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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.

  • Understanding Toxicities of Targeted Agents: Implications for Anti-tumor Activity and Management.
    Liu S, Kurzrock R Understanding Toxicities of Targeted Agents: Implications for Anti-tumor Activity and Management. [Journal Article, Review]Semin Oncol 2015 Dec; 42(6):863-75.AbstractAggregator Full TextTargeted treatments have distinctive side effects: dermatologic problems (rash, hand-food skin reaction, skin/hair whitening), endocrine dysfunction (hyperglycemia, hypothyroidism, dyslipidemia), as well as hypertension, diarrhea, liver problems, ocular toxicity and proteinuria. Toxicities can be classified as: (1) on-target, mechanism-driven toxicities that are either related or unrelated to response; and (2) off-target side effects. Off-target toxicities may be specific to the class of agent, eg, small molecule tyrosine kinase inhibitor versus antibody versus cytotoxic; alternatively, they may also be mediated by metabolites or immune reactions. Both on- and off-target toxicities can be amplified or attenuated by drug concentrations or end-organ sensitivity, which in turn can be attributable to genetic polymorphisms regulating metabolism or tissue responsiveness. On-target side effects are important to identify as some are associated with response and, therefore, controlling these side effects is preferable to dose reduction or treatment discontinuation. Side effects caused by relevant target impact may be recognized when different types of agents, eg, small molecule inhibitors and antibodies, with the same target have the same side effect. These on-target effects may also correlate with better outcomes. We discuss toxicity of targeted agents in the context of understanding target impact, drug-drug interactions, and implications for optimized management.

  • Regulatory T cells in Arthritis.
    Komatsu N, Takayanagi H Regulatory T cells in Arthritis. [Journal Article]Prog Mol Biol Transl Sci 2015.:207-15.AbstractPublisher Full TextRheumatoid arthritis (RA) is one of the most common autoimmune diseases and is characterized by inflammation and subsequent bone destruction in multiple joints. In mice, depletion of regulatory T (Treg) cells results in the onset of a variety of autoimmune diseases including arthritis, while replenishment of Treg cells alleviates arthritic symptoms. The importance of Treg cells in RA is supported by the effectiveness of CTLA4-Ig therapy, an increased Treg cell/effector T cell ratio after anti-IL-6R or anti-TNF-α treatment and the identification of CTLA-4 as an RA-associated gene. Thus, Treg cells constitute a useful target in the treatment of RA. Foxp3(+) T cells consist of heterogeneous populations in terms of their surface markers, suppressive function, and plasticity. Plastic Foxp3(+) T cells are able to convert into pathogenic Th17 cells, which have been shown to exacerbate arthritis in mice. Therefore, it is important to identify a stable suppressive Foxp3(+) Treg cell subpopulation along with suppressive molecules and surface markers. In addition, considering the recent studies on the identification of arthritic antigens, the generation of antigen-specific Treg cells from naïve CD4(+) T cells or effector T cells is now feasible, along with the induction of Foxp3 and stabilization of the suppressive function by epigenetic modification of Treg cell signature genes. These approaches will lead to the establishment of new therapeutic strategies against arthritis that work by increasing the Treg cell/effector T cell ratio in favor of Treg cells. Here, we summarize our understanding of the role of Treg cells in arthritis based on recent human and murine studies.

