Gene therapy in Orthopaedics - DNB Orthopaedics MS Orthopedics MRCS Exam GUIDE -

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Tuesday 16 January 2018

Gene therapy in Orthopaedics

GENE THERAPY in orthopaedics

  • Definition
    • treatment directed to cure genetic diseases by introducing normal genes into patients to overcome the effect of defective genes
    • these genes delivers individual proteins to specific cells
  • History
    • I therapeutic trial : 1990 for SCID in ADA deficiency
    • Orthopaedics : only in RA
  • Design
    • includes
      • gene for specific protein (transgene)
      • identify target tissue
      • choosing vector and vector delivery method
      • choosing a promoter to regulate gene
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    • Somatic gene therapy : targets non-reproductive cells
    • Germ line gene therapy : targets gamete cells – manipulations are passed to progeny
    • viral vectors
      • done by viral transduction
      • genetically engineered virus permitted to initially infect the cell – further replication inside cell is prevented
      • can not infect other cells d/t deficiency in replication
      • ADV, AAV, HSV, Retrovirus
    • non viral vectors
      • done by transfection (eukaryotic cells made to take up foreign DNA from environment)
      • not as effective as viral vectors
      • Naked DNA
      • DNA -protein complex
      • Liposomes ( for delivering genes to chondrocytes)
      • Gene gun ( for muscles and cartilage cells)
    • Systemic gene therapy
      • targets all cells
      • injected directly to blood
      • treating metastatic diseases
      • poor penetration in tissues with decreased blood supply – cartilage and menisci
    • Local gene therapy
      • injected to specific tissue
      • direct
        • ACL, MCL, Meniscus, Tendon, Ligament
      • indirect
        • target cell is removed form body – exposed to vector in vitro and reinserted
        • spine, articular cartilage, skeletal muscle
  • Scope in Orthopaedics
    • Rheumatoid arthritis
      • indirect gene therapy
      • synovial cells harvested – transduced to produce IRAP – injected back to diseased joint
      • IRAP blocks IL-1 intraarticularly
    • Osteochondral defect
      • indirect delivery of genes encoding BMP-2, IGF-1, TGF-beta to articular cartilage – increases proteoglycan synthesis
    • Tendons and ligaments
      • better integration in ligaments injury reconstruction if engineered to express BMP-2, IGF, PDGF
    • Intervertebral disc
      • direct delivery of TGF-beta to nucleus pulposus – increased proteoglycan synthesis
    • Skeletal muscle
      • indirect gene therapy
      • basal lamina of muscles can not be penetrated by virus
      • IGF-1 and NGF improve muscle healing
    • Spine fusion
      • BMP-2 injections : solid fusion
    • Bone healing
      • direct
        • using adeno virus with BMP gene
        • immune response to virus can occur
      • indirect
        • with osteogenic precursors and stem cells
  • definitive clinical trials only done for Rheumatoid arthritis
  • more research going on
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  11. For the clinical management of orthopaedic disorders that are challenging to treat with conventional surgical or medicinal procedures, gene therapy provides new opportunities. Changes to the signaling peptides involved may be able to treat or alleviate a variety of disorders, including impaired bone healing, the need for significant bone production, cartilage repair, and metabolic bone illnesses. Gene therapy may induce tumor necrosis and boost tumor sensitivity to treatment in orthopaedic oncology. Gene transfer may help heal articular cartilage, menisci, intervertebral disks, ligaments, and tendons, according to growing body of research. These advancements have the potential to revolutionize a variety of musculoskeletal care fields by enabling therapies that are less intrusive, more potent, and more affordable than currently used methods.

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