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  • Journal article
    Alton EW, Beekman JM, Boyd AC, Brand J, Carlon MS, Connolly MM, Chan M, Conlon S, Davidson HE, Davies JC, Davies LA, Dekkers JF, Doherty A, Gea-Sorli S, Gill DR, Griesenbach U, Hasegawa M, Higgins TE, Hironaka T, Hyndman L, McLachlan G, Inoue M, Hyde SC, Innes JA, Maher TM, Moran C, Meng C, Paul-Smith MC, Pringle IA, Pytel KM, Rodriguez-Martinez A, Schmidt AC, Stevenson BJ, Sumner-Jones SG, Toshner R, Tsugumine S, Wasowicz MW, Zhu Jet al., 2016,

    Preparation for a first-in-man lentivirus trial in patients with cystic fibrosis

    , Thorax, Vol: 72, Pages: 137-147, ISSN: 0040-6376

    We have recently shown that non-viral gene therapy can stabilise the decline of lung function in patients with cystic fibrosis (CF). However, the effect was modest, and more potent gene transfer agents are still required. Fuson protein (F)/Hemagglutinin/Neuraminidase protein (HN)-pseudotyped lentiviral vectors are more efficient for lung gene transfer than non-viral vectors in preclinical models. In preparation for a first-in-man CF trial using the lentiviral vector, we have undertaken key translational preclinical studies. Regulatory-compliant vectors carrying a range of promoter/enhancer elements were assessed in mice and human air-liquid interface (ALI) cultures to select the lead candidate; cystic fibrosis transmembrane conductance receptor (CFTR) expression and function were assessed in CF models using this lead candidate vector. Toxicity was assessed and 'benchmarked' against the leading non-viral formulation recently used in a Phase IIb clinical trial. Integration site profiles were mapped and transduction efficiency determined to inform clinical trial dose-ranging. The impact of pre-existing and acquired immunity against the vector and vector stability in several clinically relevant delivery devices was assessed. A hybrid promoter hybrid cytosine guanine dinucleotide (CpG)- free CMV enhancer/elongation factor 1 alpha promoter (hCEF) consisting of the elongation factor 1α promoter and the cytomegalovirus enhancer was most efficacious in both murine lungs and human ALI cultures (both at least 2-log orders above background). The efficacy (at least 14% of airway cells transduced), toxicity and integration site profile supports further progression towards clinical trial and pre-existing and acquired immune responses do not interfere with vector efficacy. The lead rSIV.F/HN candidate expresses functional CFTR and the vector retains 90-100% transduction efficiency in clinically relevant delivery devices. The data support the progression of the F/HN-pseudotype

  • Journal article
    Griesenbach U, Alton EWFW, Boyd AC, Davies G, Davies JC, Gill DR, Higgins TE, Hyde SC, Innes JA, Porteous DJet al., 2015,

    A Phase I/IIa safety and efficacy study of nebulized liposome-mediated gene therapy for cystic fibrosis supports a multidose trial

    , American Journal of Respiratory and Critical Care Medicine, Vol: 192, Pages: 1389-1392, ISSN: 1535-4970
  • Journal article
    Leoni G, Wasowicz MY, Chan M, Meng C, Farley R, Brody SL, Inoue M, Hasegawa M, Alton EW, Griesenbach Uet al., 2015,

    Ex Vivo and In Vivo Lentivirus-Mediated Transduction of Airway Epithelial Progenitor Cells.

