Biomedical Engineering Reference
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Figure 6. Spinal fusion is achieved in a rat model when devitalized bone matrix is loaded with bone marrow
cells over-expressing LIM-1 cDNA. Anteroposterior (A) and lateral (B) radiographs of a rat spine 4 weeks
post-surgery. Complete spinal fusion where bone marrow cells expressed LIM-1 cDNA is shown (arrow-
heads) and no fusion where cells contained an inactive form of LIM-1 cDNA (arrows).
host cells, rather than transfected cells only. These studies show promising results in small
animals and strongly support an advance towards clinical use for the treatment of human
spinal fusions. Although animal studies indicate gene therapy as an attractive treatment for
spinal fusion, problems arise when translating such a therapy to humans.
For example, gene dosage is a consideration for any gene therapy application. The use of
BMPs for spinal fusion is no exception. Rhesus monkeys needed eight times as much
bovine-derived osteoinductive factor to achieve spinal fusion compared to the rabbit model. 180
Other issues of concern include duration of expression and localization of osteoinductive pro-
tein expression. Ossification of the ligamentum flavum and secondary spinal cord compression
in mice when BMP-2 had been delivered to the lumbar extradural space has also been re-
ported. 188 Localization and duration of BMP activity can be controlled by incorporating tissue
specific, inducible promoters. For example osteocalcin is an osteoblast specific protein and the
osteocalcin promoter has been used to drive tissue specific expression of growth factors for gene
therapy. 188 Further, using an inducible system such as the tet on/off system, allowing for con-
trolled expression of the transgene. 189 In the presence of tetracycline or its derivative doxycy-
cline, BMP is not expressed. In their absence, exogenous BMP expression is turned on. A
tetracycline-regulated system was able to control rhBMP-2 expression in vivo and promote
bone healing in a mouse radial critical-sized defect model (Fig. 7). 189 Further, when rhBMP-2
expression was turned on, bone specific genes were up-regulated. 189 The function of BMP
endogenously is another factor to consider when designing a gene therapy for bone using BMP.
Bone inductive proteins of BMP vary across species. 180 Therefore, the functions of BMP must
be characterized specifically in each animal to be treated by gene therapy using BMP DNA.
This holds true for any gene therapy application to bone and will be echoed in gene therapy
applications to other bone defects. In conclusion, osteoinductive factors that are delivered to
the wound site via gene therapy were shown to promote successful spinal fusion in animal
models. Other genes of interest must also be investigated. With these come additional advan-
tages and limitations that must be considered when evaluating the potentials of such treat-
ments for humans.
 
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