  • Histomorphometry and Bone Matrix Mineralization Before and After Bisphosphonate Treatment in Boys with Duchenne Muscular Dystrophy: A Paired Trans-Iliac Biopsy Study.
    Misof BM, Roschger P, McMillan HJ, et al. Histomorphometry and Bone Matrix Mineralization Before and After Bisphosphonate Treatment in Boys with Duchenne Muscular Dystrophy: A Paired Trans-Iliac Biopsy Study. [JOURNAL ARTICLE]J Bone Miner Res 2015 Nov 28.AbstractPublisher Full TextDuchenne muscular dystrophy (DMD) is a genetic disorder causing progressive muscle weakness. To prolong independent ambulation, DMD patients are treated with glucocorticoids which in turn can increase bone fragility. In a cohort with vertebral fractures, intravenous bisphosphonate (i.v. BP) therapy stabilized vertebrae and reduced back pain. To characterize the effects of glucocorticoid therapy and bisphosphonate treatment on bone tissue and material properties paired trans-iliac biopsy samples (before and after on average 2.4 years of i.v. BP) from nine boys with DMD were studied for histomorphometry and bone mineralization density distribution (BMDD) and compared to reference values. Before i.v. BP, the boys had low cancellous bone volume (BV/TV) and cortical thickness (Ct.Wi) (both on average 56% of the healthy average, p < 0.001 vs. reference), and mineralizing surface (MS/BS) in the lower normal range (on average 74% of the healthy average). The average degree of mineralization of cancellous (Cn.CaMean) and cortical compartments (Ct.CaMean) was 21.48 (20.70; 21.90) wt% and 20.42 (19.32; 21.64) wt%, respectively (median (25(th) , 75(th) percentiles)) which was not different from reference. After i.v. BP, BV/TV and Ct.Wi were, on average, unchanged. However, at the individual patient level, BV/TV Z-scores increased in 2, remained unchanged in 4 and declined in 3 patients. Additionally, on average, MS/BS decreased (-85%, p < 0.001), Cn.CaMean (+2.7%) increased while the heterogeneity of cancellous (Cn.CaWidth -19%) and cortical bone mineralization (Ct.CaWidth -8%, all p < 0.05) decreased vs. baseline. The changes in bone mineralization are consistent with the anti-resorptive action of i.v. BP. At the same time, our observations point to the need for novel therapies with less or absent bone turnover suppression, including the fact that bone turnover was low even before bisphosphonate therapy, that bone turnover declined further (as expected) with treatment and that declines in trabecular bone volume were observed in some boys despite bisphosphonate therapy. This article is protected by copyright. All rights reserved.

  • Delineation of MGMT Hypermethylation as a Biomarker for Veliparib-Mediated Temozolomide-Sensitizing Therapy of Glioblastoma.
    Gupta SK, Kizilbash SH, Carlson BL, et al. Delineation of MGMT Hypermethylation as a Biomarker for Veliparib-Mediated Temozolomide-Sensitizing Therapy of Glioblastoma. [Journal Article]J Natl Cancer Inst 2015 May; 108(5)AbstractPublisher Full TextSensitizing effects of poly-ADP-ribose polymerase inhibitors have been studied in several preclinical models, but a clear understanding of predictive biomarkers is lacking. In this study, in vivo efficacy of veliparib combined with temozolomide (TMZ) was evaluated in a large panel of glioblastoma multiforme (GBM) patient-derived xenografts (PDX) and potential biomarkers were analyzed.The efficacy of TMZ alone vs TMZ/veliparib was compared in a panel of 28 GBM PDX lines grown as orthotopic xenografts (8-10 mice per group); all tests of statistical significance were two-sided. DNA damage was analyzed by γH2AX immunostaining and promoter methylation of DNA repair gene O6-methylguanine-DNA-methyltransferase (MGMT) by Clinical Laboratory Improvement Amendments-approved methylation-specific polymerase chain reaction.The combination of TMZ/veliparib statistically significantly extended survival of GBM models (P < .05 by log-rank) compared with TMZ alone in five of 20 MGMT-hypermethylated lines (average extension in median survival = 87 days, range = 20-150 days), while the combination was ineffective in six MGMT-unmethylated lines. In the MGMT promoter-hypermethylated GBM12 line (median survival with TMZ+veliparib = 189 days, 95% confidence interval [CI] = 59 to 289 days, vs TMZ alone = 98 days, 95% CI = 49 to 210 days, P = .04), the profound TMZ-sensitizing effect of veliparib was lost when MGMT was overexpressed (median survival with TMZ+veliparib = 36 days, 95% CI = 28 to 38 days, vs TMZ alone = 35 days, 95% CI = 32 to 37 days, P = .87), and a similar association was observed in two nearly isogenic GBM28 sublines with an intact vs deleted MGMT locus. In comparing DNA damage signaling after dosing with veliparib/TMZ or TMZ alone, increased phosphorylation of damage-responsive proteins (KAP1, Chk1, Chk2, and H2AX) was observed only in MGMT promoter-hypermethylated lines.Veliparib statistically significantly enhances (P < .001) the efficacy of TMZ in tumors with MGMT promoter hypermethylation. Based on these data, MGMT promoter hypermethylation is being used as an eligibility criterion for A071102 (NCT02152982), the phase II/III clinical trial evaluating TMZ/veliparib combination in patients with GBM.

