Development of KA34 as a cartilage regenerative therapy for Osteoarthritis

Johnson, Kenneth A.; Woods, Andrew J.; Joseph, S.B.; Chatterjee, Arnab K.; Zhu, Shoutian; Wisler, John; Klyushnichenko, Vadim; Li, J.; Lotz, Martin; Tremblay, Matthew S.; Schultz, Peter G.

doi:10.1016/j.joca.2020.02.814

Cited by 8 publications

(7 citation statements)

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“…This is timely work as IA administered KGN analogue is currently being evaluated in a clinical trial for OA therapy. 22 …”

Section: Discussionmentioning

confidence: 99%

“… 26 Recently, a more potent and stable analogue of KGN, KA34 was shown to be effective in cartilage repair and pain modulation in injury models of rats and dogs with weekly or biweekly IA injections. 22 These preclinical studies have led to a Phase I clinical trial (NCT03133676) to evaluate the safety and tolerability of single and multiple IA doses of KA34 in OA patients. These are promising developments further highlighting the importance of developing sustained release formulations to reduce the need for multiple injections, which is also associated with local injection site pain, inflammation and discomfort.…”

Section: Introductionmentioning

confidence: 99%

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Single-Dose Intra-Cartilage Delivery of Kartogenin Using a Cationic Multi-Arm Avidin Nanocarrier Suppresses Cytokine-Induced Osteoarthritis-Related Catabolism

Shaw

Vedadghavami

et al. 2022

CARTILAGE

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Objective Kartogenin (KGN) has proven as a both chondrogenic and chondroprotective drug for osteoarthritis (OA) therapy. However, being a small hydrophobic molecule, KGN suffers from rapid joint clearance and inability to penetrate cartilage to reach chondrocytes following intra-articular administration. As such multiple high doses are needed that can lead to off-target effects including stimulation and tissue outgrowth. Here we design charge-based cartilage targeting formulation of KGN by using a multi-arm cationic nano-construct of Avidin (mAv) that can rapidly penetrate into cartilage in high concentrations owing to weak-reversible electrostatic binding interactions with negatively charged aggrecan-glycosaminoglycans (GAGs) and form an extended-release drug depot such that its therapeutic benefit can be reaped in just a single dose. Design We synthesized 2 novel formulations, one with a releasable ester linker (mAv-OH-KGN, release half-life ~58 h) that enables sustained KGN release over 2 weeks and another with a non-releasable amide linker (mAv-NH-KGN) that relies on mAv’s ability to be uptaken and endocytosed by chondrocytes for drug delivery. Their effectiveness in suppressing cytokine-induced catabolism was evaluated in vitro using cartilage explant culture model. Results A single 100 μM dose of cartilage homing mAv-KGN was significantly more effective in suppressing cytokine-induced GAG loss, cell death, inflammatory response and in rescuing cell metabolism than a single dose of free KGN; multiple doses of free KGN were needed to match this therapeutic response. Conclusion mAv mediated delivery of KGN is promising and can facilitate clinical translation of KGN for OA treatment with only a single dose.

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“…This is timely work as IA administered KGN analogue is currently being evaluated in a clinical trial for OA therapy. 22 …”

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Single-Dose Intra-Cartilage Delivery of Kartogenin Using a Cationic Multi-Arm Avidin Nanocarrier Suppresses Cytokine-Induced Osteoarthritis-Related Catabolism

Shaw

Vedadghavami

et al. 2022

CARTILAGE

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“…A chondroprotective activity, with signs of cartilage repair after injury has been also reported after intra-articular injection of adipose-derived stem cells in experimental OA ( ter Huurne et al, 2012 ), but results obtained from clinical trials were not convincing ( Pers et al, 2016 ; Emadedin et al, 2018 ; Freitag et al, 2019 ; Kim et al, 2019 ; Lee et al, 2019 ). Evaluations on emerging drugs promoting chondrogenesis, such as kartogenin and sprifermin, are ongoing ( Eckstein et al, 2020 ; Johnson et al, 2020 ).…”

