Advancing cell therapies for intervertebral disc regeneration from the lab to the clinic: recommendations of the ORS spine section

Intervertebral disc degeneration is strongly associated with chronic low back pain, a leading cause of disability worldwide. Current back pain treatment approaches (both surgical and conservative) are limited to addressing symptoms, not necessarily the root cause. Not surprisingly therefore, long‐term efficacy of most approaches is poor. Cell‐based disc regeneration strategies have shown promise in preclinical studies, and represent a relatively low‐risk, low‐cost, and durable therapeutic approach suitable for a potentially large patient population, thus making them attractive from both clinical and commercial standpoints. Despite such promise, no such therapies have been broadly adopted clinically. In this perspective we highlight primary obstacles and provide recommendations to help accelerate successful clinical translation of cell‐based disc regeneration therapies. The key areas addressed include: (a) Optimizing cell sources and delivery techniques; (b) Minimizing potential risks to patients; (c) Selecting physiologically and clinically relevant efficacy metrics; (d) Maximizing commercial potential; and (e) Recognizing the importance of multidisciplinary collaborations and engaging with clinicians from inception through to clinical trials

Oncolytic Adenovirus: Strategies and Insights for Vector Design and Immuno-Oncolytic Applications

Adenoviruses (Ad) are commonly used both experimentally and clinically, including oncolytic virotherapy applications. In the clinical area, efficacy is frequently hampered by the high rates of neutralizing immunity, estimated as high as 90% in some populations that promote vector clearance and limit bioavailability for tumor targeting following systemic delivery. Active tumor targeting is also hampered by the ubiquitous nature of the Ad5 receptor, hCAR, as well as the lack of highly tumor-selective targeting ligands and suitable targeting strategies. Furthermore, significant off-target interactions between the viral vector and cellular and proteinaceous components of the bloodstream have been documented that promote uptake into non-target cells and determine dose-limiting toxicities. Novel strategies are therefore needed to overcome the obstacles that prevent efficacious Ad deployment for wider clinical applications. The use of less seroprevalent Ad serotypes, non-human serotypes, capsid pseudotyping, chemical shielding and genetic masking by heterologous peptide incorporation are all potential strategies to achieve efficient vector escape from humoral immune recognition. Conversely, selective vector arming with immunostimulatory agents can be utilized to enhance their oncolytic potential by activation of cancer-specific immune responses against the malignant tissues. This review presents recent advantages and pitfalls occurring in the field of adenoviral oncolytic therapies

A new constitutive model for hydration-dependent mechanical properties in biological soft tissues and hydrogels

It is challenging to noninvasively determine the mechanical properties of biological soft tissues in vivo. In this study, based on the biphasic theory and the transport models, a new constitutive model for hydration-dependent mechanical properties in hydrated soft materials was derived: [Formula: see text] , where H(A) = λ + 2μ is the aggregate modulus, ϕ(f) is the volume fraction of fluid (i.e., hydration), A and n (>2) are two parameters related to the transport properties of the biphasic materials. A linear model for hydration-dependent shear modulus in the literature was verified for hydrogels. The effects of tissue hydration on mechanical properties (aggregate modulus and Poisson’s ratio) were investigated. It was found that the value of Poisson’s ratio was very sensitive to the tissue hydration in soft materials with high water content. The predictions of the aggregate modulus and shear modulus for hydrogels by the model compared well with those from experimental results. This study is important for developing new techniques for noninvasively assessing the mechanical properties of biological soft tissues using quantitative MRI methods as well as for designing scaffolds with proper mechanical properties for tissue engineering applications

Incorporation of Peptides Targeting EGFR and FGFR1 into the Adenoviral Fiber Knob Domain and Their Evaluation as Targeted Cancer Therapies

Oncolytic virotherapies based on Adenovirus 5 (Ad5) hold promise as adjunctive cancer therapies; however their efficacy when delivered systemically is hampered by poor target cell specificity and pre-existing anti-Ad5 immunity. Ovarian cancer represents a promising target for virotherapy, since the virus can be delivered locally into the peritoneal cavity. Both Epidermal Growth Factor Receptor (EGFR) and Fibroblast Growth Factor Receptor 1 (FGFR1) are over-expressed in the majority of human tumours, including ovarian cancer. To generate adenoviral vectors with improved tumour specificity, we generated a panel of Ad5 vectors with altered tropism for EGFR and FGFR, rather than the natural Ad5 receptor, hCAR. We have included mutations within AB loop the viral fibre knob (KO1 mutation) to preclude interaction with, hCAR, combined with insertions in the HI loop to incorporate peptides that bind either EGFR (peptide YHWYGYTPQNVI, GE11) or FGFR1 (peptides MQLPLAT, M* and LSPPRYP, LS). Viruses were produced to high titres, and the integrity of the fibre protein was validated by Western blotting. The KO1 mutation efficiently ablated hCAR interactions, and significantly increased transduction was observed in hCARlow/EGFRhigh cell lines using Ad5.GE11, whilst transduction levels using Ad5.M* or Ad5.LS were not increased. In the presence of physiological concentrations of human blood clotting factor X (hFX), significantly increased levels of transduction via the hFX-mediated pathway were observed in cell lines, but not in primary tumour cells derived from epithelial ovarian cancer (EOC) ascites samples. Ad5 mediated transduction of EOC cells were completely abolished by the presence of 2.5% serum from patients, whilst surprisingly, incorporation of the GE11 peptide resulted in significant evasion of neutralisation in the same samples. We thus speculate that incorporation of the YHWYGYTPQNVI dodecapeptide within the fibre knob domain may provide a novel means of circumventing pre-existing Ad5 immunity that warrants further investigation

MRI follow-up of subchondral signal abnormalities in a selected group of chronic low back pain patients

Subchondral signal abnormalities have been suggested to play an important role in chronic low back pain (LBP) syndromes. Their natural course is not well known. In this study the morphology and natural course of isolated subchondral signal abnormalities in the lumbosacral spine were analyzed with MRI. Twenty-four chronic LBP patients with a subchondral hypointensity on T1-weighted image (hyperintense on T2), indicating edema, were selected from a base population of 1,015 consecutive LBP patients to a follow-up MRI study within 18–72 months. Exclusion criteria were age >60 years, nerve root compression, a more specific back disease or a recent or major spine operation. The size and location of each subchondral signal abnormality and endplate lesion and the degree of degenerative disc changes were evaluated and compared between the baseline and follow-up studies. Most subchondral hypointensities were found at the L4/L5 or L5/S1 disc space, anteriorly and in both adjacent endplates. Almost all (53/54) hypointensities were associated with an endplate lesion. Twelve of the 54 subchondral hypointensities enlarged, six remained constant and 36 decreased or disappeared while five new ones appeared. Twenty-two (41%) hypointensities changed totally to hyperintensities or to mixed lesions. If the hypointensity increased, decreased or changed into hyperintensity, a change tended to develop in the adjacent endplate. If the hypointensity was absent or unchanged, endplate lesions did not tend to progress. In the absence of disc herniation or other specific spinal disease, subchondral hypointensities indicating edema are uncommon. They seem to have a highly variable course. There appears to be a link between endplate lesions and subchondral signal abnormalities. Further study is needed to explain the contribution of these findings to low back symptoms