  • Hairy cell leukemia: Past, present and future.
    Getta BM, Park JH, Tallman MS Hairy cell leukemia: Past, present and future. [Journal Article, Review]Best Pract Res Clin Haematol 2015 Dec; 28(4):269-72.AbstractAggregator Full TextThis brief review highlights the sequence of therapeutic milestones and advances in our understanding of the biology of hairy cell leukemia (HCL) with a focus on recent molecular findings and how these may be applied to improve disease outcomes in the future. Targeted therapy is discussed in the context of the recently identified BRAF mutation and other genetic findings.

  • Hairy cell leukaemia-variant: Disease features and treatment.
    Matutes E, Martínez-Trillos A, Campo E Hairy cell leukaemia-variant: Disease features and treatment. [Journal Article, Review]Best Pract Res Clin Haematol 2015 Dec; 28(4):253-63.AbstractAggregator Full TextHairy cell leukaemia-variant (HCL-V) is a rare B-cell malignancy that affects elderly males and manifests with splenomegaly, lymphocytosis and cytopenias without monocytopenia. The neoplastic cells have morphological features of prolymphocytes and hairy cells. The immunophenotype is that of a clonal B-cell CD11c and CD103 positive but, unlike classical HCL, CD25, CD123 and CD200 negative. The spleen histology is similar to classical HCL and the pattern of bone marrow infiltration is interstitial and/or intrasinusoidal. Mutations of the immunoglobulin heavy chain (IGVH) are seen in two thirds of cases with a preferential VH4-34 family usage. There is no distinct chromosomal abnormality but del17p13 and mutations of the TP53 gene are frequent. Mutations in the MAP2K1 gene have been documented in half of the cases. The course is chronic with median survivals of 7-9 years. Patients are refractory to purine analogues and the most effective therapy is the combination of 2-chlorodeoxyadenosine and Rituximab.

  • Genetic predictors of the response to the treatment of hepatitis C virus infection.
    Dzekova-Vidimliski P, Nikolov IG, Matevska-Geshkovska N, et al. Genetic predictors of the response to the treatment of hepatitis C virus infection. [Journal Article]Bosn J Basic Med Sci 2015; 15(4):55-9.AbstractPublisher Full TextThe genome-wide association studies have identified a strong association between interleukin 28B (IL28B) gene polymorphisms and the response to treatment in patients with hepatitis C virus (HCV) infection. The aim of the study was to evaluate the association between three most widely studied IL28B gene polymorphisms and the response to antiviral treatment of chronic hepatitis C. We performed the genotyping of the three IL28B gene polymorphisms: rs12979860, rs8099917, and rs12980275 in 72 Caucasian patients with chronic hepatitis C, previously treated with the combination therapy of pegylated interferon alpha (PEGIFN α) and ribavirin (RBV). The patients included in the study had finished the treatment regimen at least 6 months before enrolling in the study. We used the sustained viral response (SVR) for the evaluation of the effectiveness of the antiviral treatment, and it was tested with an assay with a sensitivity of 20 IU/mL. An SVR was achieved in 59.7% (43/72) of the treated patients. The three IL28B gene polymorphisms (CC genotype of rs12979860, TT genotype of rs8099917, and AA genotype of rs12980275) were associated with the SVR (p=0.029, p=0.016, and p=0.028, respectively) in the study patients with chronic hepatitis C treated with the combination therapy of PEGIFN α and RBV. The association of IL28B gene polymorphisms with the treatment response points to the possibility of personalized medicine for the treatment of HCV infection.

