N-acetyl mannosamine as a therapeutic agent
Inventors
Huizing, Marjan • Gahl, William A. • Manoli, Irini • Klootwijk, Enriko
Assignees
US Department of Health and Human Services
Publication Number
US-8410063-B2
Publication Date
2013-04-02
Expiration Date
2028-05-30
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Abstract
The invention relates to compositions and methods for treating kidney and muscle dysfunction that involves use of therapeutic amounts of N-acetyl mannosamine.
Core Innovation
The invention relates to compositions and methods for treating kidney and muscle dysfunction through administration of therapeutic amounts of N-acetyl mannosamine (ManNAc) or its derivatives. These methods focus on increasing sialic acid levels in mammals by administering an effective amount of ManNAc, which promotes sialic acid biosynthesis.
The invention addresses treatment of diseases caused by sialic acid deficiency, particularly myopathies such as hereditary inclusion body myopathy (HIBM) and distal myopathy with rimmed vacuoles (Nonaka myopathy), as well as kidney diseases characterized by proteinuria and hematuria stemming from hyposialylation. The methods improve kidney function by enhancing sialylation of key kidney membrane components like podocalyxin and the glomerular basement membrane (GBM), thus correcting malformed or dysfunctional kidney membranes.
The problem solved by the invention is the lack of effective treatments for HIBM and related muscular dystrophies as well as kidney disorders caused by sialic acid deficiency. HIBM is a progressive neuromuscular disease lacking available treatment, while kidney disorders involving proteinuria and hematuria due to kidney membrane defects caused by hyposialylation also have limited therapeutic options. The invention provides therapeutic methods using ManNAc and derivatives to increase sialic acid synthesis, thereby ameliorating these conditions.
Claims Coverage
The patent includes two primary independent claims covering methods for treating kidney diseases and muscular dystrophies using N-acetyl mannosamine or its derivatives. The inventive features relate to therapeutic use, dosage, disease targets, and formulation.
Method of treating kidney diseases with N-acetyl mannosamine or derivatives
A method comprising oral administration of an effective amount of a sialic acid precursor, specifically N-acetyl mannosamine or its derivatives defined by Formula I, to treat kidney diseases involving proteinuria and/or hematuria characterized by defects in kidney membrane structure, such as malformed glomerular basement membrane and/or dysfunctional or fused podocytes.
Therapeutic effects on kidney membrane function and morphology
The method increases enzymatic activity of UDP-GlcNAc 2-epimerase/N-acetylmannosamine kinase (GNE), enhances sialylation of kidney podocalyxin, improves podocyte foot process morphology, and restores glomerular basement membrane integrity.
Specified effective dosage ranges for treatment
Administration of N-acetyl mannosamine in amounts ranging approximately from 0.1 g/day to 50 g/day, with a preferred therapeutic amount between 1 g and 20 g per day for treating kidney disorders.
Method of treating muscular dystrophies including HIBM and Nonaka myopathy
A method comprising administering an effective amount of N-acetyl mannosamine to treat distal myopathy with rimmed vacuoles (DMRV, Nonaka myopathy) or hereditary inclusion body myopathy (HIBM).
Formulations and administration routes
N-acetyl mannosamine or its derivatives may be microencapsulated or formulated in coatings, envelopes, or protective matrices such as liposomes, enabling oral administration including as food products.
The independent claims collectively cover therapeutic methods using orally administered N-acetyl mannosamine or its derivatives to treat kidney diseases characterized by membrane defects and muscle dystrophies such as HIBM and DMRV. The claims encompass effective dosages, improvements in enzymatic activity and sialylation, and various pharmaceutical formulations.
Stated Advantages
Administration of N-acetyl mannosamine increases sialic acid production, overcoming feedback inhibition in the biosynthesis pathway, thus providing therapeutic benefits for muscle and kidney diseases caused by sialic acid deficiency.
Treatment with ManNAc improves kidney function by increasing sialylation of podocalyxin, restoring podocyte morphology, and repairing glomerular basement membrane integrity.
ManNAc administration increases GNE enzymatic activity and protein expression in affected tissues, contributing to therapeutic effects.
The compound can be administered safely at effective doses with good tolerability, including in formulations suitable for oral administration or sustained release.
Documented Applications
Treatment of hereditary inclusion body myopathy (HIBM) and distal myopathy with rimmed vacuoles (Nonaka myopathy).
Treatment of kidney diseases and conditions involving proteinuria and hematuria due to defective kidney membranes such as malformed glomerular basement membranes and podocyte dysfunction.
Use as a food supplement or incorporated into food products to increase sialic acid production for therapeutic purposes.
Interested in licensing this patent?