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  • Ovid Technologies (Wolters Kluwer Health)  (5)
  • 1
    Online Resource
    Online Resource
    The MFHR1 Fusion Protein Is a Novel Synthetic Multitarget Complement Inhibitor with Therapeutic Potential
    Ovid Technologies (Wolters Kluwer Health) ; 2018
    In:  Journal of the American Society of Nephrology Vol. 29, No. 4 ( 2018-4), p. 1141-1153
    Details
    In: Journal of the American Society of Nephrology, Ovid Technologies (Wolters Kluwer Health), Vol. 29, No. 4 ( 2018-4), p. 1141-1153
    Abstract: The complement system is essential for host defense, but uncontrolled complement system activation leads to severe, mostly renal pathologies, such as atypical hemolytic uremic syndrome or C3 glomerulopathy. Here, we investigated a novel combinational approach to modulate complement activation by targeting C3 and the terminal pathway simultaneously. The synthetic fusion protein MFHR1 links the regulatory domains of complement factor H (FH) with the C5 convertase/C5b-9 inhibitory fragment of the FH-related protein 1. In vitro , MFHR1 showed cofactor and decay acceleration activity and inhibited C5 convertase activation and C5b-9 assembly, which prevented C3b deposition and reduced C3a/C5a and C5b-9 generation. Furthermore, this fusion protein showed the ability to escape deregulation by FH-related proteins and form multimeric complexes with increased inhibitory activity. In addition to substantially inhibiting alternative and classic pathway activation, MFHR1 blocked hemolysis mediated by serum from a patient with aHUS expressing truncated FH. In FH−/− mice, MFHR1 administration augmented serum C3 levels, reduced abnormal glomerular C3 deposition, and ameliorated C3 glomerulopathy. Taking the unique design of MFHR1 into account, we suggest that the combination of proximal and terminal cascade inhibition together with the ability to form multimeric complexes explain the strong inhibitory capacity of MFHR1, which offers a novel basis for complement therapeutics.
    Type of Medium: Online Resource
    ISSN: 1046-6673 , 1533-3450
    URL: Article
    DOI: 10.1681/ASN.2017070738
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2018
    detail.hit.zdb_id: 2029124-3
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  • 2
    Online Resource
    Online Resource
    Phenotypic Spectrum of Children with Nephronophthisis and Related Ciliopathies
    Ovid Technologies (Wolters Kluwer Health) ; 2017
    In:  Clinical Journal of the American Society of Nephrology Vol. 12, No. 12 ( 2017-12), p. 1974-1983
    Details
    In: Clinical Journal of the American Society of Nephrology, Ovid Technologies (Wolters Kluwer Health), Vol. 12, No. 12 ( 2017-12), p. 1974-1983
    Abstract: Genetic heterogeneity and phenotypic variability are major challenges in familial nephronophthisis and related ciliopathies. To date, mutations in 20 different genes ( NPHP1 to -20 ) have been identified causing either isolated kidney disease or complex multiorgan disorders. In this study, we provide a comprehensive and detailed characterization of 152 children with a special focus on extrarenal organ involvement and the long-term development of ESRD. Design, setting, participants, & measurements We established an online-based registry (www.nephreg.de) to assess the clinical course of patients with nephronophthisis and related ciliopathies on a yearly base. Cross-sectional and longitudinal data were collected. Mean observation time was 7.5±6.1 years. Results In total, 51% of the children presented with isolated nephronophthisis, whereas the other 49% exhibited related ciliopathies. Monogenetic defects were identified in 97 of 152 patients, 89 affecting NPHP genes. Eight patients carried mutations in other genes related to cystic kidney diseases. A homozygous NPHP1 deletion was, by far, the most frequent genetic defect ( n =60). We observed a high prevalence of extrarenal manifestations (23% [14 of 60] for the NPHP1 group and 66% [61 of 92] for children without NPHP1 ). A homozygous NPHP1 deletion not only led to juvenile nephronophthisis but also was able to present as a predominantly neurologic phenotype. However, irrespective of the initial clinical presentation, the kidney function of all patients carrying NPHP1 mutations declined rapidly between the ages of 8 and 16 years, with ESRD at a mean age of 11.4±2.4 years. In contrast within the non- NPHP1 group, there was no uniform pattern regarding the development of ESRD comprising patients with early onset and others preserving normal kidney function until adulthood. Conclusions Mutations in NPHP genes cause a wide range of ciliopathies with multiorgan involvement and different clinical outcomes.
