Gene therapy

  • Article
    | Open Access

    Patients with mutations in the ASL gene present with argininosuccinic aciduria characterised by hyperammonaemia and cognitive impairment. Here, the authors show that cerebral disease involves neuronal nitrosative/oxidative stress that is not induced by hyperammonaemia, and that it can be reversed using AAV-ASL directed to liver and brain in mice.

    • Julien Baruteau
    • , Dany P. Perocheau
    •  & Simon N. Waddington
  • Article
    | Open Access

    Suppression of gene expression due to aberrant promoter methylation contributes to organ fibrosis. Here, the authors couple a deactivated Cas9 to the TET3 catalytic domain to induce expression of four antifibrotic genes, and show that lentiviral-mediated delivery is effective in reducing kidney fibrosis in mouse models.

    • Xingbo Xu
    • , Xiaoying Tan
    •  & Michael Zeisberg
  • Article
    | Open Access

    In vivo reprogramming of somatic cells is hampered by the need for vectors to express the OKSM factors in selected organs. Here the authors report new AAV-based vectors capable of in vivo reprogramming at low doses.

    • Elena Senís
    • , Lluc Mosteiro
    •  & Dirk Grimm
  • Article
    | Open Access

    The correction of genetic defects in utero could allow for improved outcomes of gene therapy. Here, the authors demonstrate safe delivery of nanoparticles to fetal mouse tissues, and show that nanoparticles containing peptide nucleic acids to edit the beta-globin gene are effective in a mouse model of beta-thalassemia.

    • Adele S. Ricciardi
    • , Raman Bahal
    •  & W. Mark Saltzman
  • Article
    | Open Access

    Duchenne muscular dystrophy is a progressive degenerative disease of muscles caused by mutations in the dystrophin gene. Here the authors use AAV vectors to deliver microdystrophin to dogs with muscular dystrophy, and show restoration of dystrophin expression and reduction of symptoms up to 26 months of age.

    • Caroline Le Guiner
    • , Laurent Servais
    •  & George Dickson
  • Article
    | Open Access

    Abnormal angiogenesis causes many ocular diseases. Here the authors employ CRISPR/Cas9 gene editing technology to silence VEGFR2, a major regulator of angiogenesis, in retinal endothelium and abrogate angiogenesis in the mouse models of oxygen-induced retinopathy and laser-induced choroid neovascularization.

    • Xionggao Huang
    • , Guohong Zhou
    •  & Hetian Lei
  • Article
    | Open Access

    Homologous recombination mediated gene targeting is highly inefficient in human cells due to random integration events, Here the authors show that dual repression of polymerase θ and DNA ligase IV eliminate random integration events.

    • Shinta Saito
    • , Ryo Maeda
    •  & Noritaka Adachi
  • Article
    | Open Access

    While CRISPR-Cas9 is a powerful technology, it’sin vivoapplication can be limited by unwanted off-target editing events. Here the authors present SLiCES, a self-limiting Cas9 circuit to enhance editing by preventing residual nuclease activity.

    • Gianluca Petris
    • , Antonio Casini
    •  & Anna Cereseto
  • Article
    | Open Access

    Oculopharyngeal muscular dystrophy is caused by trinucleotide repeat expansions in thePABPN1gene. Here the authors use AAV-based gene therapy to knockdown the mutant gene and replace it with a wild-type allele, and show effectiveness in mice and in patient cells.

    • A. Malerba
    • , P. Klein
    •  & G. Dickson
  • Article
    | Open Access

    The maximum titre of therapeutic viral vectors can be adversely affected by the encoded transgene. Here the authors repress transgene expression in producing cells by employing the tryptophan RNA-binding attenuation protein and show that it improves titre of RNA- and DNA-based viral vectors expressing toxic transgenes.

    • H. E. Maunder
    • , J. Wright
    •  & D. C. Farley
  • Article
    | Open Access

    Current methods for haematopoietic stem cell gene therapy are laborious and require special licensed facilities. Here the authors develop a semi-automated protocol using a commercially available device to allow for benchtop generation of gene-modified blood cell products for transplantation, that meet current standards.

    • Jennifer E. Adair
    • , Timothy Waters
    •  & Hans-Peter Kiem
  • Article
    | Open Access

    Restoring lost excitability of injured tissue is a paramount of regenerative medicine. By using a combined expression of bacterial voltage-gated Na+ channel, Kir2.1, and connexin-43 in non-excitable human fibroblasts, here the authors generate excitable cells that rescue action potential conduction in an in vitromodel of cardiac fibrosis.

    • Hung X. Nguyen
    • , Robert D. Kirkton
    •  & Nenad Bursac
  • Article
    | Open Access

    Heart contraction, which is decreased in disease, is determined by Ca2+binding to troponin C. Here, the authors combine a protein engineering approach with gene therapy to modulate heart contractility in mice with the use of rationally designed Troponin C variants, suggesting a new therapy for diseased hearts.

    • Vikram Shettigar
    • , Bo Zhang
    •  & Jonathan P. Davis
  • Article
    | Open Access

    Familial hypercholesterolemia (FH) is a congenital disease associated with high plasma cholesterol levels. Here, the authors recapitulate FH in chimeric mice, in which livers are repopulated with hepatocytes from an FH patient, and successfully correct the disease using adenovirus-mediated gene therapy.

    • Beatrice Bissig-Choisat
    • , Lili Wang
    •  & Karl-Dimiter Bissig
  • Article
    | Open Access

    The rd1 mouse is the most widely used model to study retinal degeneration. Here, the authors identify a wide-spread mutation in these mice that may explain the failure of previous gene therapeutic approaches and show that long-lasting restoration of vision is possible in rd1 mice without this mutation.

    • Koji M. Nishiguchi
    • , Livia S. Carvalho
    •  & Robin R. Ali
  • Article |

    Hereditary hypertrophic cardiomyopathy (HCM) is caused by mutations in cardiomyocyte genes, such as MYBPC3. Here, the authors use virus-mediated gene therapy to correct Mycbpc3mutations in 1-day-old mice and, by administering just a single dose, prevent development of HCM over a period of 34 weeks.

    • Giulia Mearini
    • , Doreen Stimpel
    •  & Lucie Carrier