First-in-Man Intrathecal Application of Neurite Growth-Promoting Anti-Nogo-A Antibodies in Acute Spinal Cord Injury

Kucher, Klaus; Johns, Donald R.; Maier, Doris; Abel, Rainer; Badke, Andreas; Baron, Hagen; Thietje, Roland; Casha, Steven; Meindl, Renate; Gomez‐Mancilla, Baltazar; Pfister, C.; Rupp, R.; Weidner, Norbert; Mir, Anis K.; Schwab, Martin E.; Curt, Armin

doi:10.1177/1545968318776371

Cited by 142 publications

(86 citation statements)

References 46 publications

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“…Consistently, intrathecal administration of a Nogo-A neutralizing antibody following SCI resulted in enhanced axon growth and collateral sprouting in both rats and non-human primates (Merkler et al, 2001;Freund et al, 2006). These results led to a phase I trial (NCT00406016), which was completed in 2011 to assess the safety of intrathecal administration of ATI355 (Novartis), a recombinant human antibody directed against Nogo-A that was well-tolerated in patients with acute SCI (Kucher et al, 2018). Currently there are two ongoing phase II trials (NCT03935321 and EudraCT2016-001227-31) as a follow-up to this study, with no results posted.…”

Section: Modulating Glial Cell-axonal Growth Cone Interactions To Aidmentioning

confidence: 91%

Glial Cell-Axonal Growth Cone Interactions in Neurodevelopment and Regeneration

2020

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The developing nervous system is a complex yet organized system of neurons, glial support cells, and extracellular matrix that arranges into an elegant, highly structured network. The extracellular and intracellular events that guide axons to their target locations have been well characterized in many regions of the developing nervous system. However, despite extensive work, we have a poor understanding of how axonal growth cones interact with surrounding glial cells to regulate network assembly. Gliato-growth cone communication is either direct through cellular contacts or indirect through modulation of the local microenvironment via the secretion of factors or signaling molecules. Microglia, oligodendrocytes, astrocytes, Schwann cells, neural progenitor cells, and olfactory ensheathing cells have all been demonstrated to directly impact axon growth and guidance. Expanding our understanding of how different glial cell types directly interact with growing axons throughout neurodevelopment will inform basic and clinical neuroscientists. For example, identifying the key cellular players beyond the axonal growth cone itself may provide translational clues to develop therapeutic interventions to modulate neuron growth during development or regeneration following injury. This review will provide an overview of the current knowledge about glial involvement in development of the nervous system, specifically focusing on how glia directly interact with growing and maturing axons to influence neuronal connectivity. This focus will be applied to the clinically-relevant field of regeneration following spinal cord injury, highlighting how a better understanding of the roles of glia in neurodevelopment can inform strategies to improve axon regeneration after injury.

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Section: Modulating Glial Cell-axonal Growth Cone Interactions To Aidmentioning

confidence: 91%

Glial Cell-Axonal Growth Cone Interactions in Neurodevelopment and Regeneration

2020

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“…With regard to therapeutic intervention, NogoA and other myelin-associated inhibitors have been extensively studied in their capacity as inhibitors of repair and have been identified as promising targets for therapeutic intervention, especially for the treatment of SCI 52-61 and stroke [62][63][64][65][66][67][68] . A NogoA neutralising antibody, IN-1, has been tested in rodent models of SCI 52,54,56,69 , followed by NHPs 58,70,71 , and finally human subjects 72 . The Phase I clinical trial using ATI335 (NogoA neutralizing antibody) in acute paraplegic and tetraplegic patients reported that it is well tolerated following intrathecal administration 72 and has entered Phase II trials in subacute SCI (ClinicalTrials.gov NCT03935321).…”

