Current Issue : October-December Volume : 2022 Issue Number : 4 Articles : 5 Articles
Cancer becomes one of the main causes of human deaths in the world due to the high incidence and mortality rate and produces serious economic burdens. With more and more attention is paid on cancer, its therapies are getting more of a concern. Previous research has shown that the occurrence, progression, and treatment prognosis of malignant tumors are closely related to genetic and gene mutation. CRISPR/Cas9 has emerged as a powerful method for making changes to the genome, which has extensively been applied in various cell lines. Establishing the cell and animal models by CRISPR/ Cas9 laid the foundation for the clinical trials which possibly treated the tumor. CRISPRCas9- mediated genome editing technology brings a great promise for inhibiting migration, invasion, and even treatment of tumor. However, the potential off-target effect limits its clinical application, and the effective ethical review is necessary. The article reviews the molecular mechanisms of CRISPR/Cas9 and discusses the research and the limitation related to cancer clinical trials....
Charcot-Marie-Tooth disease type 1A (CMT1A), the most common inherited demyelinating peripheral neuropathy, is caused by PMP22 gene duplication. Overexpression of WT PMP22 in Schwann cells destabilizes the myelin sheath, leading to demyelination and ultimately to secondary axonal loss and disability. No treatments currently exist that modify the disease course. The most direct route to CMT1A therapy will involve reducing PMP22 to normal levels. To accomplish this, we developed a gene therapy strategy to reduce PMP22 using artificial miRNAs targeting human PMP22 and mouse Pmp22 mRNAs. Our lead therapeutic miRNA, miR871, was packaged into an adeno-associated virus 9 (AAV9) vector and delivered by lumbar intrathecal injection into C61-het mice, a model of CMT1A. AAV9-miR871 efficiently transduced Schwann cells in C61-het peripheral nerves and reduced human and mouse PMP22 mRNA and protein levels. Treatment at early and late stages of the disease significantly improved multiple functional outcome measures and nerve conduction velocities. Furthermore, myelin pathology in lumbar roots and femoral motor nerves was ameliorated. The treated mice also showed reductions in circulating biomarkers of CMT1A. Taken together, our data demonstrate that AAV9-miR871–driven silencing of PMP22 rescues a CMT1A model and provides proof of principle for treating CMT1A using a translatable gene therapy approach....
For patients with chronic limb-threatening ischemia and limited revascularization options, alternate means for therapeutic angiogenesis and limb salvage are needed. E-selectin is a cell adhesion molecule that is critical for inflammation and neovascularization in areas of wound healing and ischemia. Here, we tested the efficacy of modifying ischemic limb tissue by intramuscular administration of E-selectin/AAV2/2 (adeno-associated virus serotype 2/2) to modulate angiogenic and inflammatory responses in a murine hindlimb gangrene model. Limb appearance, reperfusion, and functional recovery were assessed for 3 weeks after induction of ischemia. Mice receiving E-selectin/AAV2/2 gene therapy had reduced gangrene severity, increased limb and footpad perfusion, enhanced recruitment of endothelial progenitor cells, and improved performance on treadmill testing compared to control group. Histologically, E-selectin/AAV2/2 gene therapy was associated with increased vascularity and preserved myofiber integrity. Eselectin/ AAV2/2 gene therapy also upregulated a panel of pro-angiogenic genes yet downregulated another group of genes associated with the inflammatory response. This novel gene therapy did not induce adverse effects on coagulability, or hematologic, hepatic, and renal function. Our findings highlight the potential of E-selectin/AAV2/2 gene therapy for improving limb perfusion and function in patients with chronic limbthreatening ischemia....
One in ten people worldwide has chronic kidney disease (CKD)1. A subset of patients progresses to end-stage kidney disease (ESKD), which requires dialysis or transplantation and is a risk factor for cardiovascular disease and all-cause mortality1. CKD progression is linked to breakdown of the glomerular filtration barrier, the site of ultrafiltration in the kidney, which consists of endothelial cells, the glomerular basement membrane (GBM) and epithelial podocytes2,3. Podocytes have a unique architecture with foot processes that extend from their cell bodies, interdigitate and form slit diaphragms facilitating size and charge-selective filtration and preventing the loss of plasma proteins4,5. In health, podocyte shape is maintained by a complex, highly regulated actin cytoskeleton, which supports the foot processes6,7, and anchors the cell to the GBM8. During glomerular disease, the podocyte cytoskeleton becomes disorganised often leading to podocyte loss, impaired filtration and leakage of plasma proteins, such as albumin, into the urine7,9–11. Albuminuria is a hallmark of glomerular disease, irrespective of the underlying aetiology12. Therefore, therapies that protect the podocyte cytoskeleton represent a novel strategy to preserve the integrity of the glomerular filtration barrier, prevent albuminuria and improve glomerular disease progression. Thymosin β4 (TB4) sequesters monomeric G-actin in mammalian cells13,14 and maintains high concentrations of G-actin available for polymerisation into actin filaments (F-actin)15. We have previously shown that endogenous TB4 is expressed in podocytes and has a protective role. We found that lack of endogenous TB4...
Marfan syndrome (MFS) is one of the most common inherited disorders of connective tissue caused by mutations of the fibrillin-1 gene (FBN1). Vascular abnormalities, such as the enlargement of the aorta with the risk of life-threatening rupture are frequently observed. However, current treatment is limited and therapeutic options focus solely on symptomatic therapy. Gene therapy focuses on genetically modifying cells to produce a therapeutic effect and may be a promising treatment option for MFS. Here, we first provide an overview of the historical background and characterization of MFS. Subsequently, we summarise current gene therapy options and possible translational concepts for this inherited disorder that affects connective tissue....
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