  • A snapshot of biologic drug development: Challenges and opportunities.
    Andrews L, Ralston S, Blomme E, et al. A snapshot of biologic drug development: Challenges and opportunities. [Journal Article]Hum Exp Toxicol 2015 Dec; 34(12):1279-85.AbstractPublisher Full TextSince the approval of insulin as the first recombinant therapeutic protein, the prominence of biologic therapies in drug development has grown significantly. Many modalities beyond traditional biologics are now being developed or explored for various indications with significant unmet medical needs. From early traditional replacement proteins to more recent, highly engineered antibodies, oligonucleotides, fusion proteins, and gene constructs, biologic agents have delivered life-changing therapies, despite often having scientifically and technically challenging development programs. This brief review outlines some of the major biotherapeutic classes and identifies the advantages and challenges with the development of these products.

  • Delayed intramuscular human neurotrophin-3 improves recovery in adult and elderly rats after stroke.
    Duricki DA, Hutson TH, Kathe C, et al. Delayed intramuscular human neurotrophin-3 improves recovery in adult and elderly rats after stroke. [JOURNAL ARTICLE]Brain 2015 Nov 27.AbstractPublisher Full TextThere is an urgent need for a therapy that reverses disability after stroke when initiated in a time frame suitable for the majority of new victims. We show here that intramuscular delivery of neurotrophin-3 (NT3, encoded by NTF3) can induce sensorimotor recovery when treatment is initiated 24 h after stroke. Specifically, in two randomized, blinded preclinical trials, we show improved sensory and locomotor function in adult (6 months) and elderly (18 months) rats treated 24 h following cortical ischaemic stroke with human NT3 delivered using a clinically approved serotype of adeno-associated viral vector (AAV1). Importantly, AAV1-hNT3 was given in a clinically-feasible timeframe using a straightforward, targeted route (injections into disabled forelimb muscles). Magnetic resonance imaging and histology showed that recovery was not due to neuroprotection, as expected given the delayed treatment. Rather, treatment caused corticospinal axons from the less affected hemisphere to sprout in the spinal cord. This treatment is the first gene therapy that reverses disability after stroke when administered intramuscularly in an elderly body. Importantly, phase I and II clinical trials by others show that repeated, peripherally administered high doses of recombinant NT3 are safe and well tolerated in humans with other conditions. This paves the way for NT3 as a therapy for stroke.

  • Molecular profiling of head and neck squamous cell carcinoma.
    Feldman R, Gatalica Z, Knezetic J, et al. Molecular profiling of head and neck squamous cell carcinoma. [JOURNAL ARTICLE]Head Neck 2015 Nov 28.AbstractPublisher Full TextHead and neck squamous cell carcinoma (HNSCC) exhibits high rates of recurrence, and with few approved targeted agents, novel treatments are needed. We analyzed a molecular profiling database for the distribution of biomarkers predictive of chemotherapies and targeted agents.Seven hundred thirty-five patients with advanced HNSCC (88 with known human papillomavirus [HPV] status), were profiled using multiple platforms (gene sequencing, gene copy number, and protein expression).Among the entire patient population studied, epidermal growth factor receptor (EGFR) was the protein most often overexpressed (90%), TP53 gene most often mutated (41%), and phosphatidylinositol 3-kinase (PIK3CA) most often amplified (40%; n = 5). With the exception of TP53 mutation, other biomarker frequencies were not significantly different among HPV-positive or HPV-negative patients. PIK3CA mutations and phosphatase and tensin homolog (PTEN) loss are frequent events, independent of HPV status. The immune response-modulating programmed cell death 1 (PD1) and programmed cell death ligand 1 (PDL1) axis was active across sites, stages, and HPV status.Molecular profiling utilizing multiple platforms provides a range of therapy options beyond standard of care. © 2015 Wiley Periodicals, Inc. Head Neck, 2015.