Percutaneous spinal fusion using bone morphogenetic protein-2 gene therapy

1999 ◽  
Vol 90 (1) ◽  
pp. 109-114 ◽  
Author(s):  
Tord D. Alden ◽  
Debra D. Pittman ◽  
Elisa J. Beres ◽  
Gerald R. Hankins ◽  
David F. Kallmes ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Bone Formation ◽  
Spinal Fusion ◽  
Bone Morphogenetic Protein 2 ◽  
Cmv Promoter ◽  
Content Type ◽  
Morphogenetic Protein ◽  
Adenoviral Construct ◽  
Fine Print

Object. Gene therapy has many potential applications in neurosurgery. One application involves bone morphogenetic protein-2 (BMP-2), a low-molecular-weight glycoprotein that induces bone formation in vivo. Numerous studies have demonstrated that the BMP-2 protein can enhance spinal fusion. This study was undertaken to determine whether direct injection of an adenoviral construct containing the BMP-2 gene can be used for spinal fusion. Methods. Twelve athymic nude rats were used in this study. Recombinant, replication-defective type 5 adenovirus with the cytomegalovirus (CMV) promoter and BMP-2 gene (Ad-BMP-2) was used. A second adenovirus constructed with the CMV promoter and β-galactosidase (β-gal) gene (Ad-β-gal) was used as a control. In three groups (four rats each) 7.5 µl of virus (5 × 108 particles/µl) was injected percutaneously and paraspinally at the lumbosacral junction: Group 1 received Ad-BMP-2 bilaterally; Group 2 received Ad-BMP-2 on the right, Ad-β-gal on the left; and Group 3 received Ad-β-gal bilaterally. Computerized tomography (CT) scans of the lumbosacral spine were obtained at 3, 5, 8, and 12 weeks. At 12 weeks, the animals were killed and underwent histological inspection. Ectopic bone formation was observed both on three-dimensionally reconstructed CT scans and histological examination in all rats at sites treated with Ad-BMP-2. Histological analysis demonstrated bone at different stages of maturity adjacent to the spinous processes, laminae, and transverse processes. Conclusions. Results of this study clearly demonstrated that it is possible to produce in vivo endochondral bone formation by using direct adenoviral construct injection into the paraspinal musculature, which suggests that gene therapy may be useful for spinal fusion in the future.

Bone morphogenetic protein gene therapy for the induction of spinal arthrodesis

1998 ◽  
Vol 4 (2) ◽  
pp. E14 ◽  
Author(s):  
Tord D. Alden ◽  
Gerald R. Hankins ◽  
Elisa J. Beres ◽  
David F. Kallmes ◽  
Gregory A. Helm
Keyword(s):  
Gene Therapy ◽  
Bone Formation ◽  
Spinal Fusion ◽  
Bone Morphogenetic Protein ◽  
Bone Morphogenetic Protein 2 ◽  
Lumbosacral Spine ◽  
Ct Reconstruction ◽  
Morphogenetic Protein ◽  
Adenoviral Construct

Gene therapy has many potential applications in neurosurgery. One application involves bone morphogenetic protein-2 (BMP-2), a low-molecular-weight glycoprotein that induces bone formation in vivo. Numerous studies have demonstrated that the BMP-2 protein can enhance spinal fusion. This study was undertaken to determine whether direct injection of an adenoviral construct containing the BMP-2 gene can be used for spinal fusion. Twelve athymic nude rats were used in this study. Recombinant, replication-defective type-5 adenovirus with a universal promoter and BMP-2 gene (Ad-BMP-2) was used. A second adenovirus constructed with a universal promoter and ß-galactosidase (ß-gal) gene (Ad-ß-gal) was used as a control. Seven and one-half microliters of virus was injected percutaneously and paraspinally at the lumbosacral junction in three groups (four animals each): 1) Ad-BMP-2 bilaterally, 2) Ad-BMP-2 on the right, Ad-ß-gal on the left, and 3) Ad-ß-gal bilaterally. Computerized tomography (CT) scans of the lumbosacral spine were obtained at 3, 5, and 12 weeks. At 12 weeks, the animals were killed for histological inspection. Ectopic bone formation was seen both on three-dimensional CT reconstruction and histologically in all rats at sites treated with Ad-BMP-2. Histological analysis revealed bone at different stages of maturity adjacent to the spinous processes, laminae, and transverse processes. This study clearly demonstrated that it is possible to produce in vivo endochondral bone formation by using direct adenoviral construct injection into the paraspinal musculature, which suggests that gene therapy may be useful for spinal fusion in the future.

