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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.


  • Covalent coupling of high-affinity ligands to the surface of viral vector particles by protein trans-splicing mediates cell type-specific gene transfer.
    Covalent coupling of high-affinity ligands to the surface of viral vector particles by protein trans-splicing mediates cell type-specific gene transfer. [Journal Article]Biomaterials 2017 Jul 25.:84-94.BMuik A, Reul J, Friedel T, et al. We have established a novel approach for the covalent coupling of large polypeptides to the surface of fully assembled adeno-associated viral gene transfer vector (AAV) particles via split-intein media...We have established a novel approach for the covalent coupling of large polypeptides to the surface of fully assembled adeno-associated viral gene transfer vector (AAV) particles via split-intein mediated protein-trans-splicing (PTS). This way, we achieved selective gene transfer to distinct cell types. Single-chain variable fragments (scFvs) or designed ankyrin repeat proteins (DARPins), exhibiting high-affinity binding to cell surface receptors selectively expressed on the surface of target cells, were coupled to AAV particles harboring mutations in the capsid proteins which ablate natural receptor usage. Both, the AAV capsid protein VP2 and multiple separately produced targeting ligands recognizing Her2/neu, EpCAM, CD133 or CD30 were genetically fused with complementary split-intein domains. Optimized coupling conditions led to an effective conjugation of each targeting ligand to the universal AAV capsid and translated into specific gene transfer into target receptor-positive cell types in vitro and in vivo. Interestingly, PTS-based AAVs exhibited significantly less gene transfer into target receptor-negative cells than AAVs displaying the same targeting ligand but coupled genetically. Another important consequence of the PTS technology is the possibility to now display scFvs or other antibody-derived domain formats harboring disulfide-bonds in a functionally active form on the surface of AAV particles. Hence, the custom combination of a universal AAV vector particle and targeting ligands of various formats allows for an unprecedented flexibility in the generation of gene transfer vectors targeted to distinct cell types.

  • A Children's Oncology Group and TARGET initiative exploring the genetic landscape of Wilms tumor.
    A Children's Oncology Group and TARGET initiative exploring the genetic landscape of Wilms tumor. [Journal Article]Nat Genet 2017 Aug 21.NGenGadd S, Huff V, Walz AL, et al. We performed genome-wide sequencing and analyzed mRNA and miRNA expression, DNA copy number, and DNA methylation in 117 Wilms tumors, followed by targeted sequencing of 651 Wilms tumors. In addition to...We performed genome-wide sequencing and analyzed mRNA and miRNA expression, DNA copy number, and DNA methylation in 117 Wilms tumors, followed by targeted sequencing of 651 Wilms tumors. In addition to genes previously implicated in Wilms tumors (WT1, CTNNB1, AMER1, DROSHA, DGCR8, XPO5, DICER1, SIX1, SIX2, MLLT1, MYCN, and TP53), we identified mutations in genes not previously recognized as recurrently involved in Wilms tumors, the most frequent being BCOR, BCORL1, NONO, MAX, COL6A3, ASXL1, MAP3K4, and ARID1A. DNA copy number changes resulted in recurrent 1q gain, MYCN amplification, LIN28B gain, and MIRLET7A loss. Unexpected germline variants involved PALB2 and CHEK2. Integrated analyses support two major classes of genetic changes that preserve the progenitor state and/or interrupt normal development.

  • Knockdown of IRE1α inhibits colonic tumorigenesis through decreasing β-catenin and IRE1α targeting suppresses colon cancer cells.
    Knockdown of IRE1α inhibits colonic tumorigenesis through decreasing β-catenin and IRE1α targeting suppresses colon cancer cells. [Journal Article]Oncogene 2017 Aug 21.OLi XX, Zhang HS, Xu YM, et al. The endoplasmic reticulum (ER) stress occurs frequently in cancers. The unfolded protein response (UPR) is activated to cope with ER stress. This has generated widespread interest in targeting UPR as t...The endoplasmic reticulum (ER) stress occurs frequently in cancers. The unfolded protein response (UPR) is activated to cope with ER stress. This has generated widespread interest in targeting UPR as therapeutic strategies. Inositol-requiring transmembrane kinase/endonuclease 1α (IRE1α), an ER stress sensor, is a key component of UPR. However, the role of IRE1α in tumorigenesis remains unclear. The purpose of this work is to investigate the role of IRE1α in colon cancer and to determine whether IRE1α could serve as a target for therapy. We found that knockdown of IRE1α suppressed the proliferation of colon cancer cells in vitro and xenograft growth in vivo. Inhibition of expression of IRE1α decreased stemness of colon cancer stem cells (CSCs) and attenuated growth of intestinal organoids. Genetic ablation of IRE1α prevented the colitis-associated colonic tumorigenesis in mice. The mechanistic study indicates that knockdown of IRE1α repressed the expression of β-catenin, a key factor that drives colonic tumorigenesis, through activating pancreatic ER kinase/eukaryotic translation initiation factor 2α signaling. We found that the IRE1a-specific inhibitor 4μ8C could suppress the production of β-catenin, inhibited the proliferation of colon cancer cells, repressed colon CSCs and prevented xenograft growth. The results suggest that IRE1α has a critical role in colonic tumorigenesis and IRE1α targeting might be a strategy for treatment of colon cancers.Oncogene advance online publication, 21 August 2017; doi:10.1038/onc.2017.284.

