21 What Will the Future Bring? Perspectives From Around the World
Howard An, Tony Goldschlager, Claudius Thomé, Luiz Vialle, Jaime Arias Ruiz, William Omar Contreras Lopez, and Daisuke Sakai
21.1 North America
Many research breakthroughs are covered in this book that have improved our understanding of the biology of the disc, and new biological and less-invasive therapies are being developed to help regenerate the spinal tissues, reduce pain, and restore function. The understanding of the molecular mechanisms of intervertebral disc (IVD) degeneration and the development of the animal models to research them have spurred advancements in designing and testing targeted biological treatments against degenerative disc disease (DDD). Treatments whose strategy is to biologically repair or regenerate the IVD tissues hold great promise for the treatment of discogenic low back pain (LBP) as well as for retarding or even preventing progression of lumbar spondylosis. Biological therapies that focus on introducing viable or genetically modified cells or molecules into the degenerating IVD have the potential to promote matrix repair, restore physiological function, and decrease pain.
The IVD has a unique structure, being composed of a tough outer ring, the annulus fibrosus (AF), and a gelatinous inner core, the nucleus pulposus (NP). The AF, along with the end plates of the adjacent vertebrae, enclose the NP and enable it to resist deformation that would otherwise occur under physiological loading. In a healthy disc, the NP is able to maintain its fluid pressure to balance the high external loads on the IVD because of the abundance of negatively charged proteoglycans. This molecular meshwork of proteoglycans, entrapped in a collagen network, endows the IVD with both compressive stiffness and tensile strength. The progressive loss of the proteoglycan content of the IVD, along with the resulting dehydration of the NP, has been implicated in the pathogenesis of DDD. The loss of matrix homeostasis within the NP is believed to be the result of the combination of both decreased matrix synthesis and increased matrix catabolism. Normal IVD cells synthesize proteoglycans and types I and II collagen, but in the degenerative disc, the synthesis of matrix molecules by IVD cells changes differentially with the degree of degeneration. The viable disc cells decrease in number, most likely due to apoptosis but also due to cell senescence and altered metabolic function. Proteolytic enzymes are found in higher concentrations in degenerative discs compared with normal discs. In addition, there are increased levels of pro-inflammatory cytokines, which are not only implicated in pain but are also thought to result in a further decrease in the rate of extracellular matrix (ECM) synthesis. The future of biological repair or regeneration should address cells, matrix, and pain-related molecules in both the AF and NP to achieve good outcomes over a prolonged period of time. Previous and ongoing research on anabolic growth factors such as osteogenic protein-1 (OP-1), growth and differentiation factor-5 (GDF-5), transforming growth factor β (TGF- β), etc., have shown much promise for their ability to reverse DDD by repairing or regenerating the ECM as well as downregulating the pro-inflammatory factors that are implicated in causing discogenic pain.
Multiple genetic risk factors for DDD have been described. Determining the key genetic markers that are associated with DDD should help in the identification and development of therapeutic molecules for disc repair and regeneration. There have already been several clinical trials using intradiscal protein injection for IVD repair and regeneration, but unfortunately some of these trials have been halted for unknown reasons. With that being said, there have been numerous published papers on cell therapy for IVD repair and regeneration with promising results. In the United States, there are two ongoing Food and Drug Administration (FDA)-approved clinical trials using allogenic juvenile chondrocytes and mesenchymal stem cells (MSCs). The goal of any study for the treatment of DDD should be to achieve a robust and durable regeneration of the disc matrix that is able to withstand the high biomechanical forces seen in the human disc. Because of immune responses and safety concerns, gene therapy itself has not gained traction, and no clinical trials that utilize it are available or planned in the near future.
