Gene therapy for bone regeneration could revolutionize the clinical management of many bone and musculoskeletal disorders.

Photomicrographs of regenerated bone in the adv BMP-2 group. (a–f) Scale bar=0.4 mm. (a–c) Masson trichrome stain. (a) Connective tissue fiber insertion into newly formed bone ( 200). (b) Sharpey's fiber insertion into cementum (200). (c) Mature lamellar trabecular bone (100). (d–e) H&E stain. (f) Von Kossa staining showing good mineralization of the regenerated bone (100). H&E stain, hematoxylin and eosin stain.

LONDON: Scientists claimed to have developed a new method which can mimic real bone tissue and regenerate bones using gene therapy.

 Bone has the unique ability to regenerate and continuously remodel itself throughout life. However, clinical situations arise when bone is unable to heal itself, as with segmental bone loss, fracture non-union, and failed spinal fusion. This leads to significant morbidity and mortality. Current attempts at improved bone healing have been met with limited success, fueling the development of improved techniques. Gene therapy in many ways represents an ideal approach for augmenting bone regeneration. Gene therapy allows specific gene products to be delivered to a precise anatomic location. In addition, the level of transgene expression as well as the duration of expression can be regulated with current techniques. For bone regeneration, the gene of interest should be delivered to the fracture site, expressed at appropriate levels, and then deactivated once the fracture has healed. Delivery of biological factors, mostly bone morphogenetic proteins (BMPs), has yielded promising results both in animal and clinical studies. There has also been tremendous work on discovering new growth factors and exploring previously defined ones. Finally, significant advances are being made in the delivery systems of the genes, ranging from viral and non-viral vectors to tissue engineering scaffolds. Despite some public hesitation to gene therapy, its use has great potential to expand our ability to treat a variety of human bone and musculoskeletal disorders. It is conceivable that in the near future gene therapy can be utilized to induce bone formation in virtually any region of the body in a minimally invasive manner. As bone biology and gene therapy research progresses, the goal of successful human gene transfer for augmentation of bone regeneration draws nearer.
 

Professor Fergal O'Brien, Principal Investigator on the project explained: "Previously, synthetic bone grafts had proven successful in promoting new bone growth by infusing the scaffold material with bone producing proteins. These proteins are already clinically approved for bone repair in humans but concerns exist that the high doses of protein required in clinical treatments may potentially have negative side effects for the patient such as increasing the risk of cancer. Other existing gene therapies use viral methods which also carry risks."

"By stimulating the body to produce the bone-producing protein itself, using non-viral methods these negative side effects can be avoided and bone tissue growth is promoted efficiently and safely," Professor O'Brien said.

The research is the result of a collaborative project carried out between the Tissue Engineering Research Group led by Professor Fergal O'Brien and Dr. Garry Duffy in the Department of Anatomy, RCSI; Professor Kazuhisa Bessho, Kyoto University, Japan, and Dr. Glenn Dickson, Queen's University Belfast, Northern Ireland and consists of a multi-disciplinary research effort between cell biologists, clinicians and engineers. Results of this study were recently published in the journal Advanced Materials with Dr. Caroline Curtin, a postdoctoral researcher in the Department of Anatomy, RCSI, as first author.
Bone grafts are second only to blood transfusions on the list of transplanted materials worldwide with approximately 2.2 million procedures performed annually  at an estimated cost of $2.5 billion per year . At present, the majority of these procedures involve either transplanting bone from another part of the patient's own body (autograft) or from a donor (allograft). However, these procedures have a number of risks such as infections or the bone not growing properly at the area of transplantation. Therefore there is a large potential market for bone graft substitute materials such as the innovative scaffolds being developed by the RCSI team and their collaborators.

While the biomaterials developed in this project have undoubted potential for bone repair with the capability to act as a superior alternative to existing bone graft treatments, this gene delivery platform may also have significant potential in the regeneration of other degenerated or diseased tissues in the body when combined with different therapeutic genes. This is currently a major focus of ongoing research in the Tissue Engineering Research Group which has a particular interest in using the platform to deliver genes that promote the formation of blood vessels (using angiogenic genes) in the regeneration of tissues which suffer from compromised blood supply such as heart wall tissue which has been damaged following a heart attack.

This research was funded by the European Research Council under the European Community's Seventh Framework Programme and a Science Foundation Ireland, President of Ireland Young Researcher Award.


"By stimulating the body to produce the bone-producing protein itself these negative side effects can be avoided and bone tissue growth is promoted efficiently and safely," O'Brien said.

Source :

Molecular Oncology Laboratory, Department of Surgery, The University of Chicago Medical Center, Chicago, IL 60637, USA.