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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