Ex vivo bone morphogenetic protein-9 gene therapy using human mesenchymal stem cells induces spinal fusion in rodents.
OBJECTIVE
Ex vivo gene therapy with the use of human mesenchymal stem cells (hMSCs) and bone morphogenetic protein (BMP) genes provides a local supply of precursor cells and a supraphysiological dose of osteoinductive molecules that may promote bone formation in patients with inadequate hMSC populations because of age, osteoporosis, metastatic bone disease, iatrogenic depletion, or other metabolic derangements. This study was undertaken to evaluate the efficacy of ex vivo gene therapy with the use of hMSCs and the BMP-9 gene to promote spinal fusion in the rat.


METHODS
Sixteen athymic nude rats were treated with hMSCs transduced with recombinant, replication-defective Type 5 adenovirus containing the cytomegalovirus promoter and either the BMP-9 (Ad-BMP-9) or the beta-galactosidase (Ad-beta-gal) gene. Ad-beta-gal served as the control. Each animal received a percutaneous, paraspinal injection of 10(6) hMSCs transduced with 50 plaque-forming units/cell adenovirus in the lumbar region, with Ad-BMP-9 on the left and Ad-beta-gal on the right. At 8 weeks postinjection, computed tomographic scans of the lumbosacral spine were obtained, and the lumbosacral spine specimens were examined histologically.


RESULTS
Both computed tomographic studies and histological analysis clearly demonstrated large volumes of ectopic bone at the Ad-BMP-9-transduced hMSC injection sites, resulting in successful spinal fusion and no evidence of nerve root compression or local or systemic toxicity. The contralateral regions that were treated with Ad-beta-gal-transduced hMSCs showed no evidence of osteogenesis.


CONCLUSIONS
The results of this study suggest that hMSC and BMP-9 ex vivo gene therapy may be useful in inducing spinal fusion as well as other related procedures and certainly warrants further clinical development.
Dumont
Randall J
RJ
Department of Neurological Surgery, University of Virginia, Charlottesville, VA 22908, USA.
Dayoub
Hayan
H
Li
Jin Zhong
JZ
Dumont
Aaron S
AS
Kallmes
David F
DF
Hankins
Gerald R
GR
Helm
Gregory A
GA
D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000235:genetics*; D015316:Genetic Therapy; D055427:Growth Differentiation Factor 2; D055412:Growth Differentiation Factors; D007278:Injections, Spinal; D008159:Lumbar Vertebrae / Q000000981:diagnostic imaging / Q000473:pathology; D008648:Mesoderm / Q000166:cytology; D051381:Rats; D011923:Rats, Nude; D013123:Spinal Fusion / Q000379:methods*; D033581:Stem Cell Transplantation / Q000379:methods; D014057:Tomography, X-Ray Computed
D019485:Bone Morphogenetic Proteins; C525887:GDF2 protein, human; D055427:Growth Differentiation Factor 2; D055412:Growth Differentiation Factors