Section: Discussionmentioning

confidence: 99%

“…A NogoA neutralising antibody, IN-1, has been tested in rodent models of SCI 52,54,56,69 , followed by NHPs 58,70,71 , and finally human subjects 72 . The Phase I clinical trial using ATI335 (NogoA neutralizing antibody) in acute paraplegic and tetraplegic patients reported that it is well tolerated following intrathecal administration 72 and has entered Phase II trials in subacute SCI (ClinicalTrials.gov NCT03935321). In addition, a soluble NgR decoy blocking Nogo, MAG and OMgp ligands is efficacious preclinically in chronic SCI 73,74 , and has entered clinical trials for that indication (ClinicalTrials.gov NCT03989440).…”

Section: Discussionmentioning

confidence: 99%

Primate-specific response of astrocytes to stroke limits peripheral macrophage infiltration

Boghdadi

Spurrier

Teo

et al. 2020

Preprint

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Reactive astrocytes play critical roles after brain injuries but their precise function in stroke is not well defined. Here, we utilized single nuclei transcriptomics to characterize astrocytes after ischemic stroke in nonhuman primate (NHP) marmoset monkey primary visual cortex. We identified 19 putative subtypes of astrocytes from injured and uninjured brain hemispheres and observed nearly complete segregation between stroke and control astrocyte clusters. We then screened for genes that might be limiting stroke recovery and discovered that one neurite-outgrowth inhibitory protein, NogoA, previously associated with oligodendrocytes but not astrocytes, was expressed in numerous reactive astrocyte subtypes. NogoA upregulation on reactive astrocytes was confirmed in vivo for NHP and human, but not observed to the same extent in rodent. Further in vivo and in vitro studies determined that NogoA mediated an anti-inflammatory response which limits deeper infiltration of peripheral macrophages from the lesion during the subacute post-stroke period. Specifically, these findings are relevant to the development of NogoA-targeting therapies shortly after ischemic stroke. Our findings have uncovered the complexity and species specificity of astrocyte responses, which need to be considered more when investigating novel therapeutics for brain injury.

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“…A human phase-I safety and tolerability trial with intrathecal application of anti-Nogo-A antibodies in acutely spinal cordinjured patients has been concluded successfully (Kucher et al, 2018). A phase-two randomized controlled European multicenter trial testing for upper-limb motor recovery in acute tetraplegic patients is ongoing (https://nisci-2020.eu).…”

Section: Discussionmentioning

confidence: 99%

Anti-Nogo-A Antibodies As a Potential Causal Therapy for Lower Urinary Tract Dysfunction after Spinal Cord Injury

et al. 2019

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Loss of bladder control is common after spinal cord injury (SCI) and no causal therapies are available. Here we investigated whether function-blocking antibodies against the nerve-fiber growth inhibitory protein Nogo-A applied to rats with severe SCI could prevent development of neurogenic lower urinary tract dysfunction. Bladder function of rats with SCI was repeatedly assessed by urodynamic examination in fully awake animals. Four weeks after SCI, detrusor sphincter dyssynergia had developed in all untreated or control antibody-infused animals. In contrast, 2 weeks of intrathecal anti-Nogo-A antibody treatment led to significantly reduced aberrant maximum detrusor pressure during voiding and a reduction of the abnormal EMG high-frequency activity in the external urethral sphincter. Anatomically, we found higher densities of fibers originating from the pontine micturition center in the lumbosacral gray matter in the anti-Nogo-A antibody-treated animals, as well as a reduced number of inhibitory interneurons in lamina X. These results suggest that anti-Nogo-A therapy could also have positive effects on bladder function clinically.

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First-in-Man Intrathecal Application of Neurite Growth-Promoting Anti-Nogo-A Antibodies in Acute Spinal Cord Injury

Abstract: ATI335 was well tolerated in humans; efficacy trials using intrathecal antibody administration may be considered in acute SCI.

Cited by 142 publications

References 46 publications

Glial Cell-Axonal Growth Cone Interactions in Neurodevelopment and Regeneration

Glial Cell-Axonal Growth Cone Interactions in Neurodevelopment and Regeneration

Primate-specific response of astrocytes to stroke limits peripheral macrophage infiltration

Anti-Nogo-A Antibodies As a Potential Causal Therapy for Lower Urinary Tract Dysfunction after Spinal Cord Injury

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