Introduction

Lesions in the adult articular cartilage are prevalent, unsolved problems in clinical orthopaedics and they may lead to osteoarthritis if left untreated in affected patients. A variety of therapeutic options are available to manage sites of articular cartilage damage in the clinics but thus far, none are capable of reliably and permanently regenerating the original hyaline cartilage in cartilage defects with its full structural and mechanical integrity. Gene therapy is an attractive tool to durably enhance the processes of tissue repair in cartilage lesions over extended periods of time based on the administration of (chondro)reparative gene candidates in sites of cartilage damage. Gene transfer vehicles derived from the replication-defective human adeno-associated virus (AAV), in the form of genetically manipulated, gutless recombinant AAV (rAAV) vectors (1), are particularly well adapted shuttles to deliver a number of therapeutic genes capable of enhancing cartilage repair in translational settings, including sequences coding for growth, transcription, and signaling factors. However, this therapeutic strategy still faces critical challenges in applications in vivo due to the presence of numerous obstacles potentially impeding effective and durable gene transfer. These limitations include the presence of physical barriers (synovial fluid), of biological barriers (inflammatory mediators), of neutralizing compounds (pre-existing humoral responses against viral capsids and vectors), and the undesirable dissemination of the vectors to non-target sites. Clinical application of gene transfer vectors via controlled vector delivery approaches upon vector coating or encapsulation in biocompatible hydrogel, solid, or hybrid scaffolds (biomaterial-guided clinical gene therapy) is a valuable concept to support the persistent and localized release of the gene treatments in a spatiotemporally precise manner. Such a system may restrict gene vector dissemination, augment its temporal availability, prevent the loss of the therapeutic gene product, and protect viral vector capsids from neutralization (1-3). This innovative experimental procedure, showing a strong potential for cartilage repair and perifocal osteoarthritis protection in vivo (4,5), may be safely adapted to clinical applications in patients in a close future.

Content

Lesions in the adult articular cartilage are prevalent, unsolved problems in clinical orthopaedics and they may lead to osteoarthritis if left untreated in affected patients. A variety of therapeutic options are available to manage sites of articular cartilage damage in the clinics but thus far, none are capable of reliably and permanently regenerating the original hyaline cartilage in cartilage defects with its full structural and mechanical integrity. Gene therapy is an attractive tool to durably enhance the processes of tissue repair in cartilage lesions over extended periods of time based on the administration of (chondro)reparative gene candidates in sites of cartilage damage. Gene transfer vehicles derived from the replication-defective human adeno-associated virus (AAV), in the form of genetically manipulated, gutless recombinant AAV (rAAV) vectors (1), are particularly well adapted shuttles to deliver a number of therapeutic genes capable of enhancing cartilage repair in translational settings, including sequences coding for growth, transcription, and signaling factors. However, this therapeutic strategy still faces critical challenges in applications in vivo due to the presence of numerous obstacles potentially impeding effective and durable gene transfer. These limitations include the presence of physical barriers (synovial fluid), of biological barriers (inflammatory mediators), of neutralizing compounds (pre-existing humoral responses against viral capsids and vectors), and the undesirable dissemination of the vectors to non-target sites. Clinical application of gene transfer vectors via controlled vector delivery approaches upon vector coating or encapsulation in biocompatible hydrogel, solid, or hybrid scaffolds (biomaterial-guided clinical gene therapy) is a valuable concept to support the persistent and localized release of the gene treatments in a spatiotemporally precise manner. Such a system may restrict gene vector dissemination, augment its temporal availability, prevent the loss of the therapeutic gene product, and protect viral vector capsids from neutralization (1-3). This innovative experimental procedure, showing a strong potential for cartilage repair and perifocal osteoarthritis protection in vivo (4,5), may be safely adapted to clinical applications in patients in a close future.

References

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2 . Rey-Rico A, Cucchiarini M. Controlled release strategies for rAAV-mediated gene delivery. Acta Biomater 2016;29:1-10.

3. Cucchiarini M, Madry H. Biomaterial-guided delivery of gene vectors for targeted articular cartilage repair. Nat Rev Rheumatol 2019;15:18-29.

4. Madry H, Gao L, Rey-Rico A, Venkatesan JK, Müller-Brandt K, Cai X, Goebel L, Schmitt G, Speicher-Mentges S, Zurakowski D, Menger MD, Laschke MW, Cucchiarini M. Thermosensitive hydrogel based on PEO-PPO-PEO poloxamers for a controlled in situ release of recombinant adeno-associated viral vectors for effective gene therapy of cartilage defects. Adv Mater 2020;32:e1906508.

5. Maihöfer J, Madry H, Rey-Rico A, Venkatesan JK, Goebel L, Schmitt G, Speicher-Mentges S, Cai X, Meng W, Zurakowski D, Menger MD, Laschke MW, Cucchiarini M. Hydrogel-guided, rAAV-mediated IGF-I overexpression enables long-term cartilage repair and protection against perifocal osteoarthritis in a large-animal full-thickness chondral defect model at one year in vivo. Adv Mater 2021;33:e2008451.