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Latest Articles on Gene Therapy

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.


  • Exercise training ameliorates matrix metalloproteinases 2 and 9 messenger RNA expression and mitigates adverse left ventricular remodeling in streptozotocin-induced diabetic rats.
    Exercise training ameliorates matrix metalloproteinases 2 and 9 messenger RNA expression and mitigates adverse left ventricular remodeling in streptozotocin-induced diabetic rats. [Journal Article]Cardiovasc Pathol 2017 May 18.:37-44.CPSilva FS, Bortolin RH, Araújo DN, et al. Attenuation of MMP-2 down-regulation and reduction in MMP-9 mRNA expression may constitute an underlying mechanism by which ExT counteracts progression of adverse LV remodeling in T1D.The aim was to investigate whether exercise training (ExT) would ameliorate expression of key genes for myocardial morphostructure and mitigate adverse left ventricular (LV) remodeling in experimental type 1 diabetes (T1D).Male Wistar rats were divided into four groups: sedentary control (SC, n=9), trained control (TC, n=13), sedentary diabetic (SD, n=20), and trained diabetic (TD, n=17). T1D was induced by 40 mg/kg streptozotocin (single dose, i.v.). Training program consisted of 4-week treadmill running (60 min/day, 5 days/wk). Structure of the LV was evaluated using histomorphometric techniques. Gene expression changes of LV collagens I and III, metalloproteinases (MMPs) 2 and 9, and transforming growth factor-β1 were detected by reverse transcriptase quantitative polymerase chain reaction. Compared with SC, SD rats presented LV eccentric remodeling, myocyte hypertrophy, and fibrosis, whereas TD animals showed normal LV geometry and collagen content but thinner myocytes. Expression of collagens and type I/III collagen messenger RNA (mRNA) ratio were diminished in diabetic hearts compared with SC. MMP-2 gene was down-regulated in SD, whereas TD group showed decreased MMP-9 mRNA levels and MMP-2 expression comparable to that of SC rats.Attenuation of MMP-2 down-regulation and reduction in MMP-9 mRNA expression may constitute an underlying mechanism by which ExT counteracts progression of adverse LV remodeling in T1D.

  • Clarithromycin inhibits TNF-α-induced MUC5AC mucin gene expression via the MKP-1-p38MAPK-dependent pathway.
    Clarithromycin inhibits TNF-α-induced MUC5AC mucin gene expression via the MKP-1-p38MAPK-dependent pathway. [Journal Article]Int Immunopharmacol 2017 May 24.:60-66.IIShah SA, Ishinaga H, Takeuchi K Clarithromycin is a 14-membered macrolide antibiotic. Low-dose, long-term macrolide therapy is effective in patients with chronic airway diseases, such as diffuse panbronchitis, chronic bronchitis, and...Clarithromycin is a 14-membered macrolide antibiotic. Low-dose, long-term macrolide therapy is effective in patients with chronic airway diseases, such as diffuse panbronchitis, chronic bronchitis, and chronic sinusitis. However, the mechanism underlying this clinical efficacy remains unclear. The dual specificity phosphatase MKP-1 (MAPK phosphatase-1), also called DUSP (dual specificity phosphatase-1), was initially identified as an in vitro ERK-specific phosphatase, but depending on the cell type, it can also dephosphorylate other members of the MAPK family, such as p38 and JNK, and thus suppress downstream signaling of these kinases. It was recently reported that MKP-1 appears to mediate the effects of several anti-inflammatory drugs, including glucocorticoids, but the role of MKP-1 on mucin gene expression in the presence of macrolides in the human airway remains unknown. Here, we demonstrate that the MKP-1 protein is induced by clarithromycin and that clarithromycin suppresses TNF-α-induced MUC5AC mucin gene expression in a p38 MAPK-dependent manner in human airway epithelial (NCI-H292) cells. Our study thus provides new insights into the role of MKP-1 in mediating the effects of macrolides and may help in the development of new therapeutic strategies against mucin overproduction.