    Type of Medium: Online Resource
    ISSN: 1555-9041 , 1555-905X
    URL: Article
    DOI: 10.2215/CJN.01280217
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2017
    detail.hit.zdb_id: 2216582-4
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  • 3
    Online Resource
    Online Resource
    Randomization of Left-Right Asymmetry and Congenital Heart Defects : The Role of DNAH5 in Humans and Mice
    Ovid Technologies (Wolters Kluwer Health) ; 2019
    In:  Circulation: Genomic and Precision Medicine Vol. 12, No. 11 ( 2019-11)
    Details
    In: Circulation: Genomic and Precision Medicine, Ovid Technologies (Wolters Kluwer Health), Vol. 12, No. 11 ( 2019-11)
    Abstract: Nearly one in 100 live births presents with congenital heart defects (CHD). CHD is frequently associated with laterality defects, such as situs inversus , a mirrored positioning of internal organs. Body laterality is established by a complex process: monocilia at the embryonic left-right organizer facilitate both the generation and sensing of a leftward fluid flow. This induces the conserved left-sided Nodal signaling cascade to initiate asymmetrical organogenesis. Primary ciliary dyskinesia originates from dysfunction of motile cilia, causing symptoms such as chronic sinusitis, bronchiectasis and frequently situs inversus totalis . The most frequently mutated gene in primary ciliary dyskinesia, DNAH5 is associated with randomization of body asymmetry resulting in situs inversus totalis in half of the patients; however, its relation to CHD occurrence in humans has not been investigated in detail so far. Methods: We performed genotype/phenotype correlations in 132 patients with primary ciliary dyskinesia carrying disease-causing DNAH5 mutations, focusing on situs defects and CHD. Using high-speed video microscopy-, immunofluorescence-, and in situ hybridization analyses, we investigated the initial steps of left-right axis establishment in embryos of a Dnah5 -mutant mouse model. Results: In patients with primary ciliary dyskinesia carrying disease-causing DNAH5 mutations, 65.9% (87/132) had laterality defects: 88.5% (77/87) presented with situs inversus totalis , 11.5% (10/87) presented with situs ambiguus ; and 6.1% (8/132) presented with CHD. In Dnah5 mut/mut mice, embryonic left-right organizer monocilia lack outer dynein arms resulting in immotile cilia, impaired flow at the left-right organizer, and randomization of Nodal signaling with normal, reversed or bilateral expression of key molecules. Conclusions: For the first time, we directly demonstrate the disease-mechanism of laterality defects linked to DNAH5 deficiency at the molecular level during embryogenesis. We highlight that mutations in DNAH5 are not only associated with classical randomization of left-right body asymmetry but also with severe laterality defects including CHD.
    Type of Medium: Online Resource
    ISSN: 2574-8300
    URL: Article
    DOI: 10.1161/CIRCGEN.119.002686
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2019
    detail.hit.zdb_id: 2927603-2
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  • 4
    Online Resource
    Online Resource
    Moss-Produced, Glycosylation-Optimized Human Factor H for Therapeutic Application in Complement Disorders
    Ovid Technologies (Wolters Kluwer Health) ; 2017
    In:  Journal of the American Society of Nephrology Vol. 28, No. 5 ( 2017-5), p. 1462-1474
    Details
    In: Journal of the American Society of Nephrology, Ovid Technologies (Wolters Kluwer Health), Vol. 28, No. 5 ( 2017-5), p. 1462-1474
    Abstract: Genetic defects in complement regulatory proteins can lead to severe renal diseases, including atypical hemolytic uremic syndrome and C3 glomerulopathies, and age-related macular degeneration. The majority of the mutations found in patients with these diseases affect the glycoprotein complement factor H, the main regulator of the alternative pathway of complement activation. Therapeutic options are limited, and novel treatments, specifically those targeting alternative pathway activation, are highly desirable. Substitution with biologically active factor H could potentially treat a variety of diseases that involve increased alternative pathway activation, but no therapeutic factor H is commercially available. We recently reported the expression of full-length recombinant factor H in moss ( Physcomitrella patens ). Here, we present the production of an improved moss-derived recombinant human factor H devoid of potentially immunogenic plant–specific sugar residues on protein N -glycans, yielding approximately 1 mg purified moss–derived human factor H per liter of initial P. patens culture after a multistep purification process. This glycosylation-optimized factor H showed full in vitro complement regulatory activity similar to that of plasma-derived factor H and efficiently blocked LPS-induced alternative pathway activation and hemolysis induced by sera from patients with atypical hemolytic uremic syndrome. Furthermore, injection of moss-derived factor H reduced C3 deposition and increased serum C3 levels in a murine model of C3 glomerulopathy. Thus, we consider moss-produced recombinant human factor H a promising pharmaceutical product for therapeutic intervention in patients suffering from complement dysregulation.
    Type of Medium: Online Resource
    ISSN: 1046-6673 , 1533-3450
    URL: Article
    DOI: 10.1681/ASN.2015070745
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2017
    detail.hit.zdb_id: 2029124-3
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  • 5
    Online Resource
    Online Resource
    CPV-104, a Recombinant Variant of Human Complement Factor H Produced in Moss, to Be Studied in a Phase 1/2 Clinical Trial in Patients with C3 Glomerulopathy (C3G) : SA-PO918
    Ovid Technologies (Wolters Kluwer Health) ; 2023
    In:  Journal of the American Society of Nephrology Vol. 34, No. 11S ( 2023-11), p. 985-985
    Details
    In: Journal of the American Society of Nephrology, Ovid Technologies (Wolters Kluwer Health), Vol. 34, No. 11S ( 2023-11), p. 985-985
    Type of Medium: Online Resource
    ISSN: 1046-6673
    URL: Article
    DOI: 10.1681/ASN.20233411S1985a
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2023
    detail.hit.zdb_id: 2029124-3
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