Current Issue : January-March Volume : 2023 Issue Number : 1 Articles : 5 Articles
Despite the great progress over the past few decades in both the diagnosis and treatment of a great variety of human cancers, glioblastoma remains the most lethal brain tumor. In recent years, cancer gene therapy focused on non-viral vectors which emerged as a promising approach to glioblastoma treatment. Transferrin (Tf) easily penetrates brain cells of the blood–brain barrier, and its receptor is highly expressed in this barrier and glioblastoma cells. Therefore, the development of delivery systems containing Tf appears as a reliable strategy to improve their brain cells targeting ability and cellular uptake. In this work, a cell-penetrating peptide (WRAP5), bearing a Tf-targeting sequence, has been exploited to condense tumor suppressor p53-encoding plasmid DNA (pDNA) for the development of nanocomplexes. To increase the functionality of developed nanocomplexes, the drug Temozolomide (TMZ) was also incorporated into the formulations. The physicochemical properties of peptide/pDNA complexes were revealed to be dependent on the nitrogen to phosphate groups ratio and can be optimized to promote efficient cellular internalization. A confocal microscopy study showed the capacity of developed complexes for efficient glioblastoma cell transfection and consequent pDNA delivery into the nucleus, where efficient gene expression took place, followed by p53 protein production. Of promise, these peptide/pDNA complexes induced a significant decrease in the viability of glioblastoma cells. The set of data reported significantly support further in vitro research to evaluate the therapeutic potential of developed complexes against glioblastoma....
In addition to laser photocoagulation, currently used therapeutic interventions for diabetic retinopathy (DR) include relatively short-lived anti-VEGF drugs targeting vascular endothelial growth factor (VEGF). The latter requires frequent administration via intravitreal injections to effect long-term VEGF suppression. However, due to the patient burden associated with this treatment modality, gene therapy may represent a preferable alternative, providing long-lasting yet patient-friendly effects. Here, we explore the therapeutic efficacy of rAAV2-sVEGFRv-1, a recombinant adeno-associated virus encoding a soluble variant of VEGF receptor-1, upon early DR processes. Bevacizumab, an anti-VEGF agent often prescribed off label to treat DR, was used as an experimental comparator. Administered by intravitreal injection to a streptozotocin-induced diabetic mouse model, rAAV2-sVEGFRv-1 was shown to effectively transduce the mouse retinas and express its transgene therein, leading to significant reductions in pericyte loss and retinal cell layer thinning, two processes that play major roles in DR progression. Acellular capillary formation, vascular permeability, and apoptotic activity, the latter being the cell death mechanism by which retinal neurodegeneration occurs, were also shown to be reduced by the therapeutic virus vector. Immunohistochemistry was used to visualize that rAAV2-sVEGFRv-1 has an effect on cell types important to DR pathophysiology, particularly the ganglion cell layer and glial cells. Combined with our previous work showing that the therapeutic virus vector reduces neovascularization, our current results reveal that rAAV2-sVEGFRv-1 addresses the early aspects of DR as well, thereby demonstrating its potential as a human gene therapeutic versus the condition as a whole....
Non-viral gene therapy has the potential to overcome several shortcomings in viral vectorbased therapeutics. Methods of in vivo plasmid delivery have developed over recent years to increase the efficiency of non-viral gene transfer, yet further improvements still need to be made to improve their translational capacity. Gene therapy advances for inherited retinal disease have been particularly prominent over the recent decade but overcoming physical and physiological barriers present in the eye remains a key obstacle in the field of non-viral ocular drug delivery. Minicircles are circular double-stranded DNA vectors that contain expression cassettes devoid of bacterial DNA, thereby limiting the risks of innate immune responses induced by such elements. To date, they have not been extensively used in pre-clinical studies yet remain a viable vector option for the treatment of inherited retinal disease. Here, we explore the potential of minicircle DNA delivery to the neural retina as a gene therapy approach. We consider the advantages of minicircles as gene therapy vectors as well as review the challenges involved in optimising their delivery to the neural retina....
Traumatic brain injury (TBI) is one of the leading causes of long-term neurological disabilities in the world. TBI is a signature disease for soldiers and veterans, but also affects civilians, including adults and children. Following TBI, the brain resident and immune cells turn into a “reactive” state, characterized by the production of inflammatory mediators that contribute to the development of cognitive deficits. Other injuries to the brain, including radiation exposure, may trigger TBI-like pathology, characterized by inflammation. Currently there are no treatments to prevent or reverse the deleterious consequences of brain trauma. The recognition that TBI predisposes stem cell alterations suggests that stem cell-based therapies stand as a potential treatment for TBI. Here, we discuss the inflamed brain after TBI and radiation injury. We further review the status of stem cells in the inflamed brain and the applications of cell therapy in sequestering inflammation in TBI....
One of the most serious problems in people with diabetes is diabetic foot syndrome. Due to the peripheral location of atherosclerotic lesions in the arterial system of the lower extremities, endovascular treatment plays a dominant role. However, carrying out these procedures is not always possible and does not always bring the expected results. Gene therapy, which stimulates angiogenesis, improves not only the inflow from the proximal limb but also the blood redistribution in individual angiosomes. Due to the encouraging results of sequential treatment consisting of intramuscular injections of VEGF/HGF bicistronic plasmids followed by a month of ANG1 plasmids, we decided to use the described method for the treatment of critical ischemia of the lower limbs in the course of diabetes and, more specifically, in diabetic foot syndrome. Twenty-four patients meeting the inclusion criteria were enrolled in the study. They were randomly divided into two equal groups. The first group of patients was subjected to gene therapy, where the patients received intramuscular injections of pIRES/VEGF165/HGF plasmids and 1 month of ANG-1 plasmids. The remaining patients constituted the control group. Gene therapy was well tolerated by most patients. The wounds healed significantly better in Group 1. The minimal value of ABI increased significantly in Group 1 from 0.44 ± 0.14 (± standard deviation) to 0.47 ± 0.12 (with p = 0.028) at the end of the study. There were no significant differences in the control group. In the gene treatment group, PtcO2 increased significantly (from 28.71 ± 10.89 mmHg to 33.9 ± 6.33 mmHg with p = 0.001), while in Group 2, no statistically significant changes were found. The observed resting pain decreased significantly in both groups (Group 1 decreased from 6.80 ± 1.48 to 2.10 ± 1.10; p < 0.001; the control group decreased from 7.44 ± 1.42 to 3.78 ± 1.64 with p < 0.001). In our study, we evaluated the effectiveness of gene therapy with the growth factors described above in patients with CLI in the course of complicated DM. The therapy was shown to be effective with minimal side effects. No serious complications were observed....
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