  • Diagnostic and treatment guidelines for thrombotic thrombocytopenic purpura (TTP) 2017 in Japan.
    Diagnostic and treatment guidelines for thrombotic thrombocytopenic purpura (TTP) 2017 in Japan. [Journal Article]Int J Hematol 2017 May 26.IJMatsumoto M, Fujimura Y, Wada H, et al. Thrombotic thrombocytopenic purpura (TTP) can rapidly progress into a life-threatening condition, thus the importance of appropriate diagnosis and treatment cannot be overstated. Until recently, TTP ha...Thrombotic thrombocytopenic purpura (TTP) can rapidly progress into a life-threatening condition, thus the importance of appropriate diagnosis and treatment cannot be overstated. Until recently, TTP has mainly been diagnosed by clinical findings such as thrombocytopenia and non-immune hemolytic anemia. In addition to these clinical findings, however, reduced activity of a disintegrin-like and metalloprotease with thrombospondin type 1 motif 13 (ADAMTS13) below 10% has been accepted internationally as a diagnostic criterion for TTP. In the present guidelines, we have taken all of these criteria into consideration. TTP is classified as acquired if the patient is positive for anti-ADAMTS13 autoantibodies, and as congenital if ADAMTS13 gene abnormalities are detected. Fresh-frozen plasma (FFP) transfusion is performed in patients with congenital TTP to supplement ADAMTS13. Plasma exchange therapy using FFP is conducted in patients with acquired TTP to supplement ADAMTS13 and remove anti-ADAMTS13 autoantibodies. To suppress autoantibody production, corticosteroid therapy may be administered in conjunction with plasma exchange. Recent reports show that the monoclonal anti-CD-20 antibody rituximab is effective in patients with refractory or relapsed TTP.

  • Comprehensive Approach for Identifying the T Cell Subset Origin of CD3 and CD28 Antibody-Activated Chimeric Antigen Receptor-Modified T Cells.
    Comprehensive Approach for Identifying the T Cell Subset Origin of CD3 and CD28 Antibody-Activated Chimeric Antigen Receptor-Modified T Cells. [Journal Article]J Immunol 2017 May 26.JISchmueck-Henneresse M, Omer B, Shum T, et al. The outcome of therapy with chimeric Ag receptor (CAR)-modified T cells is strongly influenced by the subset origin of the infused T cells. However, because polyclonally activated T cells acquire a lar...The outcome of therapy with chimeric Ag receptor (CAR)-modified T cells is strongly influenced by the subset origin of the infused T cells. However, because polyclonally activated T cells acquire a largely CD45RO(+)CCR7(-) effector memory phenotype after expansion, regardless of subset origin, it is impossible to know which subsets contribute to the final T cell product. To determine the contribution of naive T cell, memory stem T cell, central memory T cell, effector memory T cell, and terminally differentiated effector T cell populations to the CD3 and CD28-activated CAR-modified T cells that we use for therapy, we followed the fate and function of individually sorted CAR-modified T cell subsets after activation with CD3 and CD28 Abs (CD3/28), transduction and culture alone, or after reconstitution into the relevant subset-depleted population. We show that all subsets are sensitive to CAR transduction, and each developed a distinct T cell functional profile during culture. Naive-derived T cells showed the greatest rate of proliferation but had more limited effector functions and reduced killing compared with memory-derived populations. When cultured in the presence of memory T cells, naive-derived T cells show increased differentiation, reduced effector cytokine production, and a reduced reproliferative response to CAR stimulation. CD3/28-activated T cells expanded in IL-7 and IL-15 produced greater expansion of memory stem T cells and central memory T cell-derived T cells compared with IL-2. Our strategy provides a powerful tool to elucidate the characteristics of CAR-modified T cells, regardless of the protocol used for expansion, reveals the functional properties of each expanded T cell subset, and paves the way for a more detailed evaluation of the effects of manufacturing changes on the subset contribution to in vitro-expanded T cells.

