Cell-based strategies for IVD repair: clinical progress and translational obstacles

Abstract

Intervertebral disc (IVD) degeneration is a major cause of low back pain, a prevalent and chronic condition that has a striking effect on quality of life. Currently, no approved pharmacological interventions or therapies are available that prevent the progressive destruction of the IVD; however, regenerative strategies are emerging that aim to modify the disease. Progress has been made in defining promising new treatments for disc disease, but considerable challenges remain along the entire translational spectrum, from understanding disease mechanism to useful interpretation of clinical trials, which make it difficult to achieve a unified understanding. These challenges include: an incomplete appreciation of the mechanisms of disc degeneration; a lack of standardized approaches in preclinical testing; in the context of cell therapy, a distinct lack of cohesion regarding the cell types being tested, the tissue source, expansion conditions and dose; the absence of guidelines regarding disease classification and patient stratification for clinical trial inclusion; and an incomplete understanding of the mechanisms underpinning therapeutic responses to cell delivery. This Review discusses current approaches to disc regeneration, with a particular focus on cell-based therapeutic strategies, including ongoing challenges, and attempts to provide a framework to interpret current data and guide future investigational studies. Intervertebral disc (IVD) degeneration is a common condition associated with low back pain, but approved pharmacological interventions to prevent progression of IVD degeneration are lacking. This Review discusses the clinical progress and challenges of cell-based therapeutics for repairing the IVD. Intervertebral disc degeneration is a notable contributing factor to the incidence of low back pain. No pharmacological intervention, biologic therapy or procedure is approved for the prevention of disc degeneration; cell-based therapies are one approach currently being explored for promoting disc regeneration. Clinical trials investigating cell-based therapies are underway but are often poorly designed, with low patient numbers and an absence of appropriate controls. The broad range of disparate interventions relating to cell type, tissue source, expansion conditions, dose and delivery systems make it difficult to achieve unambiguous interpretation of results. Better imaging and biochemical diagnostics are needed to inform patient stratification protocols to identify cohorts of patients who would most benefit from cell therapy. Potential mechanisms of action of cell therapies have been proposed, including secretion of bioactive molecules, apoptosis and transfer of extracellular vesicles; however, concrete mechanistic evidence is lacking. Intervertebral disc degeneration is a notable contributing factor to the incidence of low back pain. No pharmacological intervention, biologic therapy or procedure is approved for the prevention of disc degeneration; cell-based therapies are one approach currently being explored for promoting disc regeneration. Clinical trials investigating cell-based therapies are underway but are often poorly designed, with low patient numbers and an absence of appropriate controls. The broad range of disparate interventions relating to cell type, tissue source, expansion conditions, dose and delivery systems make it difficult to achieve unambiguous interpretation of results. Better imaging and biochemical diagnostics are needed to inform patient stratification protocols to identify cohorts of patients who would most benefit from cell therapy. Potential mechanisms of action of cell therapies have been proposed, including secretion of bioactive molecules, apoptosis and transfer of extracellular vesicles; however, concrete mechanistic evidence is lacking.