N-acetyl mannosammine 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-10335426-B2
Publication Date
2019-07-02
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 relates to compositions and methods involving use of the neutral sugar N-acetyl mannosamine (ManNAc) for therapeutic purposes in humans. Such therapeutic uses include treatment of myopathies, such as hereditary inclusion body myopathy (HIBM), and certain kidney diseases involving proteinuria and hematuria. The invention provides methods to increase sialic acid in a mammal by administering effective amounts of N-acetyl mannosamine or its derivatives.
The problem being solved is the lack of treatment for hereditary inclusion body myopathy, a rare autosomal recessive neuromuscular disorder manifested by progressive muscle weakness and atrophy with no available treatment. Furthermore, certain kidney conditions characterized by proteinuria and hematuria resulting from hyposialylation of kidney membranes require new therapeutic approaches. The invention addresses the need for compositions and methods to treat both hereditary inclusion body myopathy and related kidney disorders by restoring sialic acid levels.
The invention demonstrates that administration of N-acetyl mannosamine (ManNAc) increases the production of sialic acid, a sugar vital for cell-surface glycoproteins and involved in cellular hydration and function. ManNAc is a key intermediate in the sialic acid biosynthetic pathway, bypassing the regulated, rate-limiting enzymatic step subject to feedback inhibition. Thus, administering ManNAc leads to increased sialylation, improving muscle and kidney function in diseases caused by sialic acid deficiency.
Claims Coverage
The patent includes one independent claim covering methods of treating diseases in mammals comprising administering N-acetyl mannosamine or its derivatives. The claims detail various dosage forms and administration methods.
therapeutic method of treating a condition or disease
A method of treating a condition or disease in a mammal by selecting a subject with the condition and administering an effective amount of N-acetyl mannosamine or a derivative consistent with Formula I to increase sialic acid production.
therapeutic amount administration
Administering a therapeutic amount of N-acetyl mannosamine to the mammal, specifically from about 0.1 g to about 50 g per day.
unit dosage form administration
Administering N-acetyl mannosamine in a unit dosage ranging from about 0.01 g to about 50 g per unit dose.
sustained release administration
Administering N-acetyl mannosamine or its derivatives in a sustained release form to provide prolonged therapeutic effects.
topical administration
Administering N-acetyl mannosamine or its derivatives by topical routes.
oral administration
Administering N-acetyl mannosamine orally in mammals.
microencapsulation
Administering microencapsulated N-acetyl mannosamine for controlled delivery.
reduction of proteinuria
A method wherein administration of N-acetyl mannosamine decreases proteinuria in the mammal.
The claims cover therapeutic methods of administering N-acetyl mannosamine or derivatives to treat diseases by increasing sialic acid, including various dosing amounts, sustained release, topical and oral administration, microencapsulation, and reduction of proteinuria.
Stated Advantages
Administration of N-acetyl mannosamine increases sialic acid production, leading to therapeutic benefits in muscle and kidney diseases caused by sialic acid deficiency.
Treatment improves kidney function by enhancing glomerular basement membrane integrity and podocyte morphology, reducing proteinuria and hematuria.
The method increases sialylation of key glycoproteins such as podocalyxin and PSA-NCAM, which are important for normal tissue function.
ManNAc administration improves survival and disease symptoms in an animal model of hereditary inclusion body myopathy.
Documented Applications
Treatment of hereditary inclusion body myopathy and related myopathies involving muscular atrophy caused by sialic acid deficiency.
Treatment of kidney diseases involving proteinuria and hematuria due to podocytopathy and segmental splitting of the glomerular basement membrane.
Use of N-acetyl mannosamine to improve sialylation and kidney filtration properties to reduce symptoms and progression of glomerular disorders including minimal change nephrosis, focal and segmental glomerulosclerosis, membranous glomerulonephritis, Alport disease, and thin membrane disease.
Therapeutic administration of N-acetyl mannosamine or derivatives in humans in a clinical trial setting for treating hereditary inclusion body myopathy.
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