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Quarterly published in print and online "Inventi Impact: Gene Medicines" publishes high quality unpublished as well as high impact pre-published research and reviews catering to the needs of researchers and professionals. This journal focuses on the science of gene transfer and its applications in gene and cell therapy. The areas included are - vector design, delivery and targeting, gene expression and regulation, preclinical studies, developmental aspects and clinical trials.
A biomimic reconstituted high density lipoprotein (rHDL) based system, rHDL/Stearic-PEI/VEGF complexes, was fabricated\nas an advanced nanovector for delivering VEGF plasmid. Here, Stearic-PEI was utilized to effectively condense VEGF plasmid\nand to incorporate the plasmid into rHDL. The rHDL/Stearic-PEI/VEGF complexes with diameter under 100 nm and neutral\nsurface charge demonstrated enhanced stability under the presence of bovine serum albumin. Moreover, in vitro cytotoxicity\nand transfection assays on H9C2 cells further revealed their superiority, as they displayed lower cytotoxicity with much higher\ntransfection efficiencywhen compared to PEI 10K/VEGF and Lipos/Stearic-PEI/VEGF complexes. In addition, in vivo investigation\non ischemia/reperfusion rat model implied that rHDL/Stearic-PEI/VEGF complexes possessed high transgene capacity and strong\ntherapeutic activity. These findings indicated that rHDL/Stearic-PEI/VEGF complexes could be an ideal gene delivery system for\nenhanced VEGF gene therapy of myocardial ischemia, which might be a new promising strategy for effective myocardial ischemia\ntreatment....
A comparative analysis of genome-scale transcriptomic data of two types of skin cancers, melanoma and basal cell\r\ncarcinoma in comparison with other cancer types, was conducted with the aim of identifying key regulatory factors that\r\neither cause or contribute to the aggressiveness of melanoma, while basal cell carcinoma generally remains a mild disease.\r\nMultiple cancer-related pathways such as cell proliferation, apoptosis, angiogenesis, cell invasion and metastasis, are\r\nconsidered, but our focus is on energy metabolism, cell invasion and metastasis pathways. Our findings include the\r\nfollowing. (a) Both types of skin cancers use both glycolysis and increased oxidative phosphorylation (electron transfer\r\nchain) for their energy supply. (b) Advanced melanoma shows substantial up-regulation of key genes involved in fatty acid\r\nmetabolism (b-oxidation) and oxidative phosphorylation, with aerobic metabolism being far more efficient than anaerobic\r\nglycolysis, providing a source of the energetics necessary to support the rapid growth of this cancer. (c) While advanced\r\nmelanoma is similar to pancreatic cancer in terms of the activity level of genes involved in promoting cell invasion and\r\nmetastasis, the main metastatic form of basal cell carcinoma is substantially reduced in this activity, partially explaining why\r\nthis cancer type has been considered as far less aggressive. Our method of using comparative analyses of transcriptomic\r\ndata of multiple cancer types focused on specific pathways provides a novel and highly effective approach to cancer studies\r\nin general....
Recent progress in neural stem cell- (NSC-) based tumor-targeted gene therapy showed that NSC vectors expressing an artificially\nengineered viral fusogenic protein, VSV-G H162R, could cause tumor cell death specifically under acidic tumor microenvironment\nby syncytia formation; however, the killing efficiency still had much room to improve. In the view that coexpression of another\nantitumoral gene with VSV-G can augment the bystander effect, a synthetic regulatory system that triggers transgene expression\nin a cell fusion-inducible manner has been proposed. Here we have developed a double-switch cell fusion-inducible transgene\nexpression system (DoFIT) to drive transgene expression upon VSV-G-mediated NSC-glioma cell fusion. In this binary system,\ntransgene expression is coregulated by a glioma-specific promoter and targeting sequences of a microRNA (miR) that is highly\nexpressed in NSCs but lowly expressed in glioma cells.Thus, transgene expression is Ã¢â?¬Å?switched offÃ¢â?¬Â by the miR in NSC vectors, but\nafter cell fusionwith glioma cells, the miR is diluted and loses its suppressive effect.Meanwhile, in the syncytia, transgene expression\nis Ã¢â?¬Å?switched onÃ¢â?¬Â by the glioma-specific promoter. Our in vitro and in vivo experimental data show that DoFIT successfully abolishes\nluciferase reporter gene expression in NSC vectors but activates it specifically after VSV-G-mediated NSC-glioma cell fusion....
