suspect that in some patients with Leber’s hereditary optic neuropathy, a portion of the retinal ganglion cells might remain in a “dormant” state for a certain period of time; these may be activated, within an optimal timeframe, during gene therapy for Leber’s hereditary optic neuropathy.