Recent tissue engineering-based advances for effective rAAV-mediated gene transfer in the musculoskeletal system

Abstract

Musculoskeletal tissues are diverse and significantly different in their ability to repair upon injury. Current treatments often fail to reproduce the natural functions of the native tissue, leading to an imperfect healing. Gene therapy might improve the repair of tissues by providing a temporarily and spatially defined expression of the therapeutic gene(s) at the site of the injury. Several gene transfer vehicles have been developed to modify various human cells and tissues from musculoskeletal system among which the non-pathogenic, effective, and relatively safe recombinant adeno-associated viral (rAAV) vectors that have emerged as the preferred gene delivery system to treat human disorders. Adapting tissue engineering platforms to gene transfer approaches mediated by rAAV vectors is an attractive tool to circumvent both the limitations of the current therapeutic options to promote an effective healing of the tissue and the natural obstacles from these clinically adapted vectors to achieve an efficient and durable gene expression of the therapeutic sequences within the lesions.

The Role of Three-Dimensional Scaffolds in Treating Long Bone Defects: Evidence from Preclinical and Clinical Literature—A Systematic Review

“…This preclinical review documented many studies applying allogenic cells, but only one study directly compared autologous and allogenic sources, showing overall similarly good results [ 47 ]. Finally, in light of future advancement of the augmentation strategies potential, gene therapy is investigated to improve the repair of tissues by providing a temporarily and spatially defined expression of therapeutic genes at the site of injury [ 84 ]. In fact, adapting tissue engineering platforms to gene transfer approaches mediated by viral vectors is an attractive tool to circumvent both the limitations of the current therapeutic options to promote an effective healing of the tissue.…”

“…In fact, adapting tissue engineering platforms to gene transfer approaches mediated by viral vectors is an attractive tool to circumvent both the limitations of the current therapeutic options to promote an effective healing of the tissue. Several gene transfer vehicles have been developed to modify human cells and tissues from musculoskeletal system, and future studies should demonstrate whether this technology might provide an effective solution compared to the other available augmentation strategies for bone healing [ 84 ]. Therefore, while cells and GFs are highly attractive for the healing of segmental defects, the identification of the best application strategy still requires investigation with specifically designed studies to compare cells from different sources and with different manipulation, GFs, and their combinations.…”

rAAV-mediated overexpression of TGF-β via vector delivery in polymeric micelles stimulates the biological and reparative activities of human articular chondrocytes in vitro and in a human osteochondral defect model

“…33 Providing rAAV vectors via biocompatible materials as controlled delivery systems is a novel, potent approach to overcome such pre-existing barriers. 34,35 In this regard, we previously reported that polymeric micelles that rely on poly (ethylene oxide) (PEO) and poly (propylene oxide) (PPO) copolymers in the form of linear poloxamers or X-shaped poloxamines may improve the stability and bioactivity of reporter (lacZ) rAAV gene vectors, especially those with a higher PEO/PPO ratio (poloxamer PF68 and poloxamine T908). 36 In addition, encapsulation of rAAV in PF68 or T908 polymeric micelles resulted in an effective gene transfer of the reporter gene lacZ in human OA chondrocytes in vitro and in experimental osteochondral defects without detrimental effects on the biological activities of the cells nor on their phenotype, also affording protection when anti-AAV capsid neutralizing antibodies were present.…”

Poloxamer Hydrogels for Biomedical Applications

“…The development of gene delivery carriers has emerged as a promising technology in transporting genes directly to the target site as therapeutic factors [94]. Current gene transfer vectors used in regenerative medicine approaches included no viral [95] and viral vehicles [96]. The complexation of DNA with cationic polymers (polyplexes) or lipids (lipoplexes) protected DNA against degradation by nucleases and serum components creating a less negative surface charge.…”