Abstract
The tremendous cost, pain and disability associated with degenerative disc disease (DDD) makes the development of a biological agent that can mitigate the course of DDD, a critical unmet need. We have identified and reported that a single injection of a combination of recombinant human (rh) Transforming growth factor beta 1 (TGF-β1) and Connective tissue growth factor (CTGF) proteins into the injured intervertebral disc (IVD) nucleus pulposus (NP) can mediate DDD in a pre-clinical rodent model. In this study, we developed and evaluated the efficacy of a novel molecular therapy (NTG-101) containing rhTGF-β1 and rhCTGF proteins suspended in an excipient solution using in vivo models of DDD including rat-tail and chondrodystrophic (CD) canines. Needle puncture injury in CD-canine NPs resulted in loss of hydration, disc height and showed radiographic evidence of DDD like humans. However, NTG-101-injected IVDs maintained disc height and demonstrated retention of viscoelastic properties as compared to IVDs injected with phosphate buffer saline (PBS, 1X, pH = 7.2). In addition, a single intra-discal injection of NTG-101 into the injured IVD-NPs resulted in sustained expression of healthy extra-cellular matrix (ECM) proteins (aggrecan, collagen 2A1) and reduced expression of inflammation associated proteins and molecules (IL-1β, IL-6, IL-8, MMP-13, Cox-2 and PGE2) as compared to vehicle controls. In conclusion, we demonstrated that a single intra-discal injection of the novel formulation, NTG-101 confers a robust anti-inflammatory, anti-catabolic and pro-anabolic effects in pre-clinical models of DDD thereby restoring homeostasis. These findings suggest the therapeutic potential of NTG-101 for clinical use.
Highlights
Degenerative disc disease (DDD) results in significant disability, tremendous expense and the highest number of disability-adjusted life years globally[1,2,3]
We observed a significant increase in aggrecan mRNA levels in human nucleus pulposus (NP) cells in at least 50% of the donors (H1, H4, H5 and H8, Fig. 1c), while increased Col2A1 expression was observed in all the donors (Fig. 1d)
Connective tissue growth factor (CTGF) and TGF-β1 are vital to the homeostatic regulation of the intervertebral disc (IVD)-NP18
Summary
Degenerative disc disease (DDD) results in significant disability, tremendous expense and the highest number of disability-adjusted life years globally[1,2,3]. Amongst the thousands of soluble proteins contained within NCCM, we identified and showed that a single injection containing rhTGF-β1 and rhCTGF recapitulated the anti-degenerative and pro-anabolic effects of a single injection of NCCM in rat-tail needle puncture model of DDD18. We evaluated the efficacy of a novel, molecular therapeutic ‘NTG-101’ containing a combination of rhTGF-β1 and rhCTGF proteins suspended in an excipient solution in in vivo models of DDD including rat-tail NP and CD-canine NPs. Our results demonstrated a single intra-discal injection of NTG-101 confers anti-degenerative effects leading to reduction in expression of pro-inflammatory cytokines including interleukin-1 beta (IL-1β), interleukin–6 (IL-6), interleukin–8 (IL-8), ECM degrading enzymes (MMP-13), cyclooxygenase-2 (Cox-2) while inducing pro-anabolic effects upon the IVD - NP restoring expression of healthy ECM proteins (aggrecan, collagen 2A1). These findings suggested the therapeutic potential of NTG-101 for clinical use in future
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