  • Transgenic expression of IL15 improves antiglioma activity of IL13Ralpha2-CAR T cells but results in antigen-loss variants.
    Transgenic expression of IL15 improves antiglioma activity of IL13Ralpha2-CAR T cells but results in antigen-loss variants. [Journal Article]Cancer Immunol Res 2017 May 26.CIKrenciute G, Prinzing BL, Yi Z, et al. Glioblastoma (GBM) is the most aggressive primary brain tumor in adults and is virtually incurable with conventional therapies. Immunotherapy with T cells expressing GBM-specific chimeric antigen recep...Glioblastoma (GBM) is the most aggressive primary brain tumor in adults and is virtually incurable with conventional therapies. Immunotherapy with T cells expressing GBM-specific chimeric antigen receptors (CARs) is an attractive approach to improve outcomes. Although CAR T cells targeting GBM antigens such as IL13Ralpha2 (interleukin 13 Receptor Subunit Alpha 2), HER2 (human epidermal growth factor receptor 2), and EGFRvIII (epidermal growth factor receptor variant III) have had antitumor activity in preclinical models, early phase clinical testing has demonstrated limited antiglioma activity. Transgenic expression of IL15 is an appealing strategy to enhance CAR T-cell effector function. We tested this approach in our IL13Ralpha2-positive glioma model in which limited IL13Ralpha2-CAR T-cell persistence results in recurrence of antigen-positive gliomas. T cells were genetically modified with retroviral vectors encoding IL13Ralpha2-CARs or IL15 (IL13Ralpha2-CAR.IL15 T cells). IL13Ralpha2-CAR.IL15 T cells recognized glioma cells in an antigen-dependent fashion, had greater proliferative capacity and produced more cytokines after repeated stimulations in comparison to IL13Ralpha2-CAR T cells. No autonomous IL13Ralpha2-CAR.IL15 T-cell proliferation was observed; however, IL15 expression increased IL13Ralpha2-CAR T-cell viability in the absence of exogenous cytokines or antigen. In vivo, IL13Ralpha2-CAR.IL15 T cells persisted longer, and had greater antiglioma activity than IL13Ralpha2-CAR T cells resulting in a survival advantage. Gliomas recurring after 40 days post T-cell injection had downregulated IL13Ralpha2 expression, indicating that antigen-loss variants occur in the setting of improved T-cell persistence. Thus, CAR T cells for GBM should not only be genetically modified to improve their proliferation and persistence, but also to target multiple antigens.
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  • Rapid whole genome sequencing identifies a novel homozygous NPC1 variant associated with Niemann-Pick Type C1 Disease in a 7 week old male with cholestasis.
    Rapid whole genome sequencing identifies a novel homozygous NPC1 variant associated with Niemann-Pick Type C1 Disease in a 7 week old male with cholestasis. [Journal Article]Cold Spring Harb Mol Case Stud 2017 May 26.CSHildreth A, Wigby K, Chowdhury S, et al. Niemann-Pick Type C disease (NPC; OMIM #257220) is an inborn error of intracellular cholesterol trafficking. It is an autosomal recessive disorder caused predominantly by mutations in NPC1. While chara...Niemann-Pick Type C disease (NPC; OMIM #257220) is an inborn error of intracellular cholesterol trafficking. It is an autosomal recessive disorder caused predominantly by mutations in NPC1. While characterized as a progressive neurological disorder, it can also cause cholestasis and liver dysfunction due to intrahepatocyte lipid accumulation. We report a 7 week old who was admitted with neonatal cholestasis, who was diagnosed with a novel homozygous stop-gain variant in NPC1 by rapid whole genome sequencing (WGS). WGS results were obtained 16 days prior to return of the standard clinical genetic test results, and prompted initiation of targeted therapy.

