GLP-1 Receptor Agonist NLY01 Reduces Retinal Inflammation and Neuron Death Secondary to Ocular Hypertension

Sterling, Jacob; Adetunji, Modupe O; Guttha, Samyuktha; Bargoud, Albert; Uyhazi, Katherine E.; Ross, Ahmara G.; Dunaief, Joshua L.; Cui, Qi N.

doi:10.1016/j.celrep.2020.108271

Cited by 75 publications

(76 citation statements)

References 49 publications

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“…In a previous study, it was shown that NLY01, through a favorable blood brain barrier penetration, binds upregulated GLP-1R, blocking pathological activation of microglia in animal models of neurodegenerative diseases, including Parkinson’s ( Sterling et al, 2020 ).…”

Section: Neurodegenerative Diseasesmentioning

confidence: 99%

Therapeutic Peptides Targeting PPI in Clinical Development: Overview, Mechanism of Action and Perspectives

Cabri

Cantelmi

Corbisiero

et al. 2021

Front. Mol. Biosci.

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Targeting protein-protein interactions (PPIs) has been recently recognized as an emerging therapeutic approach for several diseases. Up today, more than half a million PPI dysregulations have been found to be involved in pathological events. The dynamic nature of these processes and the involvement of large protein surfaces discouraged anyway the scientific community in considering them promising therapeutic targets. More recently peptide drugs received renewed attention since drug discovery has offered a broad range of structural diverse sequences, moving from traditionally endogenous peptides to sequences possessing improved pharmaceutical profiles. About 70 peptides are currently on the marked but several others are in clinical development. In this review we want to report the update on these novel APIs, focusing our attention on the molecules in clinical development, representing the direct consequence of the drug discovery process of the last 10 years. The comprehensive collection will be classified in function of the structural characteristics (native, analogous, heterologous) and on the basis of the therapeutic targets. The mechanism of interference on PPI will also be reported to offer useful information for novel peptide design.

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Section: Neurodegenerative Diseasesmentioning

confidence: 99%

Therapeutic Peptides Targeting PPI in Clinical Development: Overview, Mechanism of Action and Perspectives

Cabri

Cantelmi

Corbisiero

et al. 2021

Front. Mol. Biosci.

View full text Add to dashboard Cite

show abstract

“…In a mouse model of glaucoma, ocular hypertension induction is sufficient to trigger the production of cytokines necessary to drive the formation of A1 astrocytes. Genetic deletion of TNFα, Il-1α, and C1q, or treatment with a glucagon-like peptide-1 receptor (GLP-1) agonist, results in the reduction of A1 astrocytic activity and amelioration of RGC death [140]. Importantly, the functionality assignment of these reactive glial phenotypes is based on correlative evidence in bulk cell analyses.…”

Section: Increasing Donor Rgc Survival: Cell Extrinsic Environmental Factorsmentioning

confidence: 99%

Retinal Ganglion Cell Transplantation: Approaches for Overcoming Challenges to Functional Integration

Zhang

Aguzzi

Johnson

2021

Cells

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As part of the central nervous system, mammalian retinal ganglion cells (RGCs) lack significant regenerative capacity. Glaucoma causes progressive and irreversible vision loss by damaging RGCs and their axons, which compose the optic nerve. To functionally restore vision, lost RGCs must be replaced. Despite tremendous advancements in experimental models of optic neuropathy that have elucidated pathways to induce endogenous RGC neuroprotection and axon regeneration, obstacles to achieving functional visual recovery through exogenous RGC transplantation remain. Key challenges include poor graft survival, low donor neuron localization to the host retina, and inadequate dendritogenesis and synaptogenesis with afferent amacrine and bipolar cells. In this review, we summarize the current state of experimental RGC transplantation, and we propose a set of standard approaches to quantifying and reporting experimental outcomes in order to guide a collective effort to advance the field toward functional RGC replacement and optic nerve regeneration.

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“…Similar to inflammatory responses in other neurodegenerative diseases or aging [189], microglia-derived IL1α, TNFα, and C1q can mediate the induction of proinflammatory and neurotoxic astrocytes in glaucoma. Indeed, triple knockout of these molecules (IL1 −/− TNFα −/− C1q −/− ) [190], or treatment with a glucagon-like peptide-1 receptor agonist, NLY01 [191], reduced A1 transformation and protected RGCs in ocular hypertensive mice. Although a global knockout model does not provide cell type-specific information or cannot preclude the contribution of blood-born elements, these observations support the neurodegenerative potential of glial inflammatory responses in glaucoma.…”

Section: Glial Interactions For Neuroinflammationmentioning

confidence: 99%

Multifactorial Pathogenic Processes of Retinal Ganglion Cell Degeneration in Glaucoma towards Multi-Target Strategies for Broader Treatment Effects

Tezel

2021

Cells

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Glaucoma is a chronic neurodegenerative disease characterized by apoptosis of retinal ganglion cell (RGC) somas, degeneration of axons, and loss of synapses at dendrites and axon terminals. Glaucomatous neurodegeneration encompasses multiple triggers, multiple cell types, and multiple molecular pathways through the etiological paths with biomechanical, vascular, metabolic, oxidative, and inflammatory components. As much as intrinsic responses of RGCs themselves, divergent responses and intricate interactions of the surrounding glia also play decisive roles for the cell fate. Seen from a broad perspective, multitarget treatment strategies have a compelling pathophysiological basis to more efficiently manipulate multiple pathogenic processes at multiple injury sites in such a multifactorial neurodegenerative disease. Despite distinct molecular programs for somatic and axonal degeneration, mitochondrial dysfunction and glia-driven neuroinflammation present interdependent processes with widespread impacts in the glaucomatous retina and optic nerve. Since dysfunctional mitochondria stimulate inflammatory responses and proinflammatory mediators impair mitochondria, mitochondrial restoration may be immunomodulatory, while anti-inflammatory treatments protect mitochondria. Manipulation of these converging routes may thus allow a unified treatment strategy to protect RGC axons, somas, and synapses. This review presents an overview of recent research advancements with emphasis on potential treatment targets to achieve the best treatment efficacy to preserve visual function in glaucoma.

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GLP-1 Receptor Agonist NLY01 Reduces Retinal Inflammation and Neuron Death Secondary to Ocular Hypertension

Cited by 75 publications

References 49 publications

Therapeutic Peptides Targeting PPI in Clinical Development: Overview, Mechanism of Action and Perspectives

Therapeutic Peptides Targeting PPI in Clinical Development: Overview, Mechanism of Action and Perspectives

Retinal Ganglion Cell Transplantation: Approaches for Overcoming Challenges to Functional Integration

Multifactorial Pathogenic Processes of Retinal Ganglion Cell Degeneration in Glaucoma towards Multi-Target Strategies for Broader Treatment Effects

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