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-9095597-B2
Publication Date
2015-08-04
Expiration Date
2028-05-30
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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 provides compositions and methods for treating kidney and muscle dysfunction by administering therapeutic amounts of N-acetyl mannosamine (ManNAc) or derivatives thereof to increase sialic acid in mammals. The therapeutic approach targets diseases involving muscle atrophy caused by sialic acid deficiency, such as hereditary inclusion body myopathy (HIBM) and distal myopathy with rimmed vacuoles (Nonaka myopathy), as well as kidney disorders that involve proteinuria and hematuria resulting primarily or secondarily from hyposialylation.
The problem being addressed is the lack of treatment for hereditary inclusion body myopathy, a rare progressive neuromuscular disorder characterized by muscle fiber degeneration and vacuole formation, leading to severe muscle weakness and eventual incapacitation. Moreover, kidney disorders associated with poor kidney membrane formation or function, including malformed or poorly functioning glomerular basement membranes and podocyte membranes, also lack effective therapies. The invention aims to restore sialylation and thereby improve the structure and function of kidneys and muscles.
The invention demonstrates that administration of N-acetyl mannosamine bypasses the rate-limiting step in sialic acid biosynthesis, leading to increased sialic acid production without feedback inhibition. Increased sialylation improves cellular hydration, membrane charge, and function of membrane glycoproteins such as podocalyxin in kidneys and glycoproteins relevant to muscle function. Experimental results using a knockin mouse model with the GneM712T mutation showed that ManNAc administration increases survival, improves kidney morphology, restores sialylation of podocalyxin, enhances Gne protein expression, and elevates Gne-epimerase enzymatic activity, evidencing its therapeutic potential for both myopathies and kidney disorders.
Claims Coverage
The patent includes multiple independent claims covering methods of treating kidney diseases or conditions using N-acetyl mannosamine or derivatives thereof. Four main inventive features are identified relating to different administration methods and formulations.
Use of N-acetyl mannosamine or derivatives in treating kidney disease or condition
A method of treating a kidney disease or condition in a mammal by administering an effective amount of a sialic acid precursor, specifically N-acetyl mannosamine or its derivative defined by Formula I, to treat the kidney disease or condition.
Therapeutic administration of N-acetyl mannosamine
A method comprising administering a therapeutic amount of N-acetyl mannosamine to the mammal to treat a kidney disease or condition.
Sustained release administration of N-acetyl mannosamine or derivatives
A method of treating a kidney disease or condition via sustained release administration of an effective amount of N-acetyl mannosamine or a derivative defined by Formula I, including administration via indwelling devices.
Topical administration of N-acetyl mannosamine or derivatives
A method of treating a kidney disease or condition by topically administering an effective amount of N-acetyl mannosamine or a derivative defined by Formula I, using topical formulations such as creams, gels, lotions, impregnated pads, ointments, aerosol formulations, soaps, polymer coverings, or drops.
The claims cover various therapeutic methods of administering N-acetyl mannosamine or derivatives for treating kidney diseases or conditions, encompassing oral, sustained release, and topical routes, highlighting the flexibility and broad applicability of the therapeutic approach involving sialic acid precursors.
Stated Advantages
Administration of N-acetyl mannosamine leads to increased sialylation, which improves kidney function, reduces proteinuria and hematuria, and improves muscle function in conditions caused by sialic acid deficiency.
The compositions and methods provide therapeutic benefits by improving the structure and filtration properties of kidneys, reducing symptoms associated with kidney disorders such as segmental splitting of the glomerular basement membrane and podocytopathies.
ManNAc administration improves survival in animal models with Gne mutations, increases enzymatic activities and protein expression of Gne/Mnk, and restores sialylation of critical membrane glycoproteins such as podocalyxin and PSA-NCAM.
Documented Applications
Treatment of hereditary inclusion body myopathy (HIBM) and distal myopathy with rimmed vacuoles (Nonaka myopathy) in humans and animal models.
Treatment of kidney diseases and conditions involving proteinuria and hematuria due to hyposialylation, including podocytopathies, glomerular basement membrane diseases such as Alport disease and thin membrane disease, minimal change nephrosis, focal and segmental glomerulosclerosis, membranous glomerulonephritis, and idiopathic nephrotic syndrome.
Potential use as a food supplement or incorporation into food and drink items to therapeutically increase sialic acid production.
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