Section: Current and Future Pharmaceutical Therapy For Oamentioning

confidence: 99%

Immunological Events, Emerging Pharmaceutical Treatments and Therapeutic Potential of Balneotherapy on Osteoarthritis

et al. 2021

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“…In this study, the following antifolates that have been approved clinically by the U.S. Food and Drug Administration were screened; dapsone (1), methotrexate (2), pemetrexed (3), pralatrexate (4), proguanil (5), pyrimethamine (6), and trimethoprim (7), which are being used for the treatment of malaria, rheumatoid arthritis, cancer, and bacterial infection. , KGN, which has been reported to be an excellent promoter for chondrogenic differentiation of MSCs, was used as a positive control molecule . In particular, phase I clinical trial of KGN was recently completed in the United States for cartilage repair . Intra-articular injection of KGN induces cartilage regeneration through stimulating chondrogenic differentiation of endogenous stem cells.…”

Section: Introductionmentioning

confidence: 99%

“…Thermogel solution is free flowing and can be injected into a target site for thermo-sensitive gelation. Therefore, thermogels have been investigated not only for their unique transition mechanism but also for their many other biomedical applications including drug delivery, wound healing, post-operative adhesion prevention, submucosal cushion for dissection, and tissue enginnering. − In particular, thermogels can provide scaffolds for three-dimensional (3D) cell culture. − Cells are suspended in an aqueous polymer solution at a temperature below the sol-to-gel transition temperature and then are incorporated into the hydrogel formed in situ by increasing the temperature to 37 °C without the need for chemical crosslinking or UV light, which can damage cells. The hydrogel can be loaded with differentiation factors or nutrients.…”

Section: Introductionmentioning

confidence: 99%

Pralatrexate Sustainably Released from Polypeptide Thermogel Is Effective for Chondrogenic Differentiation of Mesenchymal Stem Cells

Woo

Patel

Kim

et al. 2022

ACS Appl. Mater. Interfaces

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Folic acid was reported to significantly improve chondrogenic differentiation of mesenchymal stem cells. In a similar mechanism of action, we investigated clinically approved antifolates by the U.S. Food and Drug Administration as chondrogenic-promoting compounds for tonsil-derived mesenchymal stem cells. A poly(ethylene glycol)-poly(l-alanine) thermogelling system was used as a three-dimensional cell culture matrix, where stem cells and antifolates could be incorporated simultaneously during a heat-induced in situ sol-to-gel transition. The antifolates could be supplied over several days by the sustained release of the drug from the thermogel. Initially, seven antifolates were prescreened based on cell viability and expression of a typical chondrogenic biomarker of type II collagen (COL II) at the mRNA level. Then, dapsone, pralatrexate, and trimethoprim were selected as candidate compounds in the second round screening, and detailed studies were carried out on the mRNA and protein expression of various chondrogenic biomarkers including COL II, SRY box transcription factor 9, and aggrecan. Three-dimensional cultures of stem cells in the thermogel in the absence of a chondrogenic promoter compound and in the presence of kartogenin (KGN) were performed as a negative control and positive control, respectively. The chondrogenic biomarkers were significantly increased in the selected antifolate-incorporating systems compared to the negative control system, without an increase in type I collagen (an osteogenic biomarker) expression. Pralatrexate was the best compound for inducing chondrogenic differentiation of the stem cells, even better than the positive control (KGN). Nuclear translocation of the core-binding factor β subunit (CBFβ) and enhanced nuclear runt-related transcription factor 1 (RUNX1) by antifolate treatment suggested that the chondrogenesis-enhancing mechanism is mediated by CBFβ and RUNX1. An in silico modeling study confirmed the mechanism by proving the high binding affinity of pralatrexate to a target protein of filamin A compared with other antifolate candidates. To conclude, pralatrexate was rediscovered as a lead compound, and the polypeptide thermogel incorporating pralatrexate and mesenchymal stem cells can be a very effective system in promoting chondrogenic differentiation of stem cells and might be used in injectable tissue engineering for cartilage repair.

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Development of KA34 as a cartilage regenerative therapy for Osteoarthritis

Cited by 8 publications

References 0 publications

Single-Dose Intra-Cartilage Delivery of Kartogenin Using a Cationic Multi-Arm Avidin Nanocarrier Suppresses Cytokine-Induced Osteoarthritis-Related Catabolism

Single-Dose Intra-Cartilage Delivery of Kartogenin Using a Cationic Multi-Arm Avidin Nanocarrier Suppresses Cytokine-Induced Osteoarthritis-Related Catabolism

Immunological Events, Emerging Pharmaceutical Treatments and Therapeutic Potential of Balneotherapy on Osteoarthritis

Pralatrexate Sustainably Released from Polypeptide Thermogel Is Effective for Chondrogenic Differentiation of Mesenchymal Stem Cells

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