Non-viral ocular gene therapy, pEYS606, for the treatment of non-infectious uveitis: Preclinical evaluation of the medicinal product

Non-infectious uveitis (NIU) is the first cause of blindness that can be cured if optimal anti-inflammatory therapy can be achieved. Systemic anti-TNF (Tumor Necrosis Factor) agents have been recently approved for NIU but no local delivery of anti-TNF is available. For sustained production of secret...

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Bibliographic Details
Published in:Journal of controlled release 2018-09, Vol.285, p.244-251
Main Authors: Touchard, Elodie, Benard, Romain, Bigot, Karine, Laffitte, Jean-Denis, Buggage, Ronald, Bordet, Thierry, Behar-Cohen, Francine
Format: Article
Language:English
Subjects:
Electrotransfer
Gene therapy
Non-infectious posterior uveitis
Plasmid
TNF-alpha
TNF-R1
Uveitis
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Summary:Non-infectious uveitis (NIU) is the first cause of blindness that can be cured if optimal anti-inflammatory therapy can be achieved. Systemic anti-TNF (Tumor Necrosis Factor) agents have been recently approved for NIU but no local delivery of anti-TNF is available. For sustained production of secreted therapeutic proteins into the eye, non-viral gene therapy using plasmid electrotransfer in the ciliary muscle has been proposed. In this paper, we report the development steps of pEYS606, a clinical-grade plasmid DNA, devoid of antiobiotic selection gene, encoding a fusion protein consisting of the extracellular domain of the soluble p55 TNF-α receptor linked to the human IgG1 Fc domain (hTNFR-Is/hIgG1 or Protein 6), with high affinity for human TNF-α, for non-viral gene transfer into the ocular ciliary muscle. Electrotransfer of pEYS606 in the ciliary muscle significantly reduced ocular inflammation in two well-established rat models of uveitis, the endotoxin-induced uveitis (EIU) and the experimental autoimmune uveitis (EAU). In addition, in EAU, a significant protection of photoreceptors was demonstrated after pEYS606 treatment. The improved pharmacokinetic profile of intraocularly-secreted protein as compared to direct intravitreous injection of recombinant protein allowed to demonstrate Protein 6 efficacy at very low concentrations. Based on these results, a phase I/II clinical trial is conducted [ClinicalTrials.gov Identifier: NCT03308045]. [Display omitted]
ISSN:0168-3659
1873-4995
DOI:10.1016/j.jconrel.2018.07.013