  • Exceptional Response to Nivolumab and Stereotactic Body Radiation Therapy (SBRT) in Neuroendocrine Cervical Carcinoma with High Tumor Mutational Burden: Management Considerations from the Center For Personalized Cancer Therapy at UC San Diego Moores Cancer Center.
    Exceptional Response to Nivolumab and Stereotactic Body Radiation Therapy (SBRT) in Neuroendocrine Cervical Carcinoma with High Tumor Mutational Burden: Management Considerations from the Center For Personalized Cancer Therapy at UC San Diego Moores Cancer Center. [Journal Article]Oncologist 2017 May 26.OSharabi A, Kim SS, Kato S, et al. Neuroendocrine carcinoma of the cervix is an ultra-rare malignancy with a poor prognosis and limited treatment options. Checkpoint blockade immunotherapy has rapidly developed into an emerging standard...Neuroendocrine carcinoma of the cervix is an ultra-rare malignancy with a poor prognosis and limited treatment options. Checkpoint blockade immunotherapy has rapidly developed into an emerging standard of care for several common disease types. Interestingly, in preclinical and retrospective clinical data, radiation therapy has been demonstrated to synergize with checkpoint inhibitors. Here we report a patient with metastatic, chemotherapy-refractory neuroendocrine carcinoma who presented with partial bowel obstruction due to a large tumor burden. Genomic analysis demonstrated a high number of alterations on liquid biopsy (circulating tumor DNA [ctDNA]), which prompted treatment with stereotactic body radiation therapy (SBRT) combined with anti-programmed cell death protein 1 antibody. Tissue rebiopsy and comprehensive genomic profiling confirmed high tumor mutational burden and a mismatch repair gene defect. The patient manifested near-complete systemic resolution of disease, ongoing at 10+ months. We discuss the novel treatment modality of SBRT combined with a checkpoint inhibitor and the implications of molecular profiling and tumor mutational burden as potential predictors of response. The Oncologist 2017;22:1-7 KEY POINTS: High-grade, large-cell neuroendocrine carcinoma of the cervix is an ultra-rare malignancy that carries a grim prognosis.Next-generation sequencing may reveal key mutations in MSH2 genes amongst others. MSH2 mutations target the DNA mismatch repair process and can predispose patients to malignancies with high mutational burdens.Immunotherapy combined with radiation therapy can elicit a significant response, both within and outside the field of radiation. The latter is termed the "abscopal" effect, perhaps mediated by radiation-induced cross presentation of tumor antigens resulting in immune activation.Sequencing of blood-derived ctDNA showed a high number of alterations, and tissue sequencing confirmed a high tumor mutational burden as a consequence of a mismatch repair gene defect. This observation led to a therapeutic "match" with an anti- programmed cell death protein 1 antibody combined with SBRT, resulting in a durable (10+ months), near-complete remission in a patient with advanced chemotherapy-refractory disease.

  • TPP-Dendrimer Nanocarriers for siRNA Delivery to the Pulmonary Epithelium and their Dry Powder and Metered-dose Inhaler Formulations.
    TPP-Dendrimer Nanocarriers for siRNA Delivery to the Pulmonary Epithelium and their Dry Powder and Metered-dose Inhaler Formulations. [Journal Article]Int J Pharm 2017 May 23.IJBielski E, Zhong Q, Mirza H, et al. The regulation of genes utilizing the RNA interference (RNAi) mechanism via the delivery of synthetic siRNA has great potential in the treatment of a variety of lung diseases. However, the delivery of ...The regulation of genes utilizing the RNA interference (RNAi) mechanism via the delivery of synthetic siRNA has great potential in the treatment of a variety of lung diseases. However, the delivery of siRNA to the lungs is challenging due to the poor bioavailability siRNA when delivered intraveneously, and difficulty in formulating and maintaining the activity of free siRNA when delivered directly to the lungs using inhalation devices. The use of non-viral vectors such as cationic dendrimers can help enhance the stability of siRNA and its delivery to the cell cytosol. Therefore, in this work, we investigate the ability of a triphenylphosphonium (TPP) modified generation 4 poly(amidoamine) (PAMAM) dendrimer (G4NH2-TPP) to enhance the in vitro transfection efficiency of siRNA in a model of the pulmonary epithelium and their aerosol formulations in pressurized metered dose inhalers (pMDIs) and dry powder inhalers (DPIs). Complexes of siRNA and G4NH2-TPP were prepared with varying TPP densities and increasing N/P ratios. The complexation efficiency was modulated by the presence of the TPP on the dendrimer surface, allowing for a looser complexation compared to unmodified dendrimer as determined by gel electrophoresis and polyanion competition assay. An increase in TPP density and N/P ratio led to an increase in the in vitro gene knockdown of stably green fluorescent protein (eGFP) expressing lung alveolar epithelial (A549) cells. G4NH2-12TPP dendriplexes (G4NH2 PAMAM dendrimers containing 12 TPP molecules on the surface complexed with siRNA) at N/P ratio 30 showed the highest in vitro gene knockdown efficiency. To assess the potential of TPP-dendriplexes for pulmonary use, we also developed micron particle technologies for both pMDIs and DPIs and determined their aerosol characteristics utilizing an Andersen Cascade Impactor (ACI). Mannitol microparticles encapsulating 12TPP-dendriplexes were shown to be effective in producing aerosols suitable for deep lung deposition for both pMDI formulations (fine particle fraction of 50-53%) and DPI formulations (fine particle fraction of 39%) with no impact on the in vitro gene knockdown efficiency of the siRNA. This work demonstrates the potential benefits of utilizing TPP-conjugated dendrimers in the formation of dendriplexes for siRNA delivery to the pulmonary epithelium and their aerosol formulation for local delivery to the lungs using portable inhalers.

