Novel Therapies in Osteoarthritis

Novel Therapies in Osteoarthritis

Novel Therapies in Osteoarthritis

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PRP & Cell-Based Therapies - Blood & Marrow Magic

  • Platelet-Rich Plasma (PRP): Autologous concentrated platelets (3-8x baseline).
    • Preparation: Centrifugation.
    • Types: Leukocyte-Rich (LR-PRP), Leukocyte-Poor (LP-PRP).
    • Activation: Thrombin/$CaCl_2$ releases growth factors ($PDGF$, $TGF-\eta$).
    • MOA: Modulates inflammation, promotes healing.
  • Mesenchymal Stem/Stromal Cells (MSCs):
    • Sources: Bone Marrow (BMAC - typical $1-5 \times 10^6$ cells/mL), Adipose (AD-MSCs), Umbilical Cord (UC-MSCs). 📌 B.A.U. for sources!
    • MOA: Primarily paracrine signaling (trophic factors); less by differentiation.

    ⭐ MSCs primarily exert their therapeutic effects in osteoarthritis via paracrine signaling (secretion of trophic factors) rather than direct differentiation into chondrocytes.

  • Autologous Conditioned Serum (ACS/Orthokine):
    • Preparation: Blood incubated with glass beads, serum collected.
    • MOA: ↑$IL-1Ra$, blocks $IL-1$ inflammatory effects.

![Extracellular Vesicles](extracellular vesicles)

Growth Factors & Cytokines - Signal Saviors

  • Sprifermin (rhFGF-18)
    • MOA: Recombinant human Fibroblast Growth Factor 18; ↑ chondrocyte proliferation & extracellular matrix (ECM) production.
    • Trials: Showed ↑ cartilage thickness (e.g., FORWARD trial, 100 µg dose). Intra-articular.
  • IL-1 Antagonists
    • Anakinra: Recombinant IL-1 receptor antagonist (IL-1Ra). Blocks IL-1.
      • Efficacy: Modest, short-term pain relief. Intra-articular.
    • Diacerein: Oral. Inhibits IL-1β synthesis & activity.
      • Efficacy: Symptomatic relief; potential slow-acting disease-modifying (DMOAD) effect.
  • TNF-α Inhibitors (e.g., Infliximab, Etanercept)
    • MOA: Block Tumor Necrosis Factor-alpha.
    • Role in OA: Limited efficacy in primary OA. May benefit inflammatory OA phenotypes. Not routine.
  • Other Growth Factors (Investigational)
    • BMP-7 (Bone Morphogenetic Protein-7): Promotes chondrogenesis, cartilage repair.
    • TGF-β (Transforming Growth Factor-beta): Complex role; anabolic at low doses, potentially fibrotic/catabolic at high doses.

⭐ Sprifermin (recombinant human Fibroblast Growth Factor 18) has shown evidence of increased cartilage thickness in some clinical trials for knee osteoarthritis.

Gene Therapy & RNAi - Cartilage Coders

Altering chondrocyte gene expression to combat osteoarthritis (OA).

  • Gene Therapy: Delivers therapeutic genes into joint cells.

    • Vectors:
      • Viral: AAV, Lentivirus (efficient delivery).
      • Non-viral: Plasmids (safer, lower efficiency).
    • Target Genes:
      • Anti-catabolic: $IL-1Ra$, TIMPs (↓cartilage degradation).
      • Anabolic: $SOX9$, $TGF-β$, $IGF-1$ (↑matrix synthesis).
    • Delivery: Intra-articular injection; ex vivo (cells modified, then implanted).

    ⭐ Adeno-associated virus (AAV) vectors are favored for in vivo gene therapy in osteoarthritis due to their safety profile and ability to transduce chondrocytes effectively.

  • RNA Interference (RNAi): Silences detrimental genes using:

    • Molecules: siRNA (small interfering), shRNA (short hairpin).
    • Targets: $MMPs$, $ADAMTS$ (key cartilage-degrading enzymes).

DMOADs & Pathway Inhibitors - Degeneration Decelerators

Disease-Modifying Osteoarthritis Drugs (DMOADs) aim to slow structural progression in OA. Key pathway inhibitors:

  • Wnt Pathway Inhibitors:
    • Lorecivivint (SM04690): Intra-articular.

      ⭐ Lorecivivint (SM04690) is an intra-articular small molecule inhibitor of the Wnt pathway that has shown potential as a DMOAD by promoting chondrogenesis.

    • MOA: Modulates Wnt, ↑chondrogenesis, ↓degradation. Trials ongoing.
  • ADAMTS-5 Inhibitors:
    • MOA: Block aggrecan degradation in cartilage.
    • Challenges: Specificity, delivery, efficacy.
  • Cathepsin K Inhibitors:
    • MOA: Reduce collagen degradation, bone resorption.
    • Status: Mixed OA trial results; some halted.
  • Senolytics:
    • MOA: Eliminate senescent cells, ↓inflammation & degradation.
  • PCSK9 Inhibitors:
    • Emerging role in OA; research ongoing.

OA joint therapies: structure-based and pain-based

  • PRP & MSCs: Key biologics for OA, using autologous factors/cells; efficacy varies.
  • Tanezumab (anti-NGF mAb): Potent pain relief but risk of Rapidly Progressive OA (RPOA).
  • Sprifermin (rhFGF-18): Growth factor aiming to ↑cartilage thickness, potential DMOAD.
  • Gene Therapy: Intra-articular delivery of anti-inflammatory (e.g., IL-1Ra) or chondrogenic factors.
  • Lorecivivint (Wnt inhibitor): Small molecule with DMOAD potential; targets cartilage degradation.
  • Intra-articular delivery is preferred for most novel therapies to enhance local effects.
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Practice Questions: Novel Therapies in Osteoarthritis

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Which drug used in treatment of rheumatoid arthritis acts by inhibition of T-cell proliferation?

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Flashcards: Novel Therapies in Osteoarthritis

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What is the earliest pathological change seen in osteoarthritis?_____

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What is the earliest pathological change seen in osteoarthritis?_____

Asymmetrical hyaline articular cartilage loss

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Novel Therapies in Osteoarthritis | Degenerative Disorders - OnCourse NEET-PG