Despite extensive research on IVD repair and regeneration for the past 3 decades, there is no FDA-approved biological product available for patients suffering from discogenic LBP. Further basic science and clinical trials will definitely bring compounds and even cell therapy into clinical practice. I do not believe that one will necessarily win over the other, however, because DDD is not the same in all patients. For instance, some patients with specific genetic factors may respond to molecular therapy, whereas others with more of a cell deficiency problem may respond better to cell-based therapy. Some patients may have significant discogenic pain with minimal cell and matrix loss, and therefore certain molecules may be more appropriate to address their pain by reducing inflammatory factors rather than causing matrix restoration. Whereas there is still much research to be done in this area, I do believe that the future is bright for the millions of people suffering with LBP and that continued research efforts will yield exciting new therapies for treatment of DDD.
– Howard An
It is an honor to present the Australian perspective on biological approaches to spinal disc repair and regeneration. The future is exciting; however, this is only because of the great contributions of the past. I would like to briefly outline some of these contributions as these illustrate the path travelled and a road-map of where we are likely heading.
Much of our current understanding of the IVD, including its biochemistry, structure, and the role of the notochordal cell comes from Professor Ghosh’s work in Sydney, Australia.1 It is through understanding these facts that regenerative therapies can be developed; however, it is necessary to have animal models with which to test such therapies. In the 1990 Volvo Spinal research award, Osti et al described the surgical induction of an annular “rim lesion” in an ovine model2 that simulated the known pathology of human disc degeneration. This seminal work, which was carried out in Professor Robert Fraser’s laboratory in Adelaide, Australia, has not only contributed to our basic understanding of the underlying molecular mechanisms of disc degeneration, but also provided us with an animal model that has been used for numerous preclinical studies to evaluate stem cells and other biological therapies for the promotion of disc regeneration.
In this regard, the identification of mesenchymal precursor cells (MPCs) by Australian investigators3,4 as the earliest and most clonogenic cell-line has provided a readily available source of stem cells that are now under commercial development by the Australian company Mesoblast Ltd. for the treatment of disc degeneration and other degenerative disorders. MPCs are perivascular cells found in all vascularized tissues in the body, including bone marrow, dental pulp, and adipose tissue. MPCs are the precursors of all multipotential fibroblastoid colony-forming units (CFU-F), which give rise to all the mesenchymal lineage stem cells and which can differentiate under appropriate stimuli into bone, fat and cartilage. MPCs have specific surface markers such as STRO-1, VCAM-1 (CD106), STRO-3, STRO-4 (HSP-90b), or CD146 that facilitate their extraction and purification using the principles of antibody immunoselection.3,4
Two important advantages of these cells are that their numbers can be greatly expanded in culture while maintaining their undifferentiated phenotype, and can be used allogenically because they are immunologically tolerated when transplanted into unrelated recipients.5
MPCs have been tested in the ovine models of disc degeneration. In the initial study, discs were injured by the intradiscal injection of the enzyme chondroitinase-ABC (C-ABC) and then rescued with the MPCs.6 Assessment of the disc response to treatment using magnetic resonance imaging (MRI), biochemistry, and histological studies, as well as radiography to assess the disc height index, revealed improvement in the discs injected with MPCs compared with controls. The authors concluded that the injection of MPCs into degenerate IVDs could contribute to the regeneration of a new ECM. Oehme et al showed similar results using a modified Osti annular injury ovine model.7
A Phase II clinical study whereby MPCs were injected into the degenerate IVDs of patients with chronic discogenic LBP had positive results at 12 months, which included a reduction in pain scores, increase in functional endpoints, and a decreased need for analgesia and secondary interventions compared with placebo controls.8 A Phase III study is now under way, and if the safety and efficacy outcomes are positive then this modality of treatment could revolutionize the treatment of discogenic back pain, one of the most common causes of disability worldwide.9
In the pipeline are some other exciting therapeutic developments. Several preclinical studies have now shown that the viability and chondrogenic potential of MPCs are enhanced when formulated with the agent pentosan polysachharide (PPS).7,10,11 This agent not only suppresses some of the mediators of disc matrix degradation but also upregulates endogenous cell anabolic activities and acts synergistically with MSCs to enhance matrix regeneration.7,10,11
Finally, I believe that novel biological approaches aimed at augmenting and enhancing current surgical techniques will have a significant future impact.12