Overview of latest articles and publications on gene therapy in PubMed, including Human Gene Therapy, Journal of Molecular Medicine and Journal of Gene Medicine. PubMed is a service of the US National Library of Medicine that includes over 18 million citations from MEDLINE and other life science journals.
- A Pilot Study Evaluating Combinatorial and Simultaneous Delivery of Polyethylenimine-Plasmid DNA Complexes Encoding for VEGF and PDGF for Bone Regeneration in Calvarial Bone Defects.
D'Mello SR, Elangovan S, Hong L, et al. A Pilot Study Evaluating Combinatorial and Simultaneous Delivery of Polyethylenimine-Plasmid DNA Complexes Encoding for VEGF and PDGF for Bone Regeneration in Calvarial Bone Defects. [JOURNAL ARTICLE]Curr Pharm Biotechnol 2015; 16(7):655-660.Gene therapy is a promising strategy to deliver growth factors of interest locally in a sustained fashion and has the potential to overcome barriers to using recombinant protein therapy such as sustainability and cost. Recent studies demonstrate the safety and efficacy of non-viral delivery of plasmid DNA (pDNA) encoding a single growth factor to enhance bone healing. This pilot study is aimed at testing a non-viral gene delivery system that can deliver two different plasmids encoding two different growth factors. Polyethylenimine (PEI), a cationic polymer, was utilized as a gene delivery vector and collagen scaffold was used as a carrier to deliver the PEI-pDNA complexes encoding platelet derived growth factor B (PDGF-B) and/or vascular endothelial growth factor (VEGF). Calvarial defects in rats were implanted with scaffolds containing PEI-pPDGF-B complexes, PEI-pVEGF complexes or containing both PEIpPDGF- B and PEI-pVEGF complexes in a 1:1 ratio of plasmids. The results indicated that bone regeneration as measured using micro-CT and histological assessments was inferior in groups treated with PEI-(pPDGF-B + pVEGF) complexes, compared to defects treated with PEI-pPDGF-B complexes. This pilot study that explores the feasibility and efficacy of combinatorial non-viral gene delivery system for bone regeneration appears to provide a rationale for investigation of sequential delivery of growth factors at specific time points during the healing phases and this will be explored further in future studies.
- Risk factors and clinical outcomes of acute myeloid leukaemia with central nervous system involvement in adults.
Cheng CL, Li CC, Hou HA, et al. Risk factors and clinical outcomes of acute myeloid leukaemia with central nervous system involvement in adults. [JOURNAL ARTICLE]BMC Cancer 2015 May 2; 15(1):344.Acute myeloid leukaemia (AML) with central nervous system (CNS) involvement in adults is uncommon, and studies of this subject are scant.We conducted a retrospective study to investigate the clinical aspects, cytogenetic abnormalities, molecular gene mutations and outcomes of adult AML patients with CNS involvement. Three hundred and ninety-five patients with newly diagnosed AML were reviewed.Twenty (5.1%) patients had CNS involvement, including 7 (1.8%) with initial CNS disease and 4 (1%) who suffered an isolated CNS relapse. The patients with CNS involvement were younger, had higher leukocyte, platelet, and peripheral blast cell counts, FAB M4 morphology, and chromosome translocations involving 11q23 (11q23 abnormalities) more frequently than did the patients without CNS involvement. No differences in sex, haemoglobin levels, serum LDH levels, immunophenotype of leukaemia cells, or molecular gene mutations were observed between the two groups. Multivariate analyses showed that age ≤ 45 years (OR, 5.933; 95% CI, 1.82 to 19.343), leukocyte counts ≥ 50,000/μl (OR, 3.136; 95% CI, 1.083 to 9.078), and the presence of 11q23 abnormalities (OR, 5.548; 95% CI, 1.208 to 25.489) were significant predictors of CNS involvement. Patients with initial CNS disease had 5-year overall survival and relapse-free survival rates that were similar to those without initial CNS disease. However, three of four patients who suffered an isolated CNS relapse died, and their prognosis was as poor as that of patients who suffered a bone marrow relapse.CNS involvement in adult patients with AML is rare. Three significant risk factors for CNS involvement including age ≤ 45 years, leukocyte counts ≥ 50,000/μl and the presence of 11q23 abnormalities were identified in this study. Future investigations to determine whether adult AML patients having these specific risk factors would benefit from CNS prophylactic therapy are necessary.
