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Gene therapy approaches to regenerating the musculoskeletal system

  • Review Article
  • Published:

From Nature Reviews Rheumatology

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Key Points

  • Gene transfer offers a solution to the problem of delivering morphogens and other regenerative products sustainably to sites of injury

  • Nascent proteins synthesized locally after gene transfer are likely to have undergone authentic post-translational modification and have higher activity than recombinant counterparts

  • Gene transfer can provide regulated transgene expression and deliver products with an intracellular action (for example, transcription factors and noncoding RNAs) or proteins that need to be inserted into a specific cellular compartment (for example, receptors)

  • Several strategies exist for transferring genes to sites of injury using different viral or nonviral vectors in vivo or by ex vivo delivery in conjunction with progenitor or differentiated cells

  • Preclinical progress has been made in cartilage repair, bone healing and the regeneration of muscle, intervertebral disc, meniscus, tendon and ligament

  • A small number of osteoarthritis and cartilage repair clinical trials have taken place

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 agents. 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 that could lead to human trials. 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.

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Figure 1: Strategies for gene transfer to sites of musculoskeletal injury.
Figure 2: Gene transfer to osteochondral defects using genetically modified, clotted, autologous bone marrow (gene plugs).
Figure 3: Healing of critical-size femoral defect in the rat using genetically modified muscle graft.

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Acknowledgements

The authors' work in this area has been supported by the AO Foundation and by NIH grants R01 AR050243, R01 AR052809, R01 AR43623, R21 AR049606, R01 AR048566, R01 AR057422 and R01 AR051085 from National Institute for Arthritis and Musculoskeletal Skin Diseases, 1P01AG043376-01A1 from National Institute on Aging, X01 NS066865 from National Center for Advancing Translation Sciences, and W81XWH-13-2-0052 from the Department of Defense (the Armed Forces Institute of Regenerative Medicine II).

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  1. Rehabilitation Medicine Research Center, Mayo Clinic, 200 First Street SW, Rochester, 55905, MN, USA

    Christopher H. Evans

  2. Department of Orthopaedic Surgery, Stem Cell Research Center, University of Pittsburgh, 450 Technology Drive, Bridgeside Point II, Suite 206, Pittsburgh, 15219, PA, USA

    Johnny Huard

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Both authors contributed to researching data for the article, discussing the content, writing and review/editing of the manuscript before submission.

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Correspondence to Christopher H. Evans.

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C.H.E. declares that he is a co-inventor on patents pertaining to the subject matter of this Review, and that he is a scientific advisory board member for TissueGene, Inc. J.H. declares that he receives remuneration as a consultant and royalties from Cook Myosite, Inc.

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Evans, C., Huard, J. Gene therapy approaches to regenerating the musculoskeletal system. Nat Rev Rheumatol 11, 234–242 (2015). https://doi.org/10.1038/nrrheum.2015.28

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