    , Current Gene Therapy, Vol: 15, Pages: 581-590, ISSN: 1875-5631

    A key challenge in pulmonary gene therapy for cystic fibrosis is to provide long-term correction of the genetic defect. This may be achievable by targeting airway epithelial stem/progenitor cells with an integrating vector. Here, we evaluated the ability of a lentiviral vector, derived from the simian immunodeficiency virus and pseudotyped with F and HN envelope proteins from Sendai virus, to transduce progenitor basal cells of the mouse nasal airways. We first transduced basal cell-enriched cultures ex vivo and confirmed efficient transduction of cytokeratin-5 positive cells. We next asked whether progenitor cells could be transduced in vivo. We evaluated the transduction efficiency in mice pretreated by intranasal administration of polidocanol to expose the progenitor cell layer. Compared to control mice, polidocanol treated mice demonstrated a significant increase in the number of transduced basal cells at 3 and 14 days post vector administration. At 14 days, the epithelium of treated mice contained clusters (4 to 8 adjacent cells) of well differentiated ciliated, as well as basal cells suggesting a clonal expansion. These results indicate that our lentiviral vector can transduce progenitor basal cells in vivo, although transduction required denudation of the surface epithelium prior to vector administration.

  • Journal article
    Alton EWFW, Armstrong DK, Ashby D, Alton EWFW, Armstrong DK, Ashby D, Bayfield KJ, Bilton D, Bloomfield EV, Boyd AC, Brand J, Buchan R, Calcedo R, Carvelli P, Chan M, Cheng SH, Collie DDS, Cunningham S, Davidson HE, Davies G, Davies JC, Davies LA, Dewar MH, Doherty A, Donovan J, Dwyer NS, Elgmati HI, Featherstone RF, Gavino J, Gea-Sorli S, Geddes DM, Gibson JSR, Gill DR, Greening AP, Griesenbach U, Hansell DM, Harman K, Higgins TE, Hodges SL, Hyde SC, Hyndman L, Innes JA, Jacob J, Jones N, Keogh BF, Limberis MP, Lloyd-Evans P, Maclean AW, Manvell MC, McCormick D, McGovern M, McLachlan G, Meng C, Montero MA, Milligan H, Moyce LJ, Murray GD, Nicholson AG, Osadolor T, Parra-Leiton J, Porteous DJ, Pringle IA, Punch EK, Pytel KM, Quittner AL, Rivellini G, Saunders CJ, Scheule RK, Sheard S, Simmonds NJ, Smith K, Smith SN, Soussi N, Soussi S, Spearing EJ, Stevenson BJ, Sumner-Jones SG, Turkkila M, Ureta RP, Waller MD, Wasowicz MY, Wilson JM, Wolstenholme-Hogg Pet al., 2015,

    Repeated nebulisation of non-viral CFTR gene therapy in patients with cystic fi brosis: a randomised, double-blind, placebo-controlled, phase 2b trial (vol 3, pg 684, 2015)

    , LANCET RESPIRATORY MEDICINE, Vol: 3, Pages: 684-691, ISSN: 2213-2600

    Background Lung delivery of plasmid DNA encoding the CFTR gene complexed with a cationic liposome is a potential treatment option for patients with cystic fi brosis. We aimed to assess the effi cacy of non-viral CFTR gene therapy in patients with cystic fi brosis.Methods We did this randomised, double-blind, placebo-controlled, phase 2b trial in two cystic fi brosis centres with patients recruited from 18 sites in the UK. Patients (aged ≥12 years) with a forced expiratory volume in 1 s (FEV1) of 50–90% predicted and any combination of CFTR mutations, were randomly assigned, via a computer-based randomisation system, to receive 5 mL of either nebulised pGM169/GL67A gene–liposome complex or 0·9% saline (placebo) every 28 days (plus or minus 5 days) for 1 year. Randomisation was stratifi ed by % predicted FEV1 (<70 vs≥70%), age (<18 vs ≥18 years), inclusion in the mechanistic substudy, and dosing site (London or Edinburgh). Participants and investigators were masked to treatment allocation. The primary endpoint was the relative change in % predicted FEV1. The primary analysis was per protocol. This trial is registered with ClinicalTrials.gov, number NCT01621867.Findings Between June 12, 2012, and June 24, 2013, we randomly assigned 140 patients to receive placebo (n=62) or pGM169/GL67A (n=78), of whom 116 (83%) patients comprised the per-protocol population. We noted a signifi cant, albeit modest, treatment eff ect in the pGM169/GL67A group versus placebo at 12 months’ follow-up (3·7%, 95% CI 0·1–7·3; p=0·046). This outcome was associated with a stabilisation of lung function in the pGM169/GL67A group compared with a decline in the placebo group. We recorded no signifi cant diff erence in treatment-attributable adverse events between groups. Interpretation Monthly application of the pGM169/GL67A gene therapy formulation was associated with a signif

