Gene therapy methods in bone and joint disorders

Ulrich-Vinther, Michael

doi:10.1080/17453690610046512

Cited by 32 publications

(2 citation statements)

References 492 publications

(330 reference statements)

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“…duration (Ulrich-Vinther, 2007). AAV, on the other hand, is a very promising vector system that may provide the best balance between safety and in vivo gene delivery efficiency (Evans et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

Persistence, Localization, and External Control of Transgene Expression After Single Injection of Adeno-Associated Virus into Injured Joints

et al. 2013

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A single intra-articular injection of adeno-associated virus (AAV) results in stable and controllable transgene expression in normal rat knees. Because undamaged joints are unlikely to require treatment, the study of AAV delivery in joint injury models is crucial to potential therapeutic applications. This study tests the hypotheses that persistent and controllable AAV-transgene expression are (1) highly localized to the cartilage when AAV is injected postinjury and (2) localized to the intra-articular soft tissues when AAV is injected preinjury. Two AAV injection time points, postinjury and preinjury, were investigated in osteochondral defect and anterior cruciate ligament transection models of joint injury. Rats injected with AAV tetracycline response element (TRE)-luciferase received oral doxycycline for 7 days. Luciferase expression was evaluated longitudinally for 6 months. Transgene expression was persistent and controllable with oral doxycycline for 6 months in all groups. However, the location of transgene expression was different: postinjury AAV-injected knees had luciferase expression highly localized to the cartilage, while preinjury AAV-injected knees had more widespread signal from intraarticular soft tissues. The differential transgene localization between preinjury and postinjury injection can be used to optimize treatment strategies. Highly localized postinjury injection appears advantageous for treatments targeting repair cells. The more generalized and controllable reservoir of transgene expression following AAV injection before anterior cruciate ligament transection (ACLT) suggests an intriguing concept for prophylactic delivery of joint protective factors to individuals at high risk for early osteoarthritis (OA). Successful external control of intra-articular transgene expression provides an added margin of safety for these potential clinical applications.

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Section: Discussionmentioning

confidence: 99%

Persistence, Localization, and External Control of Transgene Expression After Single Injection of Adeno-Associated Virus into Injured Joints

et al. 2013

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“…To date, AAV vectors have been evaluated in over 130 clinical trials worldwide 21 . However, AAV-based gene therapies for bone and joint disorders are limited 22 .…”

Section: Introductionmentioning

confidence: 99%

Bone-targeting AAV-mediated silencing of Schnurri-3 prevents bone loss in osteoporosis

et al. 2019

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RNAi-based bone anabolic gene therapy has demonstrated initial success, but many practical challenges are still unmet. Here, we demonstrate that a recombinant adeno-associated virus 9 (rAAV9) is highly effective for transducing osteoblast lineage cells in the bone. The adaptor protein Schnurri-3 (SHN3 ) is a promising therapeutic target for osteoporosis, as deletion of shn3 prevents bone loss in osteoporotic mice and short-term inhibition of shn3 in adult mice increases bone mass. Accordingly, systemic and direct joint administration of an rAAV9 vector carrying an artificial-microRNA that targets shn3 (rAAV9- amiR-shn3 ) in mice markedly enhanced bone formation via augmented osteoblast activity. Additionally, systemic delivery of rAAV9- amiR-shn3 in osteoporotic mice counteracted bone loss and enhanced bone mechanical properties. Finally, we rationally designed a capsid that exhibits improved specificity to bone by grafting the bone-targeting peptide motif (AspSerSer) 6 onto the AAV9-VP2 capsid protein. Collectively, our results identify a bone-targeting rAAV-mediated gene therapy for osteoporosis.

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Biological activation of bone‐related biomaterials by recombinant adeno‐associated virus vector

Nasu

Ito

Tsutsumi

et al. 2009

Journal Orthopaedic Research

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Gene therapy is a promising clinical tool that is no longer limited as a method to supplement genetic deficits, but rather is considered reliable for delivering proteins to specific tissues or cells. Recombinant adeno-associated virus (rAAV) vector is one of the most potent gene transfer vehicles. Many biomaterials have been used in reconstructive surgery, but their biological inactivity has limited their use. To overcome shortcomings of available bone-related biomaterials, we investigated the combination of rAAV with biomaterials. Taking advantage of the method of lyophilizing rAAV onto biomaterials, we showed that an rAAV coating successfully induced b-galactosidase protein expression by rat fibroblasts on hydroxyapatite, b-tricalcium phosphate, and titanium alloy in vitro. b-Galactosidase expression was detected for 8 weeks after implantation of rAAV-coated hydroxyapatite into rat back muscles in vivo. A coating of bone morphogenetic protein-2-expressing rAAV induced significant de novo bone formation on hydroxyapatite in rat back muscles. Our study demonstrates that the combination of lyophilized rAAV and biomaterials presents a promising strategy for bone regenerative medicine. ß

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Gene therapy methods in bone and joint disorders

Cited by 32 publications

References 492 publications

Persistence, Localization, and External Control of Transgene Expression After Single Injection of Adeno-Associated Virus into Injured Joints

Persistence, Localization, and External Control of Transgene Expression After Single Injection of Adeno-Associated Virus into Injured Joints

Bone-targeting AAV-mediated silencing of Schnurri-3 prevents bone loss in osteoporosis

Biological activation of bone‐related biomaterials by recombinant adeno‐associated virus vector

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