Nogo receptor-Fc delivered by haematopoietic cells enhances neurorepair in a multiple sclerosis model

Abstract

Nogo receptor 1 is the high affinity receptor for the potent myelin-associated inhibitory factors that make up part of the inflammatory extracellular milieu during experimental autoimmune encephalomyelitis. Signaling through the Nogo receptor 1 complex has been shown to be associated with axonal degeneration in an animal model of multiple sclerosis and neuronal deletion of this receptor homologue, in a disease specific manner, is associated with preserving axons even in the context of neuroinflammation. The local delivery of Nogo receptor(1-310)-Fc, a therapeutic fusion protein has been successfully applied as a treatment in animal models of spinal cord injury and glaucoma. As multiple sclerosis and experimental autoimmune encephalomyelitis exhibit large numbers of inflammatory cell infiltrates within the CNS lesions, we utilized transplantable hematopoietic stem cells as a cellular delivery method of the Nogo receptor(1-310)-Fc fusion protein. We identified that CNS-infiltrating macrophages as the predominant immune-positive cell type that overexpressed myc-tagged Nogo receptor(1-310)-Fc fusion protein at the peak stage of experimental autoimmune encephalomyelitis. These differentiated phagocytes were predominant during the extensive demyelination and axonal damage, which are associated with the engulfment of the protein complex of Nogo receptor(1-310)-Fc binding to myelin ligands. Importantly, mice transplanted with hematopoietic stem cells transduced with the lentiviral vector carrying Nogo receptor(1-310)-Fc, recovered from the peak of neurological decline during experimental autoimmune encephalomyelitis, exhibiting axonal regeneration and eventual remyelination in the white matter tracts. There were no immunomodulatory effects of the transplanted, genetically modified hematopoietic stem cells on immune cell lineages of recipient female mice induced with experimental autoimmune encephalomyelitis. We propose that cellular delivery of Nogo receptor(1-310)-Fc fusion protein through genetically modified hematopoietic stem cells, can modulate multifocal experimental autoimmune encephalomyelitis lesions and potentiate neurological recovery.

How does Nogo receptor influence demyelination and remyelination in the context of multiple sclerosis?

“…The principle of directly targeting inflammatory demyelinating lesions without potential off-target effects is fundamental to this directed therapeutic approach, superior to other strategies where ubiquitous targets may affect neural circuits. This is highlighted by our very recent findings that demonstrate profound modification of the spinal cord lesions where neurorepair is exhibited in the recipient mice ( Ye et al, 2023 ). Since Nogo-A has been an attractive target in neurological research and recently, a clinical phase I safety, tolerability and pharmacokinetics trial for RRMS has been completed (NCT01435993), it is fundamentally important to ensure that the disease-associated lesional milieu is modified to promote repair and the best chance for neurophysiological recovery.…”

“…The therapeutic effect of direct delivery of NgR(ecto)-Fc is being addressed by our group since all aspects of CNS neuropathology and the clinical manifestations occur in the lentiviral-transduced hematopoietic stem cell (HSC)-transplanted recipient mice following EAE, either with or without NgR(ecto)-Fc ( Ye et al, 2023 ). The therapeutic effects in the transplanted mice occur following the peak of EAE where neurobiological recovery is observed.…”

“…Rationale of the current approach for future clinical research has now been articulated in our recent study whereby our experiments have clearly identified modulation of disease-associated macrophages/microglia and A1 astrocyte neurodegenerative phenotypes to alternative-activated neuroreparative phenotypes respectively, during the targeted cellular delivery of the NgR-Fc therapeutic protein. This would be of great benefit potentially to progressive MS patients that demonstrate smoldering lesions that exhibit specific activity of these phenotypes expanding the neurodegenerative outcomes in the CNS ( Ye et al, 2023 ).…”

The Heterogeneous Multiple Sclerosis Lesion: How Can We Assess and Modify a Degenerating Lesion?

“…Furthermore, NgR(310)ecto-Fc can also inhibit myelin-mediated axonal degeneration by blocking Nogo-A/NgR signaling [ 365 ]. Our recent data demonstrated significant remyelination and axonal repair during EAE following transplantation with NgR(310)ecto-Fc-transduced HSCs [ 367 ].…”