  • Journal article
    Alton EWFW, Boyd AC, Cheng SH, Davies JC, Davies LA, Dayan A, Gill DR, Griesenbach U, Higgins T, Hyde SC, Innes JA, McLachlan G, Porteous D, Pringle I, Scheule RK, Sumner-Jones Set al., 2014,

    Toxicology study assessing efficacy and safety of repeated administration of lipid/DNA complexes to mouse lung

    , GENE THERAPY, Vol: 21, Pages: 89-95, ISSN: 0969-7128
  • Journal article
    Alton EWFW, Baker A, Baker E, Boyd AC, Cheng SH, Coles RL, Collie DDS, Davidson H, Davies JC, Gill DR, Gordon C, Griesenbach U, Higgins T, Hyde SC, Innes JA, McCormick D, McGovern M, McLachlan G, Porteous DJ, Pringle I, Scheule RK, Shaw DJ, Smith S, Sumner-Jones SG, Tennant P, Vrettou Cet al., 2013,

    The safety profile of a cationic lipid-mediated cystic fibrosis gene transfer agent following repeated monthly aerosol administration to sheep

    , BIOMATERIALS, Vol: 34, Pages: 10267-10277, ISSN: 0142-9612
  • Journal article
    Alton EWFW, Boyd AC, Cheng SH, Cunningham S, Davies JC, Gill DR, Griesenbach U, Higgins T, Hyde SC, Innes JA, Murray GD, Porteous DJet al., 2013,

    A randomised, double-blind, placebo-controlled phase IIB clinical trial of repeated application of gene therapy in patients with cystic fibrosis

    , THORAX, Vol: 68, Pages: 1075-1077, ISSN: 0040-6376
  • Journal article
    Kernan NG, Alton EWFW, Cullinan P, Griesenbach U, Bilton Det al., 2013,

    Oral contraceptives do not appear to affect cystic fibrosis disease severity

    , EUROPEAN RESPIRATORY JOURNAL, Vol: 41, Pages: 67-73, ISSN: 0903-1936
  • Conference paper
    Griesenbach U, Inoue M, Meng C, Farley R, Chan M, Newman NK, Brum A, You J, Kerton A, Shoemark A, Boyd AC, Davies JC, Higgins TE, Gill DR, Hyde SC, Innes JA, Porteous DJ, Hasegawa M, Alton EWFWet al., 2012,

    ASSESSMENT OF F/HN-PSEUDOTYPED LENTIVIRUS AS A CLINICALLY RELEVANT VECTOR FOR LUNG GENE THERAPY

    , Winter Meeting of the British-Thoracic-Society 2012, Publisher: BMJ PUBLISHING GROUP, Pages: A105-A105, ISSN: 0040-6376
  • Journal article
    McLachlan G, Davidson H, Holder E, Davies LA, Pringle IA, Sumner-Jones SG, Baker A, Tennant P, Gordon C, Vrettou C, Blundell R, Hyndman L, Stevenson B, Wilson A, Doherty A, Shaw DJ, Coles RL, Painter H, Cheng SH, Scheule RK, Davies JC, Innes JA, Hyde SC, Griesenbach U, Alton EWFW, Boyd AC, Porteous DJ, Gill DR, Collie DDSet al., 2011,

    Pre-clinical evaluation of three non-viral gene transfer agents for cystic fibrosis after aerosol delivery to the ovine lung

    , GENE THERAPY, Vol: 18, Pages: 996-1005, ISSN: 0969-7128

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