Murine spinal fusion induced by engineered mesenchymal stem cells that conditionally express bone morphogenetic protein—2

2005 ◽  
Vol 3 (1) ◽  
pp. 47-52 ◽  
Author(s):  
Amir Hasharoni ◽  
Yoram Zilberman ◽  
Gadi Turgeman ◽  
Gregory A. Helm ◽  
Meir Liebergall ◽  
...  
Keyword(s):  
Gene Expression ◽  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Spinal Fusion ◽  
Genetically Engineered ◽  
Bone Morphogenetic Protein 2 ◽  
Content Type ◽  
Histological Studies ◽  
Morphogenetic Protein ◽  
Fine Print

Object. The authors hypothesized that spinal fusion can be achieved and monitored by using cell-mediated gene therapy. Mesenchymal stem cells (MSCs) genetically engineered to express recombinant human bone morphogenetic protein—2 (rhBMP-2) conditionally, were implanted into the paraspinal muscles of mice to establish spinal fusion. The goal was to demonstrate an MSC-based gene therapy platform in which controlled gene expression is used to obtain spinal fusion in a murine model. Methods. Mesenchymal stem cells expressing the rhBMP-2 gene were injected into the paravertebral muscle in mice. Bone formation in the paraspinal region was longitudinally followed by performing micro—computerized tomography scanning, histological studies, and an analysis of osteocalcin expression to demonstrate the presence of engrafted engineered MSCs. The minimal period of rhBMP-2 expression by the engineered MSCs required to induce fusion was determined. The results of this study demonstrate that genetically engineered MSCs induce bone formation in areas adjacent to and touching the posterior elements of the spine. This newly formed bone fuses the spine, as demonstrated by radiological and histological studies. The authors demonstrate that injected cells induce active osteogenesis at the site of implantation for up to 4 weeks postinjection. They found that a 7-day induction of rhBMP-2 expression in genetically engineered MSCs was sufficient to form new bone tissue, although the quantity of this bone increased as longer expression periods were implemented. Conclusions. After their injection genetically engineered MSCs can efficiently form new bone in the paraspinal muscle of the mouse to obtain spinal fusion. The extent and quantity of this newly formed bone can be monitored by controlling the duration of rhBMP-2 gene expression.

The use of bone morphogenetic protein—6 gene therapy for percutaneous spinal fusion in rabbits

2004 ◽  
Vol 1 (1) ◽  
pp. 90-94 ◽  
Author(s):  
Jeffrey J. Laurent ◽  
K. Michael Webb ◽  
Elisa J. Beres ◽  
Kevin McGee ◽  
Jinzhong Li ◽  
...  
Keyword(s):  
Gene Therapy ◽  
New Zealand ◽  
Spinal Fusion ◽  
Ct Scanning ◽  
Content Type ◽  
Morphogenetic Protein ◽  
New Zealand White Rabbits ◽  
Percutaneous Administration ◽  
Multiple Levels ◽  
Fine Print