Objective: Dual vector AAV systems are being utilised to enable gene therapy for disorders in which the disease\ngene is too large to fit into a single capsid. Fragmented adeno-associated viral (fAAV) vectors containing single\ninverted terminal repeat truncated transgenes have been considered as one such gene replacement strategy. Here\nwe aim to add to the current understanding of the molecular mechanisms employed by fAAV dual vector systems.\nMethods: Oversized (>8 kb) transgene constructs containing ABCA4 coding sequence were packaged\nas truncated fragments <5 kb in size into various AAV serotypes. In vitro transductions with these fAAV vector\npreparations were conducted with mRNA and protein expression products assessed by way of RT-PCR, qPCR and\nwestern blot techniques.\nResults: Transductions with fAAV vector preparations yielded ABCA4 mRNA, but did not generate detectable\nlevels of protein. Sequencing of the transcript population revealed the presence of full length ABCA4 CDS with\nadditional hybrid ABCA4 variants, indicating truncated transgenes without regions of overlap were joining and forming\nstable hybrid transgenes. In contrast, an ABCA4 overlapping dual vector system (OV) with a defined complementary\nregion generated only full length mRNA transcripts plus detectable ABCA4 protein.\nConclusion: Despite previous success shown with the fAAV approach, the lack of repeatability and identification\nof stable hybrid transcripts capable of protein production suggests there is more refinement required before\nconsidering this approach in a clinical setting....
Background: Chronic obstructive pulmonary disease presents with two different phenotypes: chronic bronchitis\nand emphysema with parenchymal destruction. Decreased expression of vascular endothelial growth factor and\nincreased endothelial cell apoptosis are considered major factors for emphysema. Stem cells have the ability of\nvascular regeneration and function as a repair mechanism for the damaged endothelial cells. Currently, minimally\ninvasive interventional procedures such as placement of valves, bio-foam or coils are performed in order to improve\nthe disturbed mechanical function in emphysema patients. However, these procedures cannot restore functional\nlung tissue. Additionally stem cell instillation into the parenchyma has been used in clinical studies aiming to\nimprove overall respiratory function and quality of life.\nMethods: In our current experiment we induced emphysema with a DDMC non-viral vector in BALBC mice and\nsimultaneously instilled stem cells testing the hyposthesis that they might have a protective role against the\ndevelopment of emphysema. The mice were divided into four groups: a) control, b) 50.000 cells, c) 75.000 and\nd) 100.000 cells.\nResults: Lung pathological findings revealed that all treatment groups had less damage compared to the control\ngroup. Additionally, we observed that emphysema lesions were less around vessels in an area of 10 ?m.\nConclusions: Our findings indicate that stem cell instillation can have a regenerative role if applied upon a tissue\nscaffold with vessel around.\nVirtual Slides: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/\nvs/13000_2014_195...
Adeno-Associated Viruses (AAV) are widely used gene-therapy vectors for both clinical\napplications and laboratory investigations. The titering of different AAV preparations is important\nfor quality control purposes, as well as in comparative studies. However, currently available methods\nare limited in their ability to detect various serotypes with sensitivity and convenience. Here, we took\nadvantage of a newly discovered AAV receptor protein with high affinity to multiple AAV serotypes,\nand developed an ELISA-like method named â??VIRELISAâ? (virus receptor-linked immunosorbent\nassay) by adopting fusion with a streptavidin-binding peptide (SBP). It was demonstrated that\noptimized VIRELISA assays exhibited satisfactory performance for the titering of AAV2â?¦..â?¦â?¦â?¦...