- Hepatitis B Virus Genotypes and Variants.
Lin CL, Kao JH Hepatitis B Virus Genotypes and Variants. [REVIEW]Cold Spring Harb Perspect Med 2015; 5(5)At least 10 hepatitis B virus (HBV) genotypes (A to J) with distinct geographic distributions and several HBV mutants, including precore/core promoter mutations and pre-S/S deletion mutations, have been recognized to be not only predictive of liver disease progression but also associated with response to antiviral therapy. HBV genotype-specific pathogenesis may contribute to heterogeneous clinical outcomes in chronic hepatitis B patients across the world. For example, patients with HBV genotypes C and D infection have a lower rate of spontaneous HBeAg seroconversion. In addition, HBV genotypes C and D have a higher frequency of core promoter and pre-S mutations than genotypes A and B. Genotypes C and D also carry a higher lifetime risk of cirrhosis and HCC development than genotypes A and B. Core promoter and pre-S mutations also correlate with an increased risk of hepatocellular carcinoma (HCC). Therapeutically, genotypes A and B patients have a better response to interferon-based therapy than genotypes C and D patients, but the response to nucleos(t)ide analogs is comparable across different HBV genotypes. In conclusion, HBV genotypes and variants may serve as viral genetic markers to predict disease progression as well as help practicing physicians optimize individualized antiviral therapy in clinical practice.
- Co-delivery of doxorubicin and tumor-suppressing p53 gene using a POSS-based star-shaped polymer for cancer therapy.
Li Y, Xu B, Bai T, et al. Co-delivery of doxorubicin and tumor-suppressing p53 gene using a POSS-based star-shaped polymer for cancer therapy. [Journal Article]Biomaterials 2015 Jul.:12-23.In this work, a star-shaped polymer consisting of a cationic poly[2-(dimethylamino) ethyl methacrylate] (PDMAEMA) shell and a zwitterionic poly[N-(3-(methacryloylamino) propyl)-N,N-dimethyl-N-(3-sulfopropyl) ammonium hydroxide] (PMPD) corona was grafted from a polyhedral oligomeric silsesquioxanes (POSS)-based initiator via atomic transfer radical polymerization (ATRP). The reported star-shaped polymer could form stable micelles in aqueous solutions even in the presence of serum. In addition, anti-cancer drug doxorubicin and tumor-suppressing p53 gene were loaded in the process of micelle formation. The formed polyplex was biocompatible and highly efficient for both drug and gene delivery. Furthermore, the polyplex was able to cause a high apoptotic rate of tumor cells both in vitro and in vivo. This combination delivery strategy offers a promising method for cancer therapy and can be used for further clinical applications.
- Anti-depressant therapy and cancer risk: A nested case-control study.
Boursi B, Lurie I, Mamtani R, et al. Anti-depressant therapy and cancer risk: A nested case-control study. [JOURNAL ARTICLE]Eur Neuropsychopharmacol 2015 Apr 17.Previous studies demonstrated a possible association between anti-depressant therapy with selective serotonin reuptake inhibitors (SSRI) and tricyclic anti-depressants (TCA), several genetic and hormonal pathways and cancer risk, with inconsistent results. Exposure to serotonin-norepinephrine reuptake inhibitors (SNRI) was not studied extensively. We sought to evaluate the association between exposure to SSRIs, TCAs and SNRIs and the five most common solid tumors. We conducted nested case-control studies using a large UK population-representative database. Cases were those with any medical code for the specific malignancy. For every case, four controls matched on age, sex, practice site, and duration of follow-up before index date were selected using incidence-density sampling. Exposure of interest was SSRI, SNRI or TCA therapy before index date. Odds ratios (ORs) and 95% CIs were estimated for each anti-depressant class using conditional logistic-regression analysis, adjusted for potential confounders, such as obesity, smoking history and alcohol consumption.109,096 cancer patients and 426,402 matched controls were included. Current SSRI users with treatment initiation>one year before index date had modestly higher risk for lung and breast cancers with ORs of 1.27 (95% CI 1.16-1.38) and 1.12 (95% CI 1.06-1.18), respectively. Among current TCA users, there was a higher risk only for lung cancers with OR of 1.45 (95% CI 1.31-1.6). There was no statistically significant association between current SNRI therapy and cancer risk.Treatment with SSRI and TCA might be associated with increased lung cancer risk. SSRI therapy might be associated with modest increase in breast cancer risk.
