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

João Pedro Garcia, Jeroen Stein, Yunpeng Cai, Frank Riemers, Ezequiel Wexselblatt, Jesper Wengel, Marianna Tryfonidou, Avner Yayon, Kenneth A. Howard, Laura B. Creemers*

*Corresponding author for this work

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Abstract

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.

Original languageEnglish
JournalJournal of Controlled Release
Volume294
Pages (from-to)247-258
ISSN0168-3659
DOIs
Publication statusPublished - 28. Jan 2019

Fingerprint

Hydrogel
Hyaluronic Acid
Chondrocytes
Joints
Disintegrins
Confocal Microscopy
Flow Cytometry
Peptide Hydrolases
Enzymes
Pharmaceutical Preparations
Population

Keywords

  • ADAMTS5
  • Antisense oligonucleotide
  • Chondrocytes
  • Gapmer
  • Hydrogel
  • Osteoarthritis

Cite this

Garcia, João Pedro ; Stein, Jeroen ; Cai, Yunpeng ; Riemers, Frank ; Wexselblatt, Ezequiel ; Wengel, Jesper ; Tryfonidou, Marianna ; Yayon, Avner ; Howard, Kenneth A. ; Creemers, Laura B. / Fibrin-hyaluronic acid hydrogel-based delivery of antisense oligonucleotides for ADAMTS5 inhibition in co-delivered and resident joint cells in osteoarthritis. In: Journal of Controlled Release. 2019 ; Vol. 294. pp. 247-258.
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abstract = "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.",
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Fibrin-hyaluronic acid hydrogel-based delivery of antisense oligonucleotides for ADAMTS5 inhibition in co-delivered and resident joint cells in osteoarthritis. / Garcia, João Pedro; Stein, Jeroen; Cai, Yunpeng; Riemers, Frank; Wexselblatt, Ezequiel; Wengel, Jesper; Tryfonidou, Marianna; Yayon, Avner; Howard, Kenneth A.; Creemers, Laura B.

In: Journal of Controlled Release, Vol. 294, 28.01.2019, p. 247-258.

Research output: Contribution to journalJournal articleResearchpeer-review

TY - JOUR

T1 - Fibrin-hyaluronic acid hydrogel-based delivery of antisense oligonucleotides for ADAMTS5 inhibition in co-delivered and resident joint cells in osteoarthritis

AU - Garcia, João Pedro

AU - Stein, Jeroen

AU - Cai, Yunpeng

AU - Riemers, Frank

AU - Wexselblatt, Ezequiel

AU - Wengel, Jesper

AU - Tryfonidou, Marianna

AU - Yayon, Avner

AU - Howard, Kenneth A.

AU - Creemers, Laura B.

PY - 2019/1/28

Y1 - 2019/1/28

N2 - 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.

AB - 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.

KW - ADAMTS5

KW - Antisense oligonucleotide

KW - Chondrocytes

KW - Gapmer

KW - Hydrogel

KW - Osteoarthritis

U2 - 10.1016/j.jconrel.2018.12.030

DO - 10.1016/j.jconrel.2018.12.030

M3 - Journal article

C2 - 30572032

AN - SCOPUS:85058950393

VL - 294

SP - 247

EP - 258

JO - Journal of Controlled Release

JF - Journal of Controlled Release

SN - 0168-3659

ER -