Gene therapy for bone healing

Abstract

Clinical problems in bone healing include large segmental defects, nonunion and delayed union of fractures, and spinal fusions. Gene-transfer technologies have the potential to aid healing by permitting the local delivery and sustained expression of osteogenic gene products within osseous lesions. Key questions for such an approach include the choice of transgene, vector and gene-transfer strategy. Most experimental data have been obtained using cDNAs encoding osteogenic growth factors such as bone morphogenetic protein-2 (BMP-2), BMP-4 and BMP-7, in conjunction with both nonviral and viral vectors using in vivo and ex vivo delivery strategies. Proof of principle has been convincingly demonstrated in small-animal models. Relatively few studies have used large animals, but the results so far are encouraging. Once a reliable method has been developed, it will be necessary to perform detailed pharmacological and toxicological studies, as well as satisfy other demands of the regulatory bodies, before human clinical trials can be initiated. Such studies are very expensive and often protracted. Thus, progress in developing a clinically useful gene therapy for bone healing is determined not only by scientific considerations, but also by financial constraints and the ambient regulatory environment.

Non-viral gene therapy for bone tissue engineering

“…In mouse and goat experiments it was found that besides osteogenic differentiation, bone formation including bone marrow and cartilaginous tissue has been induced as a result of the transfection with BMP-2 plasmid DNA. This is consistent with literature describing ectopically induced bone formation after transfections with BMP-2 plasmid DNA 259 . Transfected MSCs or delivered BMP-2 plasmid DNA significantly increase bone formation both intramuscularly and at orthotopic locations compared to negative controls.…”

Evaluation of fibrin-based gene-activated matrices for BMP2/7 plasmid codelivery in a rat nonunion model

“…Nevertheless, inconsistent results due to single outliers failed to show statistically significant differences. This insignificant therapeutic effect was found in numerous studies, which demonstrated non-viral gene transfer as a safe but relative inefficient strategy to increase bone growth [10,12,13]. Results of this study highlight the importance of promoting non-viral gene transfer by alternative methods.…”

“…Such Gene therapeutic approaches could increase the efficiency of BMPs and reduce costs as well as potential side effects. Viral delivery of DNA vectors to the target tissue was shown to be highly effective but could result in a fatal immune response of the host [10,11]. In contrast non-viral gene transfer using plasmids is regarded as a relatively safe but inefficient strategy [12,13].…”

Scaffold‐Based microRNA Therapies in Regenerative Medicine and Cancer

“…[102,106] Whether one of the routes may be better suited for clinical translation remains to be elucidated, although in situ transfecting scaffolds hold greater potential to exist as "off-the-shelf" products. [107] Many distinct scaffold types have been tuned to serve the purpose of miRNA delivery, including several hydrogels, [58,92,106,[108][109][110][111][112][113][114] electrospun fibers, [63,[115][116][117][118] and more prolifically porous or spongy scaffolds. [46,47,50,54,55,96,112,[119][120][121][122][123][124][125][126][127][128][129][130] Before reviewing the details of their applications, summarized in Table 2 and described further in the next section, we will discuss the key characteristics making these materials amenable to miRNA delivery.…”