Kidney Week

Abstract: SA-PO386

N-Acetylmannosamine (ManNAc) Therapy Mitigates Glomerular Hyposialylation and Proteinuria

Session Information

• Glomerular Diseases: Clinical, Outcomes, Trials - III
  October 27, 2018 | Location: Exhibit Hall, San Diego Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Glomerular Diseases

• 1203 Glomerular Diseases: Clinical, Outcomes, and Trials

Authors

• Huizing, Marjan, Medical Genetics Branch, NHGRI, NIH, Bethesda, Maryland, United States

Marjan Huizing,

• Troost, Jonathan P., University of Michigan, Ann Arbor, Michigan, United States

Jonathan P. Troost,

• Leoyklang, Petcharat, Medical Genetics Branch, NHGRI, NIH, Bethesda, Maryland, United States

Petcharat Leoyklang,

• Bodine, Steven P., Medical Genetics Branch, NHGRI, NIH, Bethesda, Maryland, United States

Steven P. Bodine,

• Kretzler, Matthias, University of Michigan, Ann Arbor, Michigan, United States

Matthias Kretzler,

• Gahl, William, Medical Genetics Branch, NHGRI, NIH, Bethesda, Maryland, United States

William Gahl,

• Kopp, Jeffrey B., Kidney Disease Branch, NIDDK, NIH, Bethesda, Maryland, United States

Jeffrey B. Kopp,

• Malicdan, May christine, Medical Genetics Branch, NHGRI, NIH, Bethesda, Maryland, United States

May christine Malicdan,

Background

Glomerular hyposialylation of glycoproteins and glycolipids has been implicated in human and experimental nephrotic syndromes. In this study we assessed the prevalence of glomerular hyposialylation in human nephrotic syndromes and explored therapeutic potential of the sialic acid precursor N-acetylmannosamine (ManNAc) in three different nephrotic mouse models.

Methods

We created neuraminidase-induced and adriamycin-induced nephrotic mice and a nephrotic knock-in mouse model deficient in Gne, a central enzyme in sialic acid biosynthesis. ManNAc was administered in drinking water (~1 g/kg/d) to all three mouse models and clinical/biochemical parameters were assessed at different timepoints. Human glomerular sialylation was assessed by lectin histochemistry and confocal imaging in kidney biopsies of 91 well-phenotyped subjects with minimal change disease (MCD; 29 subjects), focal segmental glomerulosclerosis (FSGS; 37 subjects) or membranous nephropathy (MN; 25 subjects) supplied by the Nephrotic Syndrome Study Network (NEPTUNE).

Results

In all three mouse models, ManNAc administration increased glomerular sialylation and markedly reduced proteinuria and podocyte injury within a week of treatment. Hyposialylation was detected in an unexpectedly high percentage (~72%) of human kidney biopsies across all three disease entities, indicating that this condition may occur frequently, remains greatly unexplored and, importantly, may be treatable. Correlating sialylation status to clinical, pathological or other documented subject data, showed a trend of correlation of severe glomerular hyposialylation with decreased eGFR, increased interstitial fibrosis and increased tubular atrophy, in particular in FSGS subjects.

Conclusion

These encouraging preclinical data, together with minimal toxicity of oral ManNAc therapy in humans (demonstrated in Phase 1 and 2 clinical trials for the rare hyposialylation disorder GNE myopathy) led to obtaining an Investigational New Drug approval to start a Phase 1 clinical trial to evaluate the safety, tolerability and pharmacokinetics of ManNAc in subects with primary podocyte diseases (ClinicalTrials.gov NCT02639260). Preliminary results of this ongoing study are promising regarding safety and tolerability in subjects with glomerular disease.

Funding

• NIDDK Support – Escala Therapeutics, Leadiant Biosciences