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
Publication Number
US-8951978-B2
Publication Date
2015-02-10
Expiration Date
2027-11-29
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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 the preparation and use of congeners of the aminoglycoside gentamicin, specifically the C2 congener and its derivatives and pharmaceutically active salts, to treat diseases caused by genetic mutations that introduce a premature stop codon into a gene. This treatment aims to promote ribosomal readthrough of the premature stop codon, allowing the synthesis of a full-length, functional protein otherwise absent or defective in such genetic disorders.
The problem addressed is that many aminoglycosides, including native gentamicin, possess severe nephrotoxicity and ototoxicity, limiting their long-term use despite their potential to suppress premature stop codons. Diseases such as Duchenne Muscular Dystrophy (DMD), Cystic Fibrosis (CF), Becker's muscular dystrophy, and Hurler's Syndrome involve premature stop codons leading to non-functional proteins. Traditional gentamicin cannot be safely administered chronically to these patients due to its toxicity. This invention identifies and isolates a gentamicin congener, C2, with significantly reduced nephrotoxicity while retaining the ability to promote stop codon readthrough, thereby overcoming this limitation.
Additionally, the invention covers methods of treating genetic diseases by administering therapeutically effective doses of the purified C2 congener or mixtures enriched with C2, as well as compositions and kits for promoting readthrough of stop codons. The C2 congener exhibits substantially less nephrotoxicity, as demonstrated by in vitro cell assays and animal studies, making it suitable for longer-term and higher-dose administration compared to native gentamicin.
Claims Coverage
The patent includes multiple independent claims focusing on methods of treating genetic diseases caused by premature stop codons using a gentamicin congener, specifically enriched formulations containing the C2 congener or its pharmaceutically acceptable salts, and the scope covers various stop codon sequences and specified diseases.
Use of gentamicin C2 congener enriched formulations to treat genetic diseases caused by premature stop codons
A method of treating a genetic disease by identifying a patient with a pathology involving a premature stop codon in an otherwise functional gene, wherein the disease is selected from Duchenne Muscular Dystrophy, cystic fibrosis, Hurler's syndrome, and Becker muscular dystrophies, then formulating and administering a therapeutically effective dose of an aminoglycoside enriched in the isolated and purified gentamicin C2 congener or a pharmaceutically acceptable salt thereof.
Treatment targeting specific premature stop codon sequences
A method of treating genetic diseases involving identification of patients with premature stop codons selected from UAAC, UAGC, UGAC, UAAG, UAGG, UGAG, UAAU, UAGU, UGAU, UAAA, UAGA, and UGAA, and formulating and administering therapeutic doses of an aminoglycoside enriched in gentamicin C2 congener or pharmaceutically acceptable salts, specifically including the UAGC stop codon.
The claims cover the use of the isolated and purified gentamicin C2 congener or its pharmaceutically acceptable salts, alone or in enriched mixtures, for treating genetic diseases caused by the presence of premature stop codons, encompassing specific disease conditions and target stop codon sequences, thereby providing a therapeutic approach with reduced nephrotoxicity.
Stated Advantages
The C2 congener exhibits markedly reduced nephrotoxicity compared to native gentamicin, allowing safer administration over prolonged periods or at higher doses.
C2 retains bactericidal activity and efficiently promotes readthrough of premature stop codons in mutated genes, enabling production of functional proteins.
Formulations enriched in the C2 congener reduce the cellular toxicity typically associated with aminoglycoside antibiotics.
The reduced toxicity of C2 facilitates its use for long-term treatment of chronic genetic diseases caused by premature stop codons, which was not feasible with native gentamicin.
Documented Applications
Treatment of monogenetic diseases caused by premature stop codons, including Duchenne Muscular Dystrophy, Becker's muscular dystrophy, Hurler's Syndrome, and Cystic Fibrosis.
Use in human and animal patients to suppress premature stop codons and restore functional protein expression.
Pharmaceutical compositions and kits for promoting ribosomal readthrough of specific stop codons under in vitro and in vivo conditions.
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