  • Methylome and transcriptome profiling in Myasthenia Gravis monozygotic twins.
    Methylome and transcriptome profiling in Myasthenia Gravis monozygotic twins. [Journal Article]J Autoimmun 2017 May 23.JAMamrut S, Avidan N, Truffault F, et al. This is the first study to characterize the DNA methylation profile in MG, and the expression profile of immune cells in MZ twins with MG. Results suggest that numerous small changes in gene expression...To identify novel genetic and epigenetic factors associated with Myasthenia gravis (MG) using an identical twins experimental study design.The transcriptome and methylome of peripheral monocytes were compared between monozygotic (MZ) twins discordant and concordant for MG, as well as with MG singletons and healthy controls, all females. Sets of differentially expressed genes and differentially methylated CpGs were validated using RT-PCR for expression and target bisulfite sequencing for methylation on additional samples.>100 differentially expressed genes and ∼1800 differentially methylated CpGs were detected in peripheral monocytes between MG patients and controls. Several transcripts associated with immune homeostasis and inflammation resolution were reduced in MG patients. Only a relatively few genes differed between the discordant healthy and MG co-twins, and both their expression and methylation profiles demonstrated very high similarity.This is the first study to characterize the DNA methylation profile in MG, and the expression profile of immune cells in MZ twins with MG. Results suggest that numerous small changes in gene expression or methylation might together contribute to disease. Impaired monocyte function in MG and decreased expression of genes associated with inflammation resolution could contribute to the chronicity of the disease. Findings may serve as potential new predictive biomarkers for disease and disease activity, as well as potential future targets for therapy development. The high similarity between the healthy and the MG discordant twins, suggests that a molecular signature might precede a clinical phenotype, and that genetic predisposition may have a stronger contribution to disease than previously assumed.

  • Codon-Optimized RPGR Improves Stability and Efficacy of AAV8 Gene Therapy in Two Mouse Models of X-Linked Retinitis Pigmentosa.
    Codon-Optimized RPGR Improves Stability and Efficacy of AAV8 Gene Therapy in Two Mouse Models of X-Linked Retinitis Pigmentosa. [Journal Article]Mol Ther 2017 May 24.MTFischer MD, McClements ME, Martinez-Fernandez de la Camara C, et al. X-linked retinitis pigmentosa (XLRP) is generally a severe form of retinitis pigmentosa, a neurodegenerative, blinding disorder of the retina. 70% of XLRP cases are due to mutations in the retina-speci...X-linked retinitis pigmentosa (XLRP) is generally a severe form of retinitis pigmentosa, a neurodegenerative, blinding disorder of the retina. 70% of XLRP cases are due to mutations in the retina-specific isoform of the gene encoding retinitis pigmentosa GTPase regulator (RPGR(ORF15)). Despite successful RPGR(ORF15) gene replacement with adeno-associated viral (AAV) vectors being established in a number of animal models of XLRP, progression to human trials has not yet been possible. The inherent sequence instability in the purine-rich region of RPGR(ORF15) (which contains highly repetitive nucleotide sequences) leads to unpredictable recombination errors during viral vector cloning. While deleted RPGR may show some efficacy in animal models, which have milder disease, the therapeutic effect of a mutated RPGR variant in patients with XLRP cannot be predicted. Here, we describe an optimized gene replacement therapy for human XLRP disease using an AAV8 vector that reliably and consistently produces the full-length correct RPGR protein. The glutamylation pattern in the RPGR protein derived from the codon-optimized sequence is indistinguishable from the wild-type variant, implying that codon optimization does not significantly alter post-translational modification. The codon-optimized sequence has superior stability and expression levels in vitro. Significantly, when delivered by AAV8 vector and driven by the rhodopsin kinase promoter, the codon-optimized RPGR rescues the disease phenotype in two relevant animal models (Rpgr(-/y) and C57BL/6J(Rd9/Boc)) and shows good safety in C57BL6/J wild-type mice. This work provides the basis for clinical trial development to treat patients with XLRP caused by RPGR mutations.

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