Notch3<sup>ECD</sup> immunotherapy improves cerebrovascular responses in CADASIL mice

Ghezali, Lamia; Capone, Carmen; Baron-Menguy, Céline; Ratelade, Julien; Christensen, Søren; Pedersen, Lars Østergaard; Domenga-Denier, Valérie; Pedersen, Jan T.; Joutel, Anne

doi:10.1002/ana.25284

Cited by 33 publications

(34 citation statements)

References 36 publications

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“…One solution has been the introduction of therapeutic monoclonal antibodies specific to Notch3, providing a strategy to down-regulate activity of Notch3. Monoclonal Notch3 antibody treatment has already been tested in experimental models of CADASIL, where treatment was shown to improve cerebrovascular function in the TgN3 R169C CADASIL mouse model [139], which has a gain of function of Notch3 [140]. Studies are now exploring potential therapeutic use of monoclonal antibodies for PAH.…”

Section: Notch3 Inhibition As a Potential Therapeutic Target In Pulmomentioning

confidence: 99%

Notch3 signalling and vascular remodelling in pulmonary arterial hypertension

et al. 2019

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Notch signalling is critically involved in vascular morphogenesis and function. Four Notch isoforms (Notch1–4) regulating diverse cellular processes have been identified. Of these, Notch3 is expressed almost exclusively in vascular smooth muscle cells (VSMCs), where it is critically involved in vascular development and differentiation. Under pathological conditions, Notch3 regulates VSMC switching between the contractile and synthetic phenotypes. Abnormal Notch3 signalling plays an important role in vascular remodelling, a hallmark of several cardiovascular diseases, including pulmonary arterial hypertension (PAH). Because of the importance of Notch3 in VSMC (de)differentiation, Notch3 has been implicated in the pathophysiology of pulmonary vascular remodelling in PAH. Here we review the current literature on the role of Notch in VSMC function with a focus on Notch3 signalling in pulmonary artery VSMCs, and discuss potential implications in pulmonary artery remodelling in PAH.

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Section: Notch3 Inhibition As a Potential Therapeutic Target In Pulmomentioning

confidence: 99%

Notch3 signalling and vascular remodelling in pulmonary arterial hypertension

et al. 2019

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“…In that study, intraperitoneal injections of 5E1 in transgenic mice showed that 5E1 clone could detect NOTCH3-ECD deposits, but failed to reduce NOTCH3-ECD/GOM deposition. However, 5E1 injection had beneficial effects on cerebrovascular function by normalizing vasodilatory responses and myogenic tone (Ghezali et al, 2018). The evidence that peripheral immunotherapy targeting NOTCH3-ECD protects against cerebrovascular dysfunction despite continued NOTCH3-ECD accumulation/GOM deposition might challenge the concept of proteins accumulation as the driving force in CADASIL, emphasizing the role of other possible mechanism, such as cerebrovascular flow hemodynamics, in the pathogenesis of the disease (Ghezali et al, 2018).…”

Section: Therapeutic Approachmentioning

confidence: 99%

“…The evidence that peripheral immunotherapy targeting NOTCH3-ECD protects against cerebrovascular dysfunction despite continued NOTCH3-ECD accumulation/GOM deposition might challenge the concept of proteins accumulation as the driving force in CADASIL, emphasizing the role of other possible mechanism, such as cerebrovascular flow hemodynamics, in the pathogenesis of the disease (Ghezali et al, 2018). More studies are required to determine if this approach could have beneficial effects in CADASIL patients (Ghezali et al, 2018).…”

Section: Therapeutic Approachmentioning

confidence: 99%

Pathophysiological Mechanisms and Potential Therapeutic Targets in Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy (CADASIL)

2020

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Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), is a hereditary small-vessels angiopathy caused by mutations in the NOTCH 3 gene, located on chromosome 19, usually affecting middleages adults, whose clinical manifestations include migraine with aura, recurrent strokes, mood disorders, and cognitive impairment leading to dementia and disability. In this review, we provide an overview of the current knowledge on the pathogenic mechanisms underlying the disease, focus on the corresponding therapeutic targets, and discuss the most promising treatment strategies currently under investigations. The hypothesis that CADASIL is an appropriate model to explore the pathogenesis of sporadic cerebral small vessel disease is also reviewed.

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“…However, the consequences of agonist antibodies were not investigated on more archetypal, N-terminally located, CADASIL mutants that have been reported not to have Notch signalling deficits. An alternative approach targeting the proposed toxic effect of Notch3 aggregates has also been tested using an antibody against the Notch EGF module-containing region of the ECD [104]. The aggregates in the mouse transgenic CADASIL model were successfully decorated with the antibody and some reversal of impaired cerebral blood flow responses were also achieved.…”

Section: Notch3 and Cerebral Autosomal Dominant Arteriopathy With Submentioning

confidence: 99%

Notch3 in Development, Health and Disease

Hosseini-Alghaderi

Baron

2020

Biomolecules

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Notch3 is one of four mammalian Notch proteins, which act as signalling receptors to control cell fate in many developmental and adult tissue contexts. Notch signalling continues to be important in the adult organism for tissue maintenance and renewal and mis-regulation of Notch is involved in many diseases. Genetic studies have shown that Notch3 gene knockouts are viable and have limited developmental defects, focussed mostly on defects in the arterial smooth muscle cell lineage. Additional studies have revealed overlapping roles for Notch3 with other Notch proteins, which widen the range of developmental functions. In the adult, Notch3, in collaboration with other Notch proteins, is involved in stem cell regulation in different tissues in stem cell regulation in different tissues, and it also controls the plasticity of the vascular smooth muscle phenotype involved in arterial vessel remodelling. Overexpression, gene amplification and mis-activation of Notch3 are associated with different cancers, in particular triple negative breast cancer and ovarian cancer. Mutations of Notch3 are associated with a dominantly inherited disease CADASIL (cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy), and there is further evidence linking Notch3 misregulation to hypertensive disease. Here we discuss the distinctive roles of Notch3 in development, health and disease, different views as to the underlying mechanisms of its activation and misregulation in different contexts and potential for therapeutic intervention.

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Notch3^ECD immunotherapy improves cerebrovascular responses in CADASIL mice

Abstract: This study establishes immunotherapy targeting Notch3 as a new avenue for disease-modifying treatment in CADASIL that warrants further development. Ann Neurol 2018;84:246-259.

Cited by 33 publications

References 36 publications

Notch3 signalling and vascular remodelling in pulmonary arterial hypertension

Notch3 signalling and vascular remodelling in pulmonary arterial hypertension

Pathophysiological Mechanisms and Potential Therapeutic Targets in Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy (CADASIL)

Notch3 in Development, Health and Disease

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Notch3ECD immunotherapy improves cerebrovascular responses in CADASIL mice

Abstract: This study establishes immunotherapy targeting Notch3 as a new avenue for disease-modifying treatment in CADASIL that warrants further development. Ann Neurol 2018;84:246-259.

Cited by 33 publications

References 36 publications

Notch3 signalling and vascular remodelling in pulmonary arterial hypertension

Notch3 signalling and vascular remodelling in pulmonary arterial hypertension

Pathophysiological Mechanisms and Potential Therapeutic Targets in Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy (CADASIL)

Notch3 in Development, Health and Disease

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Notch3^ECD immunotherapy improves cerebrovascular responses in CADASIL mice