Gene therapy approaches to regenerating the musculoskeletal system

Abstract

Injuries to the musculoskeletal system are common, debilitating and expensive. In many cases, healing is imperfect, which leads to chronic impairment. Gene transfer might improve repair and regeneration at sites of injury by enabling the local, sustained and potentially regulated expression of therapeutic gene products; such products include morphogens, growth factors and anti-inflammatory proteins. Proteins produced endogenously as a result of gene transfer are nascent molecules that have undergone post-translational modification. In addition, gene transfer offers particular advantages for the delivery of products with an intracellular site of action, such as transcription factors and noncoding RNAs, and proteins that need to be inserted into a cell compartment, such as a membrane. Transgenes can be delivered by viral or nonviral vectors via in vivo or ex vivo protocols using progenitor or differentiated cells. The first gene transfer clinical trials for osteoarthritis and cartilage repair have already been completed. Various bone-healing protocols are at an advanced stage of development, including studies with large animals, and human trials are envisaged. Other applications in the repair and regeneration of skeletal muscle, intervertebral disc, meniscus, ligament and tendon are in preclinical development. In addition to scientific, medical and safety considerations, clinical translation is constrained by social, financial and logistical issues.

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

“…5,6 Yet, the clinical application of rAAV is precluded by the natural presence of neutralizing antibodies in the patients, especially by those against the viral capsid proteins. 45 Delivery of rAAV via PEO-PPO-PEO polymeric micelles is a potent approach to overcome these hurdles that impair the efficacy of rAAV-mediated gene transfer.…”

“…Gene therapy is a valuable strategy to achieve this goal, allowing to directly transfer genes coding for candidate factors within the repair tissue as a means to prolong their therapeutic activities. 5,6 Protection against OA cartilage breakdown via gene transfer has been reported by applying sequences for agents displaying preventive and/or inhibitory activities (IL-1 receptor antagonist, inhibitors of nuclear factor-κB, thrombospondin-1, kallistatin,…”

“…[21][22][23] While gene transfer and overexpression of TGF-β was evaluated in articular chondrocytes in vitro and in situ via nonviral 24,25 and classical viral (adenoviruses and retroviruses) vectors, [26][27][28] the use of such vehicles in vivo may be impaired by their low and short-term efficiencies, especially in nondividing cells like chondrocytes, by the possibility of insertional mutagenesis (retroviral vectors), and their relatively high immunogenicity (adenoviral vectors). 5,6 In marked contrast, recombinant vectors based on the human adeno-associated virus (AAV) exhibit high, extended gene transfer efficiencies in chondrocytes in vitro and in situ within their dense ECM (up to 80% for at least 150 days) 29 due to their small size (~20 nm) and their maintenance as stable episomes, making them particularly adapted for in vivo setups. 30 Yet, while gene transfer of a recombinant adeno-associated virus (rAAV) TGF-β construct allowed to stimulate the activity of chondrocytes in cartilage explants in situ, 31,32 the performance of this vector in vivo may be hindered by neutralizing antibodies against the AAV capsid proteins mainly in the synovial fluid of patients with joint diseases.…”

Viruses: Friends and Foes

“…In the hopes of treating osteoarthritis, not only has the transduction of chondrocytes been investigated but also other important cells, including osteocytes, meniscal fibrochondrocytes, tendon/ligament cells, muscle cells, cells of the synovial lining and progenitor cells that may differentiate to form joint tissues [6]. The gene therapy approach is aimed at targeting a variety of mechanisms involved in the development of osteoarthritis, including cell proliferation and survival, the stimulation of anabolic pathways, the inhibition of inflammatory or catabolic pathways, and finally a combination of these strategies.…”

Immunogenicity and Immunomodulatory Effects of the Human Chondrocytes, hChonJ

“…Invossa™ (TissueGene-C) is a cell and gene medicine for osteoarthritis [1][2][3]. It is a mixture of primary human chondrocytes (hChonJ cells) and irradiated human chondrocytes modified to express TGF-β1 (hChonJb#7 cells) by the ratio of 3:1, and is administered into a knee joint of patients.…”