Object. Fusion procedures in the lumbar spine have been performed in the US since 1911. Since that time, the indications and techniques for spinal fusion have evolved. Despite technical advancements, spinal fusion remains a major operation, and fusion nonunion rates of up to 35% are still reported. In this study, the authors were able to induce intertransverse process fusions in immune-competent New Zealand White rabbits by percutaneous administration of an adenoviral vector containing the bone morphogenetic protein (BMP-6) gene (Ad-BMP-6). The results represent an important step forward in finding new methods to increase the success and decrease the morbidity associated with spinal fusion. Methods. Five New Zealand White rabbits were used. Injection of the adenoviral construct was performed at multiple levels (bilaterally) in each animal while using fluoroscopic guidance. Injection consisted of either Ad-BMP-6 or Ad—β-galactosidase (β-gal) (control). Because multiple levels were injected, each animal served as an internal control. The animals underwent postinjection computerized tomography (CT) scanning at 7 and 14 weeks. After undergoing final CT scanning, the animals were killed and the spines were harvested. The fusion sites were analyzed by gross inspection, histopathological methods, and micro—CT studies. Conclusions. The results of this study show that an anatomically precise fusion can be accomplished by percutaneous administration of gene therapy. The next step in these studies will be extension of the technique to nonhuman primates and eventually to human clinical studies.

scholarly journals The Bone Regeneration Capacity of BMP-2 + MMP-10 Loaded Scaffolds Depends on the Tissue Status

Pharmaceutics ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 979
Author(s):  
Patricia Garcia-Garcia ◽  
Ricardo Reyes ◽  
José Antonio Rodriguez ◽  
Tomas Martín ◽  
Carmen Evora ◽  
...  
Keyword(s):  
Bone Formation ◽  
Bone Regeneration ◽  
Growth Promotion ◽  
Tissue Growth ◽  
Bone Morphogenetic Protein 2 ◽  
Morphogenetic Protein ◽  
Therapeutic Molecules ◽  
Positive Effect

Biomaterials-mediated bone formation in osteoporosis (OP) is challenging as it requires tissue growth promotion and adequate mineralization. Based on our previous findings, the development of scaffolds combining bone morphogenetic protein 2 (BMP-2) and matrix metalloproteinase 10 (MMP-10) shows promise for OP management. To test our hypothesis, scaffolds containing BMP-2 + MMP-10 at variable ratios or BMP-2 + Alendronate (ALD) were prepared. Systems were characterized and tested in vitro on healthy and OP mesenchymal stem cells and in vivo bone formation was studied on healthy and OP animals. Therapeutic molecules were efficiently encapsulated into PLGA microspheres and embedded into chitosan foams. The use of PLGA (poly(lactic-co-glycolic acid)) microspheres as therapeutic molecule reservoirs allowed them to achieve an in vitro and in vivo controlled release. A beneficial effect on the alkaline phosphatase activity of non-OP cells was observed for both combinations when compared with BMP-2 alone. This effect was not detected on OP cells where all treatments promoted a similar increase in ALP activity compared with control. The in vivo results indicated a positive effect of the BMP-2 + MMP-10 combination at both of the doses tested on tissue repair for OP mice while it had the opposite effect on non-OP animals. This fact can be explained by the scaffold’s slow-release rate and degradation that could be beneficial for delayed bone regeneration conditions but had the reverse effect on healthy animals. Therefore, the development of adequate scaffolds for bone regeneration requires consideration of the tissue catabolic/anabolic balance to obtain biomaterials with degradation/release behaviors suited for the existing tissue status.

Safety of transforaminal lumbar interbody fusion and intervertebral recombinant human bone morphogenetic protein—2

2005 ◽  
Vol 3 (6) ◽  
pp. 436-443 ◽  
Author(s):  
Alan T. Villavicencio ◽  
Sigita Burneikiene ◽  
E. Lee Nelson ◽  
Ketan R. Bulsara ◽  
Mark Favors ◽  
...  
Keyword(s):  
Clinical Outcome ◽  
Minimally Invasive ◽  
Interbody Fusion ◽  
Transforaminal Lumbar Interbody Fusion ◽  
Bone Morphogenetic Protein 2 ◽  
Content Type ◽  
Morphogenetic Protein ◽  
Human Bone Morphogenetic Protein ◽  
Recombinant Human Bone ◽  
Fine Print

