Immunoglobulin A1 protease: A new therapeutic candidate for immunoglobulin A nephropathy

Xie, Linshen; Huang, Jun; Qin, Wei; Fan, Junming

doi:10.1111/j.1440-1797.2010.01278.x

Cited by 7 publications

(9 citation statements)

References 32 publications

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“…These bacterial IgA1 proteases offer an interesting proposition. If it is not possible to completely turn off IgA immune complex formation in IgAN, perhaps it might be possible to use these IgA1 proteases to directly target the IgA1 molecule itself and degrade circulating IgA immune complexes and dissolve away mesangial IgA deposits . In a proof‐of‐concept study, Lamm et al .…”

Section: Potential New Pathwaysmentioning

confidence: 99%

“…When systemically administered in a passive mouse model of IgAN, the IgA1 protease significantly reduced the extent of mesangial IgA immune complexes . How these observations will translate into clinical trials in humans is currently unclear, but interestingly, in 2012, Shire acquired a worldwide exclusive license from IGAN Biosciences to develop and commercialize protease‐based therapeutics for the treatment of IgAN …”

Section: Potential New Pathwaysmentioning

confidence: 99%

“…If it is not possible to completely turn off IgA immune complex formation in IgAN, perhaps it might be possible to use these IgA1 proteases to directly target the IgA1 molecule itself and degrade circulating IgA immune complexes and dissolve away mesangial IgA deposits. 61 In a proof-of-concept study, Lamm et al demonstrated that the H. influenzae IgA1 protease could cleave human IgA1 and IgA1-containing immune complexes in vitro. When systemically administered in a passive mouse model of IgAN, the IgA1 protease significantly reduced the extent of mesangial IgA immune complexes.…”

Section: Dissolution Of Mesangial Iga Deposits With Iga1 Proteasesmentioning

confidence: 99%

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Emerging therapies in immunoglobulin A nephropathy

2015

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examines a number of current and recently commenced studies in immunoglobulin A nephropathy, emphasizing newer therapies and therapeutic targets. ABSTRACT:Despite advances in our understanding of immunoglobulin A nephropathy (IgAN) over the past decade, there are currently no specific therapies capable of targeting key pathways involved in the pathogenesis of the disease. Recent studies have, however, provided new insights into important molecular pathways that are likely to be amenable to therapeutic manipulation in the future. Specifically, a deeper understanding of the role of mucosal immunity, B-cell activation and mesangial cell activation in IgAN has provided the impetus for a number of exciting phase II/III clinical trials in IgAN. In this review, we examine some of these on-going studies, first examining studies that clarify the role of traditional immunosuppression in IgAN, then focusing on novel therapies in early clinical studies, looking closely at the rationale for these agents in relation to our current understanding of the pathogenesis of IgAN. Finally, we examine emerging pathways and therapeutic agents that have the potential to be developed as novel therapies in the coming years. It is hoped that as we continue to develop a greater understanding of IgAN, emerging therapies will soon become a reality in the day-to-day treatment of patients with IgAN.

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Section: Potential New Pathwaysmentioning

confidence: 99%

Section: Potential New Pathwaysmentioning

confidence: 99%

Section: Dissolution Of Mesangial Iga Deposits With Iga1 Proteasesmentioning

confidence: 99%

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Emerging therapies in immunoglobulin A nephropathy

2015

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“…Gd-IgA1 is detectable in the glomerular deposits of IgAN [24]. Considering targeted therapies specific to IgAN, an interesting approach was the use of microbial protease to remove IgA deposits in mice, which was suggested some years ago [25] and recently proposed in human IgAN [26]. This approach has been confirmed to be a plausible new therapy for IgAN by a new experimental mouse model of IgAN that expresses human IgA1 and human CD89.…”

