Healing of massive segmental femoral bone defects in minipigs by allogenic ASCs engineered with FLPo/Frt-based baculovirus vectors

Lin, Chin-Yu; Wang, Yao‐Horng; Li, Kuei-Chang; Sung, Li‐Yu; Yeh, Chia-Lin; Lin, Kun‐Ju; Yen, Tzu‐Chen; Chang, Yu‐Han; Hu, Yu‐Chen

doi:10.1016/j.biomaterials.2015.01.052

Cited by 34 publications

(35 citation statements)

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“…These in vivo studies underscored the difficulty of healing massive calvarial bone defects. Although implantation of human BMSCs transfected with miR‐26a mimics into calvarial defect in nude mice led to nearly complete repair of the critical‐size calvarial bone defect (Li et al ., ), this could be attributed to the superior bone healing capability of BMSCs over ASCs (Lin et al ., ). Therefore, the engineered hASCs expressing BMP‐2 and miR‐148b conferred comparable or better calvarial bone healing than the miRNA‐based approaches reported previously.…”

Section: Discussionmentioning

confidence: 97%

“…In contrast, baculovirus transduces various stem cells, including hASCs, at efficiencies exceeding 95% (Lin et al ., ; Sung et al ., ). Both the FLPo/Frt‐based and Cre/loxP‐based baculovirus vectors confer substantially prolonged transgene expression (Sung et al ., ), and the FLPo/Frt‐based vectors were successfully exploited to deliver transgenes into ASCs and heal femoral (Lin et al ., ) and calvarial (Lin et al ., ) bone defects. Furthermore, the preclinical safety of the FLPo/Frt‐based vector was recently demonstrated (Li et al ., ).…”

Section: Discussionmentioning

confidence: 99%

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Improved calvarial bone repair by hASCs engineered with Cre/loxP-based baculovirus conferring prolonged BMP-2 and MiR-148b co-expression

Sung

et al. 2016

J Tissue Eng Regen Med

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Repairing large calvarial bone defects remains a challenging task. Previously, it was discovered that that miR-148b, when acting in concert with bone morphogenetic protein 2 (BMP-2), enhanced the osteogenesis of human adipose-derived stem cells (hASCs) and improved calvarial bone healing in nude mice. However, the molecular target of miR-148b remained elusive. Here it is revealed that miR-148b directly targets NOG, whose gene product (noggin) is an antagonist to BMPs and negatively regulates BMP-induced osteogenic differentiation and bone formation. A new Cre/loxP-based baculovirus system was employed to drive prolonged BMP-2 and miR-148b overexpression in hASCs, wherein the BMP-2 overexpression induced noggin expression but the concurrent miR-148b expression downregulated noggin, thus relieving the negative regulatory loop and ameliorating hASC osteogenesis without hindering hASC proliferation or triggering appreciable cytotoxicity. Implantation of the engineered hASCs coexpressing BMP-2 and miR-148b into nude mice enabled substantial repair of critical-size calvarial bone defects (4 mm diameter) at 12 weeks post-transplantation, filling 83% of the defect area, 75% of bone volume and restoring the bone density to 89% of the original bone density. Such superior healing effects indicate the potential of the Cre/loxP-based baculovirus-mediated BMP-2/miR-148b expression for calvarial bone repair. Copyright © 2016 John Wiley & Sons, Ltd.

