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.
Highlights
Osteoarthritis (OA) is the most common joint disorder in the aged population, and a leading cause of morbidity worldwide due to functional impairment and pain [1]
We show proof of principle for this approach by using a fibrin (F) and hyaluronic acid (HA) hydrogel (F:HA) as a platform for combined delivery of cells and an ADAMTS5-targeting antisense oligonucleotides (ASOs) in a novel in vitro system mimicking chondrocyte delivery for cartilage resurfacing and its interaction with surrounding native joint tissues exposed to a pro-inflammatory environment
A non-targeting gapmer was used as a negative control (ASO 1) and did not significantly affect the expression of ADAMTS5
Summary
Osteoarthritis (OA) is the most common joint disorder in the aged population, and a leading cause of morbidity worldwide due to functional impairment and pain [1]. One feature correlated with pain and radiographic stage in OA patients is the presence of cartilage lesions of variable size [6,7,8]. These are generally a result of weakening of the joint and a factor highly associated with disease progression [9]. Such lesions may be a viable target for regenerative approaches. Autologous chondrocyte implantation (ACI), or MACI (matrix-assisted ACI) have shown to be effective in repair of focal lesion of the cartilage after joint trauma, but such approach will not be viable in the OA joint, as long as both the transplanted cells and those in the neighboring tissue are in a permanently catabolic state [10]
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