Section: Biomarkers Specific To Iganmentioning

confidence: 96%

Biomarkers and targeted new therapies for IgA nephropathy

Coppo

2016

Pediatr Nephrol

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IgA nephropathy (IgAN) has variable clinical presentation and outcome. There is a need to identify children who have the potential to progress to end stage renal disease (ESRD). Biomarkers related to the pathogenetic process of IgAN can detect risk factors and identify targets for new therapies. Galactose-deficient IgA1 (Gd-IgA1) is a specific biomarker of IgAN and could be the first treatment target. In experimental mice, reduction of IgA1 deposits and hematuria was observed after treatment with a bacterial protease that selectively cleaves human IgA1. Glycan-targeted drugs that may act to neutralize Gd-IgA1 inhibit abnormal enzymatic glycosylation of IgA1 or deplete cells producing Gd-IgA1. The autoimmune response to Gd-IgA1 produces autoantibodies that are sensitive and specific biomarkers of IgAN development and progression and suggests the possible benefits of anti-B cell therapies directed against CD20, B-cell activating factor (BAFF), or B cell receptor, and also proteasome inhibitors. The activation of complement in IgAN offers new biomarkers and the rationale for using complement inhibitors, including eculizumab. Renal pathological features represent sensitive biomarkers of added value over clinical data and may drive steroid therapy in selected cases. Finally, the hypothesis of the involvement of intestinal mucosal immunity in the pathogenesis of IgAN suggests the possibility of avoiding the systemic effect of steroid. Enteric budesonide targeting Peyer's patches at the ileocecal junction is an interesting option that has provided some preliminary favorable results in IgAN. In conclusion, the identification of new biomarkers is a promising area for therapies targeting IgAN in patients at risk of progression.

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“…However, IgA is one of the most frequent immunoglobulins and is extremely important for the defence and integrity of the surfaces. Therefore, the loss of integrity could be induced .…”

Section: Targeted Inhibition Of the Generation Formation And Depositmentioning

confidence: 99%

Why, when and how should immunosuppressive therapy considered in patients with immunoglobulin A nephropathy?

Rasche

Keller

Rasche³

et al. 2016

Clinical and Experimental Immunology

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SummaryIgA nephropathy (IgAN) is the most common primary glomerulonephritis worldwide. Lifelong mesangial deposition of IgA1 complexes subsist inflammation and nephron loss, but the complex pathogenesis in detail remains unclear. In regard to the heterogeneous course, classical immunosuppressive and specific therapeutic regimens adapted to the loss of renal function will here be discussed in addition to the essential common renal supportive therapy. Renal supportive therapy alleviates secondary, surrogate effects or sequelae on renal function and proteinuria of high intraglomerular pressure and subsequent nephrosclerosis by inhibition of the renin angiotensin system (RAASB). In patients with physiological (DGFR < 1Á5 ml/min/year) or mild (DGFR 1Á5-5 ml/min/year) decrease of renal function and proteinuric forms (> 1 g/day after RAASB), corticosteroids have shown a reduction of proteinuria and might protect further loss of renal function. In patients with progressive loss of renal function (DGFR > 3 ml/min within 3 months) or a rapidly progressive course with or without crescents in renal biopsy, cyclophosphamide with high-dose corticosteroids as induction therapy and azathioprine maintenance has proved effective in one randomized controlled study of a homogeneous cohort in loss of renal function (DGFR). Mycophenolic acid provided further maintenance in non-randomized trials. Differentiated, precise, larger, randomized, placebo-controlled studies focused on the loss of renal function in the heterogeneous forms of IgAN are still lacking. Prospectively, fewer toxic agents will be necessary in the treatment of IgAN.

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Immunoglobulin A1 protease: A new therapeutic candidate for immunoglobulin A nephropathy

Cited by 7 publications

References 32 publications

Emerging therapies in immunoglobulin A nephropathy

Emerging therapies in immunoglobulin A nephropathy

Biomarkers and targeted new therapies for IgA nephropathy

Why, when and how should immunosuppressive therapy considered in patients with immunoglobulin A nephropathy?

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