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Cited by 150Virus-based gene therapy researchCystic Fibrosis Research AdvancesRNA Interference and Gene Delivery

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

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Alton, Eric W F W, Beekman, Jeffery M, Boyd, A Christopher, Brand, June, Carlon, Marianne S, Connolly, Mary M, Chan, Mario, Conlon, Sinead +30 more·2017·Thorax
DOI 10.1136/thoraxjnl-2016-208406PMC PMC5284333
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Abstract

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-pseudotyped lentiviral vector into a first-in-man CF trial in 2017.

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  • Recent pre-clinical studies provided encouraging results on lentiviral-mediated CFTR delivery which are leading to the preparation of a first-in-man lentivirus trial in patients with CF.

    “In the CF clinical field recent pre-clinical studies provided encouraging results on lentiviral-mediated CFTR delivery which are leading to the preparation of a first-in-man lentivirus trial in patients with CF11,57.”

    From Allele specific repair of splicing mutations in cystic fibrosis through AsCas12a genome editing (2019) · cites this paper as [11]

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Cited by

Sorted by citations

Authors
Alton, E. W. F. W., Beekman, J. M., Boyd, A. C., Brand, J., Carlon, M. S., Connolly, M. M., Chan, M., Conlon, S., Davidson, H. E., Davies, J. C., Davies, L. A., Dekkers, J. F., Doherty, A., Gea-Sorli, S., Gill, D. R., Griesenbach, U., Hasegawa, M., Higgins, T. E., Hironaka, T., Hyndman, L., McLachlan, G., Inoue, M., Hyde, S. C., Innes, J. A., Maher, T. M., Moran, C., Meng, C., Paul-Smith, M. C., Pringle, I. A., Pytel, K. M., Rodriguez-Martinez, A., Schmidt, A. C., Stevenson, B. J., Sumner-Jones, S. G., Toshner, R., Tsugumine, S., Wasowicz, M. W., & Zhu, J.
Affiliations
  • Imperial College London (GB)
  • Institute of Genetics and Cancer (GB)
  • KU Leuven (BE)
  • John Radcliffe Hospital (GB)
  • University Medical Center Utrecht (NL)
  • ID Pharma (Japan) (JP)
  • Roslin Institute (GB)
ORCID
Venue
Thorax
Publisher
BMJ
Published
2016-11-16
Volume
72
Issue
2
Pages
137-147
ISSN
  • 0040-6376 (ISSN-L)
  • 1468-3296
DOI
10.1136/thoraxjnl-2016-208406
PMC
PMC5284333
OpenAlex
W2549404374
Cited by
150
References
1
Citations by year
2026: 9 · 2025: 8 · 2024: 13 · 2023: 9 · 2022: 22 · 2021: 18 · 2020: 24 · 2019: 20 · 2018: 16 · 2017: 11
FWCI
12.66
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Thorax (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Lirias (KU Leuven) (submittedVersion, cc-by)
  • HighWire Press Open Archive (submittedVersion)
  • Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, cc-by)
  • Spiral (Imperial College London) (submittedVersion, other-oa)
Funders
  • Royal Brompton and Harefield NHS Foundation Trust
  • National Institute for Health and Care Research
  • Cystic Fibrosis Trust
  • National Institutes of Health
  • Medical Research Council (MR/J014699/1)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Cystic Fibrosis Research Advances
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
Keywords
cystic fibrosis, lentiviral vectors, CFTR, pulmonary gene therapy, first-in-man trial, promoter selection, vector toxicity, transduction efficiency, pre-existing immunity, adaptive immunity, vector stability, air-liquid interface culture, mouse model
MeSH terms
Animals, Cystic Fibrosis, Genetic Vectors, Humans, Promoter Regions, Genetic, Genetic Therapy, Gene Expression, Lentivirus, Gene Transfer Techniques, Peptide Elongation Factor 1, Mice

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