Recovery after spinal cord injury is enhanced by anti-Nogo-A antibody therapy — from animal models to clinical trials

Sartori, Andrea; Hofer, Anna‐Sophie

doi:10.1016/j.cophys.2019.11.001

Cited by 14 publications

(8 citation statements)

References 55 publications

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“…or CST and LMN integrity (MEP) is of utmost importance for weaker muscles -especially for those with absent MMS at baseline. In future studies, identifying the potential to recover strength may help to tailor rehabilitation to novel and intensive approaches, for example, anti-NOGO therapy 74 to release the brakes of plasticity in the spinal cord and promote axonal sprouting, and paired associative stimulation 75 -to induce long-term plasticity in the CST projections. The identification of muscles with the potential to recover early after the SCI will allow the administration of novel and promising therapies during the optimal time window for recovery.…”

Section: Discussionmentioning

confidence: 99%

Segmental analysis in cervical spinal cord injury reveals the recovery potential of hand muscles with preserved corticospinal tract: Insights beyond impairment scales

Balbinot

Kalsi‐Ryan

et al. 2021

Preprint

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Cervical spinal cord injury (SCI) severely impacts widespread bodily functions with extensive impairments for individuals, who prioritize regaining hand function. Although prior work has focused on the recovery at the person- level, the factors determining the recovery potential of individual muscles are poorly understood. There is a need for changing this paradigm in the field by moving beyond person-level classification of residual strength and sacral sparing to a muscle-specific analysis with a focus on the role of corticospinal tract (CST) sparing. The most striking part of human evolution involved the development of dextrous hand use with a respective expansion of the sensorimotor cortex controlling hand movements, which, because of the extensive CST projections, may constitute a drawback after SCI. Here, we investigated the muscle-specific natural recovery after cervical SCI in 748 patients from the European Multicenter Study about SCI (EMSCI), one of the largest datasets analysed to date. All participants were assessed within the first 4 weeks after SCI and re-assessed at 12, 24, and 48 weeks. Subsets of individuals underwent electrophysiological multimodal evaluations to discern CST and lower motor neuron (LMN) integrity [motor evoked potentials (MEP): N = 203; somatosensory evoked potentials (SSEP): N = 313; nerve conduction studies (NCS): N = 280]. We show the first evidence of the importance of CST sparing for proportional recovery in SCI, which is known in stroke survivors to represent the biological limits of structural and functional plasticity. In AIS D, baseline strength is a good predictor of segmental muscle strength recovery, while the proportionality in relation to baseline strength is lower for AIS B/C and breaks for AIS A. More severely impaired individuals showed non-linear and more variable recovery profiles, especially for hand muscles, while measures of CST sparing (by means of MEP) improved the prediction of hand muscle strength recovery. Therefore, assessment strategies for muscle-specific motor recovery in acute SCI improve by accounting for CST sparing and complement gross person-level predictions. The latter is of paramount importance for clinical trial outcomes and to target neurorehabilitation of upper limb function, where any single muscle function impacts the outcome of independence in cervical SCI.Graphical abstractSegmental analysis in cervical spinal cord injury reveals the recovery potential of hand muscles with preserved corticospinal tract: Insights beyond impairment scales. (A, upper panels) Cervical SCI (yellow) may cause impairment of motor function below the level of lesion depending on the completeness of the injury. Individuals with a sensorimotor complete lesion (AIS A), as defined by the absence of sacral sparing, show a non-proportional strength recovery as related to the baseline strength, in contrast to less severely affected patients (AIS B-D) - reflecting the limitations on structural and functional plasticity in this group. (A, lower panel) The area of spinal cord damage typically extents across several segments below the level of lesion with variable preservation of muscle innervation and is described as zone of partial preservation (ZPP). (B) The recovery of hand muscle strength is more challenged compared to more proximal muscles when accounting for the distance from the level of lesion. (C, upper panel) The strength recovery of proximal muscles is proportional to the baseline strength in AIS D (great R2 values) but limited in AIS A, likely indicating the limits of recovery in severe SCI. (C, lower panel) Also, additional clinical baseline variables [e.g., distance from the motor level of injury (DST); pin prick (PP) and light touch (LT) sensation] primarily increased the prediction of strength recovery for proximal muscles, becoming less effective in more distal muscles, such as the intrinsic hand muscles. (D) Overall, the proportional prediction of strength recovery in distal hand muscles is less strong while failing in AIS A (inversion of proportionality). (D, lower panel) The addition of neurophysiological baseline measures related to CST integrity (by means of MEP) increased the prediction of strength recovery of hand muscles, indicating the importance of residual CST projections to spinal motoneurons for hand strength recovery. Clinical studies aiming at restitution of hand function after SCI may benefit from the addition of MEP assessments early after the SCI, to unveil hand muscles with a potential for recovery.

