Hydrogel-Assisted Antisense LNA Gapmer Supply for In Situ Gene Silencing in Spinal Twine Damage.
Mol Ther Nucleic Acids. 2018 Jun 01;11:393-406
Authors: Moreno PMD, Ferreira AR, Salvador D, Rodrigues MT, Torrado M, Carvalho ED, Tedebark U, Sousa MM, Amaral IF, Wengel J, Pêgo AP
After spinal wire damage (SCI), nerve regeneration is severely hampered as a result of institution of a extremely inhibitory microenvironment on the damage web site, via the contribution of a number of elements. The potential of antisense oligonucleotides (AONs) to change gene expression at totally different ranges, permitting the regulation of cell survival and cell operate, along with the supply of chemically modified nucleic acids with favorable biopharmaceutical properties, make AONs a horny device for novel SCI remedy developments. On this work, we explored the potential of locked nucleic acid (LNA)-modified AON gapmers together with a fibrin hydrogel bridging materials to induce gene silencing in situ at a SCI lesion web site. LNA gapmers have been successfully developed towards two promising gene targets aiming at enhancing axonal regeneration-RhoA and GSK3?. The fibrin-matrix-assisted AON supply system mediated potent RNA knockdown in vitro in a dorsal root ganglion explant tradition system and in vivo at a SCI lesion web site, reaching round 75% downregulation 5 days after hydrogel injection. Our outcomes present that native implantation of a AON-gapmer-loaded hydrogel matrix mediated environment friendly gene silencing within the lesioned spinal wire and is an progressive platform that may probably mix gene regulation with regenerative permissive substrates aiming at SCI therapeutics and nerve regeneration.
PMID: 29858074 [PubMed]