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

Inventors

Molitoris, Bruce A. • Bedwell, David M. • Sandoval, Ruben M.

Assignees

UAB Research Foundation • Indiana University Research and Technology Corp • US Department of Veterans Affairs

Abstract

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.

Core Innovation

The invention relates to materials and methods for treating diseases caused by genetic disorders that include a premature stop codon within a gene. It involves the use of aminoglycosides, specifically congeners of gentamicin such as the congener C2 and derivatives thereof, which exhibit reduced nephrotoxicity compared to native gentamicin. These compounds promote ribosomal readthrough of premature stop codons, thereby enabling the production of full-length, functional proteins from mutated genes.

The problem being addressed is the clinical challenge of treating monogenetic diseases caused by premature stop codons, which result in non-functional or absent gene products. Diseases such as Duchenne Muscular Dystrophy, Cystic Fibrosis, Becker's muscular dystrophy, and Hurler's Syndrome fall within this category. While aminoglycosides like gentamicin can promote stop codon readthrough, their clinical use is limited due to severe nephrotoxicity and ototoxicity, making them unsuitable for chronic treatment.

The invention discloses that the gentamicin congener C2 can be isolated or synthesized and administered, alone or in mixtures enriched with C2, to treat genetic diseases caused by premature stop codons. Importantly, the C2 congener retains therapeutic efficacy in promoting stop codon readthrough but exhibits substantially lower nephrotoxicity. This property enables the use of higher or prolonged doses suitable for treating chronic genetic diseases requiring lifetime administration.

Claims Coverage

The patent describes two main inventive features covering treatment methods and compositions using gentamicin enriched with the C2 congener for genetic diseases involving premature stop codons.

The claims provide methods of treatment for genetic diseases involving premature stop codons using gentamicin compositions enriched with the C2 congener, highlighting reduced nephrotoxicity and suitability for chronic dosing in humans or animals.

Stated Advantages

Documented Applications