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Section: Discussionmentioning

confidence: 99%

Segmental analysis in cervical spinal cord injury reveals the recovery potential of hand muscles with preserved corticospinal tract: Insights beyond impairment scales

Balbinot

Kalsi‐Ryan

et al. 2021

Preprint

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“…The IgG1 antibody 11C7 binds to Nogo-A, which is predominantly expressed within the CNS but some reports have detected it in OSN [31,32]. The 11C7 was used as it is a promising antibody for multiple sclerosis or similar neurodegenerative diseases as it was shown that 11C7 therapy induces neuronal outgrowth in studies performed by Schwab and coworkers [33][34][35][36][37]. In general, the Fc part of IgGs is mentioned by other studies to be possibly involved in IgG uptake and transport either intra-or paracellularly [38][39][40].…”

Section: Antibody Cns Distribution After Region-specific Intranasal A...mentioning

confidence: 99%

Selective CNS Targeting and Distribution with a Refined Region-Specific Intranasal Delivery Technique via the Olfactory Mucosa

et al. 2021

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Intranasal drug delivery is a promising approach for the delivery of drugs to the CNS, but too heterogenous, unprecise delivery methods without standardization decrease the quality of many studies in rodents. Thus, the lack of a precise and region-specific application technique for mice is a major drawback. In this study, a previously developed catheter-based refined technique was validated against the conventional pipette-based method and used to specifically reach the olfactory or the respiratory nasal regions. This study successfully demonstrated region-specific administration at the olfactory mucosa resulting in over 20% of the administered fluorescein dose in the olfactory bulbs, and no peripheral bioactivity of insulin detemir and Fc-dependent uptake of two murine IgG1 (11C7 and P3X) along the olfactory pathway to cortex and hippocampus. An scFv of 11C7 showed hardly any uptake to the CNS. Elimination was dependent on the presence of the IgG’s antigen. In summary, it was successfully demonstrated that region-specific intranasal administration via the olfactory region resulted in improved brain targeting and reduced peripheral targeting in mice. The data are discussed with regard to their clinical potential.

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“…It has been identified as a CNS-specific inhibitor of neurite outgrowth [ 16 ]. RTN4 gene belongs to the reticular coding gene family and is involved in neuroendocrine secretion or membrane transport of neuroendocrine cells, and its product is a potent neurite outgrowth inhibitor [ 17 , 18 ]. Additionally, three Nogo isomers have been identified: Nogo A, B, and c. Nogo-A, the most studied isoform, has two known inhibitory domains, including the N-terminal amino-Nogo and Nogo-66, which constitute extracellular loop molecules and are involved in the inhibition of nerve regeneration [ 19 ].…”

Section: Discussionmentioning

confidence: 99%

Nogo-A Is a Potential Prognostic Marker for Spinal Cord Injury

Shi

Xie

et al. 2022

Disease Markers

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Objective. Spinal cord injury (SCI) has become prevalent worldwide in recent years, and its prognosis is poor and the pathological mechanism has not been fully elucidated. Nogo-A is one of the isoforms of the neurite outgrowth inhibitory protein reticulon 4. The purpose of this study was to determine whether Nogo-A could be used as a marker for predicting the prognosis of SCI. Methods. We screened eligible SCI patients and controls based on inclusion and exclusion criteria. We also collected baseline clinical information and peripheral venous blood of the enrolled population. Participants’ baseline serum Nogo-A levels were measured by enzyme-linked immunosorbent assay (ELISA). The American Spinal Injury Association (ASIA) scale was used to evaluate the prognosis of SCI patients after 3 months. Results. Baseline clinical information (age; gender; smoking; drinking; SBP, systolic blood pressure; DBP, diastolic blood pressure; fasting blood glucose; WBC, white blood cells; CRP, C-reactive protein) of SCI patients and controls were not statistically significant academic differences ( p > 0.05 ). The baseline serum Nogo-A levels of SCI patients and controls were 192.7 ± 13.9 ng/ml and 263.1 ± 22.4 ng/ml, respectively, and there was a statistically significant difference between the two groups ( p < 0.05 ). We divided SCI patients into 4 groups according to their baseline serum Nogo-A quartile levels and analyzed their relationship with ASIA scores. The trend test results showed that with the increase of Nogo-A level, the ASIA sensation score and ASIA motor score were significantly decreased ( p < 0.001 ). Multivariate regression analysis showed that serum Nogo-A levels remained a potential cause affecting the prognosis of SCI after adjusting for confounding factors in multiple models. Conclusions. Serum Nogo-A levels were significantly elevated in SCI patients. Moreover, elevated Nogo-A levels often indicate poor prognosis and can be used as a marker to predict the prognosis of SCI.

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Recovery after spinal cord injury is enhanced by anti-Nogo-A antibody therapy — from animal models to clinical trials

Cited by 14 publications

References 55 publications

Segmental analysis in cervical spinal cord injury reveals the recovery potential of hand muscles with preserved corticospinal tract: Insights beyond impairment scales

Segmental analysis in cervical spinal cord injury reveals the recovery potential of hand muscles with preserved corticospinal tract: Insights beyond impairment scales

Selective CNS Targeting and Distribution with a Refined Region-Specific Intranasal Delivery Technique via the Olfactory Mucosa

Nogo-A Is a Potential Prognostic Marker for Spinal Cord Injury

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