Background: There is reason to expect strong genetic influences on the risk of developing active pulmonary\r\ntuberculosis (TB) among latently infected individuals. Many of the genome wide linkage and association studies\r\n(GWAS) to date have been conducted on African populations. In order to identify additional targets in genetically\r\ndissimilar populations, and to enhance our understanding of this disease, we performed a multi-stage GWAS in a\r\nSoutheast Asian cohort from Indonesia.\r\nMethods: In stage 1, we used the Affymetrix 100 K SNP GeneChip marker set to genotype 259 Indonesian\r\nsamples. After quality control filtering, 108 cases and 115 controls were analyzed for association of 95,207 SNPs. In\r\nstage 2, we attempted validation of 2,453 SNPs with promising associations from the first stage, in 1,189 individuals\r\nfrom the same Indonesian cohort, and finally in stage 3 we selected 251 SNPs from this stage to test TB\r\nassociation in an independent Caucasian cohort (n = 3,760) from Russia.\r\nResults: Our study suggests evidence of association (P = 0.0004-0.0067) for 8 independent loci (nominal\r\nsignificance P < 0.05), which are located within or near the following genes involved in immune signaling: JAG1,\r\nDYNLRB2, EBF1, TMEFF2, CCL17, HAUS6, PENK and TXNDC4.\r\nConclusions: Mechanisms of immune defense suggested by some of the identified genes exhibit biological\r\nplausibility and may suggest novel pathways involved in the host containment of infection with TB....
Drug delivery to the brain is highly hindered by the presence of the bloodâ??brain barrier\n(BBB), which prevents the entry of many potential drugs/biomolecules into the brain. One of the\ncurrent strategies to achieve gene therapy for neurodegenerative diseases involves direct injection of\na viral vector into the brain. There are various disadvantages of viral vectors, including limitations of\ncargo size and safety concerns. Nanomolecules, such as dendrimers, serve as an excellent alternative\nto viral delivery. In this study, as proof-of-concept, we used a surface-modified dendrimer complex\nand delivered large plasmids to cells in vitro and in vivo in healthy rats via intracranial injection.\nThe dendrimers were biodegradable by chemicals found within cells and toxicity assays revealed\nthat the modified dendrimers were much less toxic than unmodified amine-surface dendrimers.\nAs mentioned in our previous publication, these dendrimers with appropriately modified surfaces are\nsafe, can deliver large plasmids to the brain, and can overcome the cargo size limitations associated\nwith viral vectors. The biocompatibility of this dendritic nanomolecule and the ability to finely tune\nits surface chemistry provides a gene delivery system that could facilitate future in vivo cellular\nreprograming and other gene therapies....
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....
Many preclinical and clinical studies of hematopoietic stem cell-based gene therapy (GT)
are based on the use of lentiviruses as the vector of choice. Assessment of the vector titer
and transduction efficiency of the cell product is critical for these studies. Efficacy and
safety of the modified cell product are commonly determined by assessing the vector
copy number (VCN) using qPCR. However, this optimized and well-established method in
the GT field is based on bulk population averages, which can lead to misinterpretation of
the actual VCN per transduced cell. Therefore, we introduce here a single cell-based
method that allows to unmask cellular heterogeneity in the GT product, even when
antibodies are not available. We use Invitrogen’s flow cytometry-based PrimeFlow™RNA
Assay with customized probes to determine transduction efficiency of transgenes of
interest, promoter strength, and the cellular heterogeneity of murine and human stem
cells. The assay has good specificity and sensitivity to detect the transgenes, as shown by
the high correlations between PrimeFlow™-positive cells and the VCN. Differences in
promoter strengths can readily be detected by differences in percentages and
fluorescence intensity. Hence, we show a customizable method that allows to
determine the number of transduced cells and the actual VCN per transduced cell in a
GT product. The assay is suitable for all therapeutic genes for which antibodies are not
available or too cumbersome for routine flow cytometry. The method also allows costaining
of surface markers to analyze differential transduction efficiencies in
subpopulations of target cells....
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