  • Lentiviral Vector Promoter is Decisive for Aberrant Transcript Formation.
    Lentiviral Vector Promoter is Decisive for Aberrant Transcript Formation. [Journal Article]Hum Gene Ther 2017 Aug 21.HGScholz S, Fronza R, Bartholomae C, et al. Lentiviral vectors hold great promise for the genetic correction of various inherited diseases. However, lentiviral vector biology is still not completely understood and warrants the precise decoding o...Lentiviral vectors hold great promise for the genetic correction of various inherited diseases. However, lentiviral vector biology is still not completely understood and warrants the precise decoding of molecular mechanisms underlying integration and post-translational modification. We investigated a series of self-inactivating (SIN) and full LTR lentiviral vectors that contained different types of promoters with or without a transgene to gain deeper insights in lentiviral target site selection and potential perturbation of cellular gene expression. Using an optimized non-restrictive linear amplification-mediated PCR (nrLAM-PCR) protocol we observed vector structure-dependent integration site profiles upon transduction of mouse lin- hematopoietic progenitors in vitro. Initial target site selection mainly depended on the presence of the promoter while being independent of its nature. Despite the increased propensity for read-through transcription of SIN lentiviral vectors, the incidence of viral-cellular fusion transcript formation involving the canonical viral splice donor or cryptic splice sites was reduced in both unselected primary lin- cells and transformed 32D cells. Moreover, the strength of the internal promoter in vectors with SIN LTRs is decisive for in vitro selection and for the abundance of chimeric transcripts, which are decreased by moderately active promoters. Our results will help to better understand vector biology and to optimize therapeutic vectors for future gene therapy applications.

  • The future looks brighter after 25 years of retinal gene therapy.
    The future looks brighter after 25 years of retinal gene therapy. [Journal Article]Hum Gene Ther 2017 Aug 21.HGAli RR, Auricchio A, Smith AJ The first report of in vivo gene delivery to the retina dates back to 1987 when a retroviral vector was injected intraocularly in newborn mice. Later came the observation that retinal cells could be su...The first report of in vivo gene delivery to the retina dates back to 1987 when a retroviral vector was injected intraocularly in newborn mice. Later came the observation that retinal cells could be successfully transduced using adenoviral and, then, adeno-associated and lentiviral vectors. By 2000, it had became clear that the eye, compared with other organs and tissues, provides a number of advantages for in vivo gene therapy with regard to safety, efficacy and route to clinical application. This has prompted the development of many successful proof-of-concept studies in animal models. The demonstration that sight could be restored in a large animal model with a congenital form of blindness was a major landmark that opened the door to the first-in-human trials for recessively inherited blinding conditions. With these first human studies demonstrating safety as well as some efficacy, retinal gene therapy has now come of age. Rapid clinical development has highlighted various new challenges, including the treatment of patients with advanced photoreceptor degeneration or dominantly inherited retinal dystrophies and those with defects in large genes, yet given the progress over the last 25 years, we expect a bright future for retinal gene therapy.

  • Consensus Molecular Subtypes of Colorectal Cancer and their Clinical Implications.
    Consensus Molecular Subtypes of Colorectal Cancer and their Clinical Implications. [Journal Article]Int Biol Biomed J 2017; 3(3):105-111.IBThanki K, Nicholls ME, Gajjar A, et al. The colorectal cancer (CRC) Subtyping Consortium has unified six independent molecular classification systems, based on gene expression data, into a single consensus system with four distinct groups, k...The colorectal cancer (CRC) Subtyping Consortium has unified six independent molecular classification systems, based on gene expression data, into a single consensus system with four distinct groups, known as the Consensus Molecular Subtypes (CMS); clinical implications are discussed in this review. This article is based on a literature review relevant to the CMS of CRC indexed in PubMed (US National Library of Medicine) as well as the authors' own published data. The CMS were determined and correlated with epigenomic, transcriptomic, microenvironmental, genetic, prognostic and clinical characteristics. The CMS1 subtype is immunogenic and hypermutated. CMS2 tumors are activated by the WNT-β-catenin pathway and have the highest overall survival. CMS3 feature a metabolic cancer phenotype and CMS4 cancers have the worst survival and have a strong stromal gene signature. The Consensus Molecular Subtypes of CRC may better inform clinicians of prognosis, therapeutic response, and potential novel therapeutic strategies.

