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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