Object. Recombinant human bone morphogenetic protein—2 (rhBMP-2) is being increasingly used for spinal fusion. There are few data regarding its clinical safety, effectiveness, and clinical outcome when applied on an absorbable collagen sponge (ACS) in conjunction with allograft for transforaminal lumbar interbody fusion (TLIF). Methods. Seventy-four consecutive patients undergoing TLIF for degenerative disc disease were divided into five groups depending on whether the patient underwent a minimally invasive or open approach, as well as the number of spinal levels surgically treated. Surgery-related data, fusion results, complications, and clinical outcome were evaluated. The mean follow-up duration was 20.6 months (range 14–28 months). The radiographic fusion rate was 100% at 12 and 24 months after the surgery. No bone overgrowth or other complications related to BMP use were demonstrated. Conclusions. Analysis of the results demonstrated that TLIF combined with a BMP-2—soaked ACS is a feasible, effective, and safe method to promote lumbar fusion. There were no significant intergroup differences in clinical outcome between patients who underwent open compared with minimally invasive procedures. Patient satisfaction rates, however, were higher in the minimally invasive procedure group. The efficacy of BMP-2 was not dependent on which approach was used or the number of spinal levels that were treated.

Treatment of progressive or recurrent pediatric malignant supratentorial brain tumors with herpes simplex virus thymidine kinase gene vector—producer cells followed by intravenous ganciclovir administration

2000 ◽  
Vol 92 (2) ◽  
pp. 249-254 ◽  
Author(s):  
Roger J. Packer ◽  
Cory Raffel ◽  
Judith G. Villablanca ◽  
Jörg-Christian Tonn ◽  
Stefan E. Burdach ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Herpes Simplex ◽  
Brain Tumors ◽  
Phase I Study ◽  
Retroviral Vector ◽  
Content Type ◽  
Supratentorial Brain Tumors ◽  
Simplex Virus ◽  
Fine Print

Object. The outcome for children with recurrent malignant brain tumors is poor. The majority of patients die of progressive disease within months of relapse, and other therapeutic options are needed. The goal of this Phase I study was to evaluate the safety of in vivo suicide gene therapy in 12 children with recurrent, malignant, supratentorial brain tumors.Methods. After optimal repeated tumor resection, multiple injections of murine vector—producing cells shedding murine replication—defective retroviral vectors coding the herpes simplex virus thymidine kinase type 1 (HSV-Tk1) gene were made into the rim of the resection cavity. Fourteen days after the vector-producing cells were injected, ganciclovir was administered for 14 days. The retroviral vector that was used only integrated and expressed HSV-Tk1 in proliferating cells, which are killed after a series of metabolic events lead to cell death. The median age of the patients was 11 years (range 2–15 years). Treated brain tumors included seven malignant gliomas, two ependymomas, and three primitive neuroectodermal tumors. The patients were treated with one of three escalating dose concentrations of vector-producer cells. Four transient central nervous system adverse effects were considered possibly related to the vector-producing cells. In no child did permanent neurological worsening or ventricular irritation develop, and tests for replication-competent retroviruses yielded negative findings.Conclusions. This Phase I study demonstrates that in vivo gene therapy in which a replication-defective retroviral vector in murine vector—producing cells is delivered by brain injections can be performed with satisfactory safety in a select group of children with localized supratentorial brain tumors.

Bone Morphogenetic Protein 2 and Retinoic Acid Accelerate in Vivo Bone Formation, Osteoclast Recruitment, and Bone Turnover

2005 ◽  
Vol 11 (3-4) ◽  
pp. 645-658 ◽  
Author(s):  
Catherine M. Cowan ◽  
Oliver O. Aalami ◽  
Yun-Ying Shi ◽  
Yu-Fen Chou ◽  
Carina Mari ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Bone Formation ◽  
Bone Turnover ◽  
Bone Morphogenetic Protein ◽  
Bone Morphogenetic Protein 2 ◽  
Morphogenetic Protein ◽  
In Vivo Bone Formation
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