  • The Effects of the Contact Activation System on Hemorrhage.
    The Effects of the Contact Activation System on Hemorrhage. [Journal Article, Review]Front Med (Lausanne) 2017.:121.FMSimão F, Feener EP The contact activation system (CAS) exerts effects on coagulation via multiple mechanisms, which modulate both the intrinsic and extrinsic coagulation cascades as well as fibrinolysis and platelet acti...The contact activation system (CAS) exerts effects on coagulation via multiple mechanisms, which modulate both the intrinsic and extrinsic coagulation cascades as well as fibrinolysis and platelet activation. While the effects of the CAS on blood coagulation measured as activated partial thromboplastin time shortening are well documented, genetic mutations that result in deficiencies in the expression of either plasma prekallikrein (PPK) or factor XII (FXII) are not associated with spontaneous bleeding or increased bleeding risk during surgery. Deficiencies in these proteins are often undiagnosed for decades and detected later in life during routine coagulation assays without an apparent clinical phenotype. Increased interest in the CAS as a potentially safe target for antithrombotic therapies has emerged, in large part, from studies on animal models with provoked thrombosis, which have shown that deficiencies in PPK or FXII can reduce thrombus formation without increasing bleeding. Gene targeting and pharmacological studies in healthy animals have confirmed that PPK and FXII blockade does not cause coagulopathies. These findings support the conclusion that CAS is not required for hemostasis. However, while deficiencies in FXII and PPK do not significantly affect bleeding associated with peripheral wounds, recent reports have demonstrated that these proteins can promote hemorrhage in the retina and brain. Intravitreal injection of plasma kallikrein (PKal) induces retinal hemorrhage and intracerebral injection of PKal increases intracranial bleeding. PPK deficiency and PKal inhibition ameliorates hematoma formation following cerebrovascular injury in diabetic animals. Moreover, both PPK and FXII deficiency are protective against intracerebral hemorrhage caused by tissue plasminogen activator-mediated thrombolytic therapy in mice with thrombotic middle cerebral artery occlusion. Thus, while the CAS is not required for hemostasis, its inhibition may provide an opportunity to reduce hemorrhage in the retina and brain. Characterization of the mechanisms and potential clinical implications associated with the effects of the CAS on hemorrhage requires further consideration of the effects of PPK and FXII on hemorrhage beyond their putative effects on coagulation cascades. Here, we review the experimental and clinical evidence on the effects of the CAS on bleeding and hemostatic mechanisms.

  • Tumor Necrosis Factor (TNF) Bioactivity at the Site of an Acute Cell-Mediated Immune Response Is Preserved in Rheumatoid Arthritis Patients Responding to Anti-TNF Therapy.
    Tumor Necrosis Factor (TNF) Bioactivity at the Site of an Acute Cell-Mediated Immune Response Is Preserved in Rheumatoid Arthritis Patients Responding to Anti-TNF Therapy. [Journal Article]Front Immunol 2017.:932.FIByng-Maddick R, Turner CT, Pollara G, et al. The impact of anti-tumor necrosis factor (TNF) therapies on inducible TNF-dependent activity in humans has never been evaluated in vivo. We aimed to test the hypothesis that patients responding to anti...The impact of anti-tumor necrosis factor (TNF) therapies on inducible TNF-dependent activity in humans has never been evaluated in vivo. We aimed to test the hypothesis that patients responding to anti-TNF treatments exhibit attenuated TNF-dependent immune responses at the site of an immune challenge. We developed and validated four context-specific TNF-inducible transcriptional signatures to quantify TNF bioactivity in transcriptomic data. In anti-TNF treated rheumatoid arthritis (RA) patients, we measured the expression of these biosignatures in blood, and in skin biopsies from the site of tuberculin skin tests (TSTs) as a human experimental model of multivariate cell-mediated immune responses. In blood, anti-TNF therapies attenuated TNF bioactivity following ex vivo stimulation. However, at the site of the TST, TNF-inducible gene expression and genome-wide transcriptional changes associated with cell-mediated immune responses were comparable to that of RA patients receiving methotrexate only. These data demonstrate that anti-TNF agents in RA patients do not inhibit inducible TNF activity at the site of an acute inflammatory challenge in vivo, as modeled by the TST. We hypothesize instead that their therapeutic effects are limited to regulating TNF activity in chronic inflammation or by alternative non-canonical pathways.

