Therapy with eculizumab for patients with CD59 p.Cys89Tyr mutation

Mevorach, Dror; Reiner, Inna; Ghorbanihaghjo, Amir; Ilan, Uri; Berkun, Yackov; Ta‐Shma, Asaf; Elpeleg, Orly; Shorer, Zamir; Edvardson, Simon; Tabib, Adi

doi:10.1002/ana.24770

Cited by 43 publications

(34 citation statements)

References 38 publications

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“…None of these patients had relapses and required hospitalization during therapy. 14 In conclusion, the phenotype of early-onset peripheral neuropathy, recurrent ischemic CNS strokes, and chronic hemolysis should be a clue for inherited CD59 deficiency. Early diagnosis is critical due to the potential treatment options.…”

Section: Discussionmentioning

confidence: 97%

Neonatal-Onset Recurrent Guillain–Barré Syndrome-Like Disease: Clues for Inherited CD59 Deficiency

et al. 2017

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Inherited CD59 deficiency is a rare autosomal recessive disorder characterized by chronic hemolysis, recurrent ischemic central nervous system strokes, and early-onset relapsing peripheral demyelinating neuropathy mimicking recurrent Guillain–Barré syndrome (GBS) or chronic inflammatory demyelinating polyneuropathy (CIDP). We report a 7-year-old girl who presented with neonatal-onset relapsing weakness accompanied by diffuse sensory-motor demyelinating peripheral polyneuropathy. She was diagnosed as having a CIDP-like disease and partially responded to immunomodulatory treatments. Cranial magnetic resonance imaging showed multiphasic brainstem and cerebellar ischemic lesions consistent with vasculopathy and chronic left middle cerebral artery infarction. Whole exome sequencing (WES) analysis revealed a frameshift deletion in CD59 (c.146delA, p.Asp49Valfs*31). Inherited CD59 deficiency should be considered in the differential diagnosis of patients with early-onset severe neurologic symptoms even without an overt hemolysis. We would like to highlight the role of WES in the diagnosis of a condition with a targeted therapy.

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Section: Discussionmentioning

confidence: 97%

Neonatal-Onset Recurrent Guillain–Barré Syndrome-Like Disease: Clues for Inherited CD59 Deficiency

et al. 2017

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“…Recent clinical reports indicate that targeting the complement cascade is gaining traction, e.g. C3 (compstatin/POT-4 peptide) [35], C5 antibody (Soliris; Alexion Pharmaceuticals) [36], Factor D (TNX-234 antibody) [37], C5aR 1 inhibitor, C1-INH (various manufacturers) in treating Paroxysmal Nocturnal Hemoglobinuria, atypical Hemolytic Uremic Syndrome, ARMD, gastrointestinal injury-related GVHD, C3 nephropathy, amyotrophic lateral sclerosis and other severe disorders. Our results in this report show that limiting complement activation may be a promising therapeutic strategy against TGF-β-induced lung fibrosis and is consistent with the report on the bleomycin injury model [4].…”

Section: Discussionmentioning

confidence: 99%

Potential Mechanisms Underlying TGF-β-mediated Complement Activation in Lung Fibrosis

Fisher¹,

Cipolla²,

Varre³

et al. 2017

Cell Mol Med

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While our previous studies suggest that limiting bleomycin-induced complement activation suppresses TGF-β signaling, the specific hierarchical interactions between TGF-β and complement in lung fibrosis are unclear. Herein, we investigated the mechanisms underlying TGF-β-induced complement activation in the pathogenesis of lung fibrosis. C57-BL6 mice were given intratracheal instillations of adenoviral vectors overexpressing TGF-β (Ad-TGFβ) or the firefly gene-luciferase (Ad-Luc; control). Two weeks later, mice with fibrotic lungs were instilled RNAi specific to receptors for C3a or C5a-C3ar or C5ar, and sacrificed at day 28. Histopathological analyses revealed that genetic silencing of C3ar or C5ar arrested the progression of TGF-β-induced lung fibrosis, collagen deposition and content (hydroxyproline, col1a1/2); and significantly suppressed local complement activation. With genetic silencing of either C3ar or C5ar, in Ad-TGFβ-injured lungs: we detected the recovery of Smad7 (TGF-β inhibitor) and diminished local release of DAF (membrane-bound complement inhibitor); in vitro: TGF-β-mediated loss of DAF was prevented. Conversely, blockade of the TGF-β receptor prevented C3a-mediated loss of DAF in both normal primary human alveolar and small airway epithelial cells. Of the 52 miRNAs analyzed as part of the Affymetrix array, normal primary human SAECs exposed to C3a, C5a or TGF-β caused discrete and overlapping miRNA regulation related to epithelial proliferation or apoptosis (miR-891A, miR-4442, miR-548, miR-4633), cellular contractility (miR-1197) and lung fibrosis . Our studies present potential mechanisms by which TGF-β activates complement and promotes lung fibrosis.

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“…The blockade of MAC formation has been explored for the treatment of a diverse array of clinical disorders, including inflammatory retinal diseases [233] and delayed or chronic haemolysis [234,235]. In asthma, control of allergen-induced responses via C5a inhibition has also been hypothesized [236].…”

Section: Complement Component 5-targeted Agents: Eculizumabmentioning

confidence: 99%

ESCMID Study Group for Infections in Compromised Hosts (ESGICH) Consensus Document on the safety of targeted and biological therapies: an infectious diseases perspective (Soluble immune effector molecules [II]: agents targeting interleukins, immunoglobulins and complement factors)

Winthrop

Mariette

Silva³

et al. 2018

Clinical Microbiology and Infection

190

122

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Therapy with eculizumab for patients with CD59 p.Cys89Tyr mutation

Cited by 43 publications

References 38 publications

Neonatal-Onset Recurrent Guillain–Barré Syndrome-Like Disease: Clues for Inherited CD59 Deficiency

Neonatal-Onset Recurrent Guillain–Barré Syndrome-Like Disease: Clues for Inherited CD59 Deficiency

Potential Mechanisms Underlying TGF-β-mediated Complement Activation in Lung Fibrosis

ESCMID Study Group for Infections in Compromised Hosts (ESGICH) Consensus Document on the safety of targeted and biological therapies: an infectious diseases perspective (Soluble immune effector molecules [II]: agents targeting interleukins, immunoglobulins and complement factors)

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