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 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].

Structure-properties relationships in triarylamine-based donor-acceptor molecules containing naphtyl groups as donor material for organic solar cells.

The effects of replacing the phenyl rings of triphenylamine (TPA) by naphtyl groups are analysed on a series of push-pull molecules containing a 2-thienyl-dicyanovinyl acceptor group. UV-Vis absorption spectroscopy and cyclic voltammetry show that the introduction of one or two naphtyl groups in the structure has limited effects on the optical properties and energy levels of the molecule. On the other hand, the evaluation of the compounds as donor material in bi-layer solar cells with C60 as acceptor shows that the number and mode of linkage of the naphtyl groups exert a marked influence on the power conversion efficiency (PCE) of the cell. Two naphtyl groups lead to a decrease of PCE with respect to TPA, while a single naphtyl group produces opposite effects depending on the linking mode. Compared to TPA, an alpha-naphtyl group leads to a small decrease of PCE while in contrast a beta-naphtyl leads to a ~35% increase of PCE due to improved short-circuit current density (Jsc) and fill-factor. The determination of the hole-mobility of these two donors by the space-charge-limited current method shows that these effects are correlated with the higher hole-mobility of the ß-naphtyl compound.

[Ethical relativism and the modern concept of tolerance]. / Relativismo ético y concepto moderno de tolerancia.

History presents many examples of men and women who find themselves in a position of having to disobey civil law. The motives for such disobedience can only be founded on moral conscience, as influenced by other laws - immutable and recognized as true. The author studies the historical context of the appearance, during the Age of the Enlightenment, of a new concept: tolerance. Ceasing to represent the expression of the classical practical virtue of prudence, ideological tolerance achieves the rank of theoretical virtue. Such a pretension has a political in essence but also innumerable ethical consequences. An ideologically tolerant society is created. The author develops this paradoxical thesis according to which an ideologically tolerant society is not prepared to tolerate the idea that there might exist a truth for which to search. Today, we see a secularization of conscientious objection concerning two particular themes: military service and matters connected with the protection of human life. Examining the paradigmatic example of abortion, the author demonstrates how society is no longer capable of reflecting peacefully upon the question of the status of the embryo, for fear of questioning the legislative choice concerning its legalization. Thus, society no longer has the capability of confronting challenges connected to practices that are detrimental to the dignity of human life, the essential criteria that would allow it to face these matters having been declared outside the confines of future reflection.