- Genetic polymorphisms in cytochrome P450 and clinical outcomes of FOLFIRI chemotherapy in patients with metastatic colorectal cancer.
Dong N, Meng F, Wu Y, et al. Genetic polymorphisms in cytochrome P450 and clinical outcomes of FOLFIRI chemotherapy in patients with metastatic colorectal cancer. [JOURNAL ARTICLE]Tumour Biol 2015 May 2.The purpose of this study is to evaluate the influence of germline polymorphisms of cytochrome P450 (CYP450) on objective response, progression-free survival (PFS) and overall suruvival (OS) in metastatic colorectal cancer (mCRC) receiving the combination chemotherapy of irinotecan, 5-fluorouracil, and leucovorin (FOLFIRI). All SNPs in CYP450, whose minor allele frequency were more than 10 %, were genotyped in 82 patients with mCRC who received first-line FOLFIRI regimen. χ (2) test or Fisher's exact test was used to assess the correlation between SNPs and objective response as appropriate and log-rank test between SNPs and PFS or OS. Cox proportional hazards models were used to analyze the association of CYP450 gene polymorphisms and clinical factors for PFS and OS. No SNP showed predictive or prognostic value for clinical outcomes, except for CYP3A5 rs776746 A>G, which was significantly associated with PFS (P = 0.0002). Multivariate analysis confirmed its prognostic value for PFS (P = 0.002). CYP3A5 rs776746 A>G polymorphisms have a prognostic contribution toward FOLFIRI regimen in mCRC. This could represent a further step toward personalized therapy.
- Advances in the understanding of the clinically relevant genetic pathways and molecular aspects of canine mammary tumours. Part 2: Invasion, angiogenesis, metastasis and therapy.
Santos AA, Matos AJ Advances in the understanding of the clinically relevant genetic pathways and molecular aspects of canine mammary tumours. Part 2: Invasion, angiogenesis, metastasis and therapy. [REVIEW]Vet J 2015 Mar 27.Significant advances have been made recently in the understanding of the molecular events and critical pathways associated with and driving cancer of the mammary gland in humans and dogs. The study of canine mammary tumour biology, particularly the interactions of neoplastic cells with stromal and immune cells, is crucial for the development of novel effective therapeutic agents and strategies. This second part of a two-part review discusses some of the latest advances in the understanding of the clinically relevant genetic and molecular pathways involved in metastasis and in the interactions between tumour and stromal cells, including inflammatory and immune cells, cancer-associated fibroblasts, and endothelial cells. Recent experimental data on the role of matrix-degrading proteases and angiogenic factors are also discussed. Finally, the clinical utility of different non-surgical therapeutic modalities is reviewed.
- Tumor regression following intravenous administration of lactoferrin- and lactoferricin-bearing dendriplexes.
Lim LY, Koh PY, Somani S, et al. Tumor regression following intravenous administration of lactoferrin- and lactoferricin-bearing dendriplexes. [JOURNAL ARTICLE]Nanomedicine 2015 Apr 28.The possibility of using gene therapy for the treatment of cancer is limited by the lack of safe, intravenously administered delivery systems able to selectively deliver therapeutic genes to tumors. In this study, we investigated if the conjugation of the polypropylenimine dendrimer to lactoferrin and lactoferricin, whose receptors are overexpressed on cancer cells, could result in a selective gene delivery to tumors and a subsequently enhanced therapeutic efficacy. The conjugation of lactoferrin and lactoferricin to the dendrimer significantly increased the gene expression in the tumor while decreasing the non-specific gene expression in the liver. Consequently, the intravenous administration of the targeted dendriplexes encoding TNFα led to the complete suppression of 60% of A431 tumors and up to 50% of B16-F10 tumors over one month. The treatment was well tolerated by the animals. These results suggest that these novel lactoferrin- and lactoferricin-bearing dendrimers are promising gene delivery systems for cancer therapy.
