Thursday, September 27, 2018 2:05 PM–3:05 PM Section on Biologics and Basic Research Abstract Presentations: 125. NTG-101: A novel, molecular therapeutic for the treatment of degenerative disc disease

BACKGROUND CONTEXT Degenerative disc disease (DDD) contributes significantly to the genesis of spinal pain. DDD-related spinal pain is an enormously expensive malady and a major cause of disability worldwide and no contemporary surgical treatments promote repair. Thus, there exists a need for the identification of effective, minimally invasive, regenerative therapeutic agents that can be clinically translated for disc repair. We have developed a novel biological therapeutic based upon the notochordal cell secretome (NTG-101) that includes TGFβ1+CTGF. Here we present extensive in vivo data concerning the ability of a single injection of NTG-101 to mitigate the progression of DDD and induce a regenerative effect upon the degenerative intervertebral disc (IVD). PURPOSE To determine the ability of a single intradiscal injection of a NTG-101 to mitigate the progression of DDD and to induce a regenerative effect in vivo. STUDY DESIGN/SETTING Image-guided needle puncture disc injury using validated preclinical animal models of DDD (rat and chondrodystrophic [CD] canine) followed by a single injection of NTG-101 and assessment at the endpoint. PATIENT SAMPLE No human patients involved. Animal care approved study using Wistar rats and chondrodystrophic canines. OUTCOME MEASURES Histological, immunohistochemical, genomic, protein detection, imaging (radiographs and MRI) and biomechanics assays. METHODS We induced DDD using image-guided needle puncture injury of the IVD nucleus pulposus (NP) in both animal models. For rats, outcomes were assessed 6 weeks post injection (10-weeks post injury). For canines, assessments were performed 14-weeks post injection, (18-weeks post injury). Assays consisted of histological and immunohistochemical scoring, expression analysis of extra-cellular matrix (ECM), inflammation, and pain associated genes or proteins using qRT-PCR, and Western blotting analysis. Imaging was quantified using radiographic and MRI techniques. Quantitative biomechanical analysis was performed using validated robotic methods. RESULTS Our results demonstrated that postinjury, both animal models showed increased expression of inflammation and pain associated genes and proteins (Cox-2, MMP-13, IL-1β, TNFα, IL-6 and IL-8) using qRT-PCR, immunohistochemistry and Western blotting. We also observed increased PGE2 levels in injured, degenerative IVD-NPs (rats and CD canines). However, a single, intra-discal injection of NTG-101 reduced the expression of Cox-2, MMP-13, IL-1β, TNFα, IL-6, and IL-8 to virtually undetectable levels in treated IVD-NPs. Furthermore, NTG-101 treated IVD-NPs markedly increased the expression of the vital ECM proteins, aggrecan and collagen type 2 and the stemness markers Oct4 and Nanog. Radiographic analysis demonstrated retention of normal disc height in NTG-101 treated discs in comparison to vehicle injected IVDs. MRI and gross pathological analysis showed that vehicle injected discs developed significant DDD whereas NTG-101 injected IVDs appeared healthy. Biomechanical analysis demonstrated that NTG-101 injected discs conferred significantly improved viscoelastic properties in flexion and lateral bending. CONCLUSIONS A single injection of NTG-101 into the injured or degenerative IVD in both rat-tail and CD – canine IVDs mitigates the progression of DDD and induces a regenerative effect resulting in a healthy IVD NP with near normal cellularity and healthy ECM. FDA DEVICE/DRUG STATUS This abstract does not discuss or include any applicable devices or drugs.