The UAB Research Foundation (The University of Alabama at Birmingham)

Indiana University

Other

Southern Research Institute

David M Bedwell

Ruben Sandoval

Bruce Molitoris

Steven Mark Rowe

Kim M Keeling

Corinne E Augelli-Szafran

Bini Mathew

John Phillip Tillotson

Terry Smalley

Kevin Jay Rodzinak

Venkateshwar Mutyam

Robert Hunter

Ming Du

The present disclosure is concerned with substituted uracil compounds, pharmaceutical compositions comprising the compounds, and methods of treating disorders associated with the presence of a premature termination codon such as, for example, cystic fibrosis, Duchenne muscular dystrophy, aniridia, Becker muscular dystrophy, spinal muscular atrophy, Hurler syndrome, hemophilia, epidermolysis bullosa (e.g., dystrophic (DEB) form, junctional (JEB) form), Usher syndrome, and cancer, using the compounds. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention.

Uracil derivatives for stimulating read-through of premature termination codons

The present disclosure provides compositions and methods for treating and/preventing diseases and conditions associated with premature termination mutations. The methods disclosed herein comprise the step of administering to the subject a therapeutically effective dose of a compound described herein that induces read-through of the premature termination codon. The methods of the present disclosure may further comprise treating the subject with enzyme replacement therapy wherein the enzyme replacement therapy is selected for the disease or condition to be treated. Furthermore, the present disclosure provides method of pharmacologically suppressing premature termination codons in a subject in need of such suppression.

Methods and compounds for stimulating read-through of premature termination codons

Various aspects related to the preparation of congeners of the aminoglycosides gentamicin such as the congener C2 and using this compound or derivatives thereof and pharmaceutically active salts to treat diseases that involve genetic mutations which introduce a missense or premature stop codon into a gene. Still other aspects include treating human or animal patients with the gentamicin congener C2 and derivatives and pharmaceutical salt thereof to overcome, or to at least mitigate, the symptoms of disease and disorders such as some forms of Becker's or Duchenne muscular dystrophy, Hurler's Syndrome and Cystic Fibrosis that have as their etiology the presence of a premature stop codon in a gene whose proper expression is necessary for good health.

Materials and methods for treating diseases caused by genetic disorders using aminoglycosides and derivatives thereof which exhibit low nephrotoxicity

The present invention provides a method of treating lysosomal storage diseases such as Hurler syndrome and Batten disease in individuals in need of such treatment, comprising the step of administering to said individuals a therapeutically effective dose of an aminoglycoside. In addition, this method may further comprise treating the individual with enzyme replacement therapy. Furthermore, the present invention provides method of pharmacologically suppressing premature stop mutations in an individual with these lysosomal storage diseases, comprising the step of administering to said individual a pharmacologically effective dose of an aminoglycoside.

Aminoglycoside treatment for lysosomal storage diseases

The present invention provides a method of stimulating expression of a functional full-length cystic fibrosis transmembrane conductance regulator protein in an individual in need of such treatment, comprising the step of administering to said individual a pharmacologically effective dose of an aminoglycoside. Also provided is a method of treating cystic fibrosis in an individual in need of such treatment, comprising the step of administering to said individual a therapeutically effective dose of an aminoglycoside. Further provided is a method of screening for a drug useful in the treatment of an individual having cystic fibrosis, comprising the step of determining said drug's ability to suppress premature stop mutations in a model of cystic fibrosis and a method of pharmacologically suppressing premature stop mutations in an individual having such mutations, comprising the step of administering to said individual a pharmacologically effective dose of an aminoglycoside.

Cystic fibrosis treatment

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Birmingham, AL, United States of America

David M Bedwell