- HGF Gene Modification in Mesenchymal Stem Cells Reduces Radiation-Induced Intestinal Injury by Modulating Immunity.
Wang H, Sun RT, Li Y, et al. HGF Gene Modification in Mesenchymal Stem Cells Reduces Radiation-Induced Intestinal Injury by Modulating Immunity. [Journal Article]PLoS One 2015; 10(5):e0124420.Effective therapeutic strategies to address intestinal complications after radiation exposure are currently lacking. Mesenchymal stem cells (MSCs), which display the ability to repair the injured intestine, have been considered as delivery vehicles for repair genes. In this study, we evaluated the therapeutic effect of hepatocyte growth factor (HGF)-gene-modified MSCs on radiation-induced intestinal injury (RIII).Female 6- to 8-week-old mice were radiated locally at the abdomen with a single 13-Gy dose of radiation and then treated with saline control, Ad-HGF or Ad-Null-modified MSCs therapy. The transient engraftment of human MSCs was detected via real-time PCR and immunostaining. The therapeutic effects of non- and HGF-modified MSCs were evaluated via FACS to determine the lymphocyte immunophenotypes; via ELISA to measure cytokine expression; via immunostaining to determine tight junction protein expression; via PCNA staining to examine intestinal epithelial cell proliferation; and via TUNEL staining to detect intestinal epithelial cell apoptosis.The histopathological recovery of the radiation-injured intestine was significantly enhanced following non- or HGF-modified MSCs treatment. Importantly, the radiation-induced immunophenotypic disorders of the mesenteric lymph nodes and Peyer's patches were attenuated in both MSCs-treated groups. Treatment with HGF-modified MSCs reduced the expression and secretion of inflammatory cytokines, including tumor necrosis factor alpha (TNF-α) and interferon-gamma (IFN-γ), increased the expression of the anti-inflammatory cytokine IL-10 and the tight junction protein ZO-1, and promoted the proliferation and reduced the apoptosis of intestinal epithelial cells.Treatment of RIII with HGF-gene-modified MSCs reduces local inflammation and promotes the recovery of small intestinal histopathology in a mouse model. These findings might provide an effective therapeutic strategy for RIII.
- Clinically feasible approaches to potentiating cancer cell-based immunotherapies.
Seledtsov VI, Goncharov AG, Seledtsova GV Clinically feasible approaches to potentiating cancer cell-based immunotherapies. [Journal Article]Hum Vaccin Immunother 2015 Apr 3; 11(4):851-69.The immune system exerts both tumor-destructive and tumor-protective functions. Mature dendritic cells (DCs), classically activated macrophages (M1), granulocytes, B lymphocytes, aβ and ɣδ T lymphocytes, natural killer T (NKT) cells, and natural killer (NK) cells may be implicated in antitumor immunoprotection. Conversely, tolerogenic DCs, alternatively activated macrophages (M2), myeloid-derived suppressor cells (MDSCs), and regulatory T (Tregs) and B cells (Bregs) are capable of suppressing antitumor immune responses. Anti-cancer vaccination is a useful strategy to elicit antitumor immune responses, while overcoming immunosuppressive mechanisms. Whole tumor cells or lysates derived thereof hold more promise as cancer vaccines than individual tumor-associated antigens (TAAs), because vaccinal cells can elicit immune responses to multiple TAAs. Cancer cell-based vaccines can be autologous, allogeneic or xenogeneic. Clinical use of xenogeneic vaccines is advantageous in that they can be most effective in breaking the preexisting immune tolerance to TAAs. To potentiate immunotherapy, vaccinations can be combined with other modalities that target different immune pathways. These modalities include 1) genetic or chemical modification of cell-based vaccines; 2) cross-priming TAAs to T cells by engaging dendritic cells; 3) T-cell adoptive therapy; 4) stimulation of cytotoxic inflammation by non-specific immunomodulators, toll-like receptor (TLR) agonists, cytokines, chemokines or hormones; 5) reduction of immunosuppression and/or stimulation of antitumor effector cells using antibodies, small molecules; and 6) various cytoreductive modalities. The authors envisage that combined immunotherapeutic strategies will allow for substantial improvements in clinical outcomes in the near future.