Gene therapy for bone healing: lessons learned and new approaches

Vega, Rodolfo E. De la; Atasoy-Zeybek, Aysegul; Panos, Joseph A.; Griensven, Martijn van; Evans, Christopher H.; Balmayor, Elizabeth R.

doi:10.1016/j.trsl.2021.04.009

Cited by 34 publications

(32 citation statements)

References 86 publications

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“…Successful intralesional delivery and expression of complementary DNA (cDNA) encoding an osteogenic product such as a BMP will result in the sustained in situ production of authentic BMP by the endogenous biological machinery of the cell. Substantial preclinical progress has been made ( 3 , 4 ), and the results confirm that low amounts of BMP-2 synthesized endogenously within the osseous lesion for a short period of time by genetically modified cells efficiently heal bone ( 3 ). Despite these encouraging results, traditional gene therapy has yet to generate a clinical product.…”

Section: Introductionmentioning

confidence: 83%

“…Local gene delivery provides a promising, alternative approach to delivering osteogenic proteins at therapeutic levels within an osseous lesion for an extended period of time ( 3 ). Successful intralesional delivery and expression of complementary DNA (cDNA) encoding an osteogenic product such as a BMP will result in the sustained in situ production of authentic BMP by the endogenous biological machinery of the cell.…”

Section: Introductionmentioning

confidence: 99%

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Efficient healing of large osseous segmental defects using optimized chemically modified messenger RNA encoding BMP-2

et al. 2022

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Large segmental osseous defects heal poorly. Recombinant, human bone morphogenetic protein-2 (rhBMP-2) is used clinically to promote bone healing, but it is applied at very high doses that cause adverse side effects and raise costs while providing only incremental benefit. We describe a previously unexplored, alternative approach to bone regeneration using chemically modified messenger RNA (cmRNA). An optimized cmRNA encoding BMP-2 was delivered to critical-sized femoral osteotomies in rats. The cmRNA remained orthotopically localized and generated BMP locally for several days. Defects healed at doses ≥25 μg of BMP-2 cmRNA. By 4 weeks, all animals treated with 50 μg of BMP-2 cmRNA had bridged bone defects without forming the massive callus seen with rhBMP-2. Moreover, such defects recovered normal mechanical strength quicker and initiated bone remodeling faster. cmRNA regenerated bone via endochondral ossification, whereas rhBMP-2 drove intramembranous osteogenesis; cmRNA provides an innovative, safe, and highly translatable technology for bone healing.

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Section: Introductionmentioning

confidence: 83%

Section: Introductionmentioning

confidence: 99%

Efficient healing of large osseous segmental defects using optimized chemically modified messenger RNA encoding BMP-2

et al. 2022

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“…By delivering the cDNAs for osteoinductive growth factors to cells within the repair milieu, prolonged stimulation can be achieved in a more physiologic range. Relative to rhBMP-2 produced in bacteria, hBMP-2 expressed as a transgene product by mammalian cells is processed, glycosylated, and transmitted to neighboring cell populations in a more natural form and context, providing enhanced bioactivity at 100 to 1000-fold lower concentrations ( Bessho et al, 1999 ; De la Vega et al, 2021 ).…”

Section: Experimental Progressmentioning

confidence: 99%

“…Following initial demonstrations that local gene delivery methods could be used to induce ectopic bone deposition in rodents ( Boden et al, 1998 ; Lieberman et al, 1998 ; Kang et al, 2004 ), numerous gene delivery strategies involving both direct and ex vivo approaches have been reported to stimulate osteogenesis and bone repair in vivo ( Bez et al, 2020 ; De la Vega et al, 2021 ). Direct gene delivery of an adenoviral vector containing the cDNA human BMP-2 into an open fracture model was found to provide robust transgene expression that peaked around 2 weeks post-delivery and then declined during weeks 3–6.…”

Section: Experimental Progressmentioning

confidence: 99%

Gene Therapy in Orthopaedics: Progress and Challenges in Pre-Clinical Development and Translation

Watson-Levings

Palmer

Levings

et al. 2022

Front. Bioeng. Biotechnol.

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In orthopaedics, gene-based treatment approaches are being investigated for an array of common -yet medically challenging- pathologic conditions of the skeletal connective tissues and structures (bone, cartilage, ligament, tendon, joints, intervertebral discs etc.). As the skeletal system protects the vital organs and provides weight-bearing structural support, the various tissues are principally composed of dense extracellular matrix (ECM), often with minimal cellularity and vasculature. Due to their functional roles, composition, and distribution throughout the body the skeletal tissues are prone to traumatic injury, and/or structural failure from chronic inflammation and matrix degradation. Due to a mixture of environment and endogenous factors repair processes are often slow and fail to restore the native quality of the ECM and its function. In other cases, large-scale lesions from severe trauma or tumor surgery, exceed the body’s healing and regenerative capacity. Although a wide range of exogenous gene products (proteins and RNAs) have the potential to enhance tissue repair/regeneration and inhibit degenerative disease their clinical use is hindered by the absence of practical methods for safe, effective delivery. Cumulatively, a large body of evidence demonstrates the capacity to transfer coding sequences for biologic agents to cells in the skeletal tissues to achieve prolonged delivery at functional levels to augment local repair or inhibit pathologic processes. With an eye toward clinical translation, we discuss the research progress in the primary injury and disease targets in orthopaedic gene therapy. Technical considerations important to the exploration and pre-clinical development are presented, with an emphasis on vector technologies and delivery strategies whose capacity to generate and sustain functional transgene expression in vivo is well-established.

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“…To address this problem, considerable strategies, such as gene therapy, codelivery of growth factors (GFs), and delivery system modifications have been developed to amplify the efficacy of low-dose BMP-2. Gene therapy includes the delivery of BMP-2 genes or siRNA of BMP-2 antagonists to targeted sites, leading to the appropriate expression level of BMP-2 for the necessary duration [ 3 , 4 ]. Codelivery of BMP-2 with GFs, involves PDGF, SDF-1, VEGF enhances the BMP-2 efficacy via augmentation of stem cells recruitment and angiogenesis [ [5] , [6] , [7] ].…”

Section: Introductionmentioning

confidence: 99%

Orchestration of energy metabolism and osteogenesis by Mg2+ facilitates low-dose BMP-2-driven regeneration

Lin

Yin

Shi

et al. 2022

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Gene therapy for bone healing: lessons learned and new approaches

Cited by 34 publications

References 86 publications

Efficient healing of large osseous segmental defects using optimized chemically modified messenger RNA encoding BMP-2

Efficient healing of large osseous segmental defects using optimized chemically modified messenger RNA encoding BMP-2

Gene Therapy in Orthopaedics: Progress and Challenges in Pre-Clinical Development and Translation

Orchestration of energy metabolism and osteogenesis by Mg2+ facilitates low-dose BMP-2-driven regeneration

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