  • Non-Thyroidal Illness Syndrome in Patients Exposed to Indoor Air Dampness Microbiota Treated Successfully with Triiodothyronine.
    Non-Thyroidal Illness Syndrome in Patients Exposed to Indoor Air Dampness Microbiota Treated Successfully with Triiodothyronine. [Journal Article]Front Immunol 2017.:919.FISomppi TL Long-term exposure to dampness microbiota induces multi-organ morbidity. One of the symptoms related to this disorder is non-thyroidal illness syndrome (NTIS). A retrospective study was carried out in ...Long-term exposure to dampness microbiota induces multi-organ morbidity. One of the symptoms related to this disorder is non-thyroidal illness syndrome (NTIS). A retrospective study was carried out in nine patients with a history of mold exposure, experiencing chronic fatigue, cognitive disorder, and different kinds of hypothyroid symptoms despite provision of levothyroxine (3,5,3',5'-tetraiodothyronine, LT4) monotherapy. Exposure to volatile organic compounds present in water-damaged buildings including metabolic products of toxigenic fungi and mold-derived inflammatory agents can lead to a deficiency or imbalance of many hormones, such as active T3 hormone. Since the 1970s, the synthetic prohormone, levothyroxine (LT4), has been the most commonly prescribed thyroid hormone in replacement monotherapy. It has been presumed that the peripheral conversion of T4 (3,5,3',5'-tetraiodothyronine) into T3 (3,5,3'-triiodothyronine) is sufficient to satisfy the overall tissue requirements. However, evidence is presented that this not the case for all patients, especially those exposed to indoor air molds. This retrospective study describes the successful treatment of nine patients in whom NTIS was treated with T3-based thyroid hormone. The treatment was based on careful interview, clinical monitoring, and laboratory analysis of serum free T3 (FT3), reverse T3 (rT3) and thyroid-stimulating hormone, free T4, cortisol, and dehydroepiandrosterone (DHEA) values. The ratio of FT3/rT3 was calculated. In addition, some patients received adrenal support with hydrocortisone and DHEA. All patients received nutritional supplementation and dietary instructions. During the therapy, all nine patients reported improvements in all of the symptom groups. Those who had residual symptoms during T3-based therapy remained exposed to indoor air molds in their work places. Four patients were unable to work and had been on disability leave for a long time during LT4 monotherapy. However, during the T3-based and supportive therapy, all patients returned to work in so-called "healthy" buildings. The importance of avoiding mycotoxin exposure via the diet is underlined as DIO2 genetic polymorphism and dysfunction of DIO2 play an important role in the development of symptoms that can be treated successfully with T3 therapy.

  • A Novel Method to Generate and Expand Clinical-Grade, Genetically Modified, Tumor-Infiltrating Lymphocytes.
    A Novel Method to Generate and Expand Clinical-Grade, Genetically Modified, Tumor-Infiltrating Lymphocytes. [Journal Article]Front Immunol 2017.:908.FIForget MA, Tavera RJ, Haymaker C, et al. Following the clinical success achieved with the first generation of adoptive cell therapy (ACT) utilizing in vitro expanded tumor-infiltrating lymphocytes (TILs), the second and third generations of T...Following the clinical success achieved with the first generation of adoptive cell therapy (ACT) utilizing in vitro expanded tumor-infiltrating lymphocytes (TILs), the second and third generations of TIL ACT are evolving toward the use of genetically modified TIL. TIL therapy generally involves the transfer of a high number of TIL, ranging from 10(9) to 10(11) cells. One of the technical difficulties in genetically modifying TIL, using a retroviral vector, is the ability to achieve large expansion of transduced TIL, while keeping the technique suitable to a Good Manufacturing Practices (GMP) environment. Consequently, we developed and optimized a novel method for the efficient production of large numbers of GMP-grade, gene-modified TIL for the treatment of patients with ACT. The chemokine receptor CXCR2 was used as the gene of interest for methodology development. The optimized procedure is currently used in the production of gene-modified TIL for two clinical trials for the treatment of metastatic melanoma at MD Anderson Cancer Center.

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