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Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

Improved calvarial bone repair by hASCs engineered with Cre/loxP-based baculovirus conferring prolonged BMP-2 and MiR-148b co-expression

Sung

et al. 2016

J Tissue Eng Regen Med

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“…The study concluded that the transduced cell sheets significantly reversed the damage caused by myocardial infarction . Other groups have also used baculovirus nanohybrids to modify stem cells to overexpress osteogenic and angiogenic growth factors for in vivo bone regeneration . As with the nonviral applications, hydrogels can also be utilized as controlled and sustained release platforms for viral nanohybrid vectors.…”

Section: Nanohybrids For Gene Therapymentioning

confidence: 99%

Polymeric Nanohybrids as a New Class of Therapeutic Biotransporters

Whitlow

Pacelli

Paul

2016

Macro Chemistry & Physics

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A possible solution to enhance existing drug and gene therapies is to develop hybrid nanocarriers capable of delivering therapeutic agents in a controlled and targeted manner. This goal can be achieved by designing nanohybrid systems, which combine organic or inorganic nanomaterials with biomacromolecules into a single composite. The unique combination of properties along with their facile fabrication enables the design of smart carriers for both drug and gene delivery. These hybrids can be further modified with cell targeting motifs to enhance their biological interactivity. In this Talents and Trends article, an overview of emerging nanohybrid-based technologies will be provided to highlight their potential use as innovative platforms for improved cancer therapies and new strategies in regenerative medicine. The clinical relevance of these systems will be reviewed to define the current challenges which still need to be addressed to allow these therapies to move from bench to bedside.

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“…Larger animal models are more similar to humans with regard to many of these factors, having the potential to be better models for orthopedic treatments. Rabbits (Inui et al, 1998;Murakami et al, 2002), sheep (Kirker-Head et al, 1998den Boer et al, 2003), goats (Xu et al, 2005;Lian et al, 2009), dogs (Cook et al, 1994;Sumner et al, 2003), pigs (Lin et al, 2015;Bez et al, 2017), horses (Backstrom et al, 2004;Ishihara et al, 2008), and non-human primates (Andersson et al, 1978;Cook et al, 2002) have all been used as animal models for orthopedic implants or regenerative approaches to bone repair. Porcine bone has similar morphology and microstructure to that of humans; however, pigs are large and difficult to handle (Reichert et al, 2009;Wancket, 2015;Perleberg et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Systematic Review of the Preclinical Technology Readiness of Orthopedic Gene Therapy and Outlook for Clinical Translation

Wilkinson

Бозо

Braxton

et al. 2021

Front. Bioeng. Biotechnol.

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Bone defects and improper healing of fractures are an increasing public health burden, and there is an unmet clinical need in their successful repair. Gene therapy has been proposed as a possible approach to improve or augment bone healing with the potential to provide true functional regeneration. While large numbers of studies have been performed in vitro or in vivo in small animal models that support the use of gene therapy for bone repair, these systems do not recapitulate several key features of a critical or complex fracture environment. Larger animal models are therefore a key step on the path to clinical translation of the technology. Herein, the current state of orthopedic gene therapy research in preclinical large animal models was investigated based on performed large animal studies. A summary and an outlook regarding current clinical studies in this sector are provided. It was found that the results found in the current research literature were generally positive but highly methodologically inconsistent, rendering a comparison difficult. Additionally, factors vital for translation have not been thoroughly addressed in these model systems, and the risk of bias was high in all reviewed publications. These limitations directly impact clinical translation of gene therapeutic approaches due to lack of comparability, inability to demonstrate non-inferiority or equivalence compared with current clinical standards, and lack of safety data. This review therefore aims to provide a current overview of ongoing preclinical and clinical work, potential bottlenecks in preclinical studies and for translation, and recommendations to overcome these to enable future deployment of this promising technology to the clinical setting.

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Healing of massive segmental femoral bone defects in minipigs by allogenic ASCs engineered with FLPo/Frt-based baculovirus vectors

Cited by 34 publications

References 53 publications

Improved calvarial bone repair by hASCs engineered with Cre/loxP-based baculovirus conferring prolonged BMP-2 and MiR-148b co-expression

Improved calvarial bone repair by hASCs engineered with Cre/loxP-based baculovirus conferring prolonged BMP-2 and MiR-148b co-expression

Polymeric Nanohybrids as a New Class of Therapeutic Biotransporters

Systematic Review of the Preclinical Technology Readiness of Orthopedic Gene Therapy and Outlook for Clinical Translation

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