Fibrin-hyaluronic acid hydrogel-based delivery of antisense oligonucleotides for ADAMTS5 inhibition in co-delivered and resident joint cells in osteoarthritis

JOURNAL OF CONTROLLED RELEASE

卷:294

Article

Garcia, Joao Pedro¹  Stein, Jeroen¹  Cai, Yunpeng²  Riemers, Frank³  Wexselblatt, Ezequiel⁴  Wengel, Jesper⁵  Tryfonidou, Marianna³  Yayon, Avner⁴  Howard, Kenneth A.²  Creemers, Laura B.¹ 

[1] Univ Med Ctr Utrecht, Dept Orthoped, Utrecht, Netherlands

[2] Aarhus Univ, Dept Mol Biol & Genet, Interdisciplinary Nanosci Ctr iNANO, Aarhus, Denmark

[3] Univ Utrecht, Fac Vet Med, Dept Clin Sci Compan Anim, Utrecht, Netherlands

[4] ProCore Biorned Ltd, Rehovot, Israel

[5] Univ Southern Denmark, Nucle Acid Ctr, Odense, Denmark

关键词: Antisense oligonucleotide;    Gapmer;    Hydrogel;    Osteoarthritis;    ADAMTS5;    Chondrocytes;   

DOI  :  10.1016/j.jconrel.2018.12.030

来源: Elsevier

【 摘 要 】

To date no disease-modifying drugs for osteoarthritis (OA) are available, with treatment limited to the use of pain killers and prosthetic replacement. The ADAMTS (A Disintegrin and Metallo Proteinase with Thrombospondin Motifs) enzyme family is thought to be instrumental in the loss of proteoglycans during cartilage degeneration in OA, and their inhibition was shown to reverse osteoarthritic cartilage degeneration. Locked Nucleic Acid (LNA)-modified antisense oligonucleotides (gapmers) released from biomaterial scaffolds for specific and prolonged ADAMTS inhibition in co-delivered and resident chondrocytes, is an attractive therapeutic strategy. Here, a gapmer sequence identified from a gapmer screen showed 90% ADAMTS5 silencing in a monolayer culture of human OA chondrocytes. Incorporation of the gapmer in a fibrin-hyaluronic acid hydrogel exhibited a sustained release profile up to 14 days. Gapmers loaded in hydrogels were able to transfect both co-embedded chondrocytes and chondrocytes in a neighboring gapmer-free hydrogel, as demonstrated by flow cytometry and confocal microscopy. Efficient knockdown of ADAMTS5 was shown up to 14 days in both cell populations, i.e. the gapmer-loaded and gapmer-free hydrogel. This work demonstrates the use applicability of a hydrogel as a platform for combined local delivery of chondrocytes and an ADAMTS-targeting gapmer for catabolic gene modulation in OA.

【 授权许可】

Free