The novel aminoglycoside NB54 exhibited superior in vitro readthrough efficiency of nonsense mutations and far lower toxicity in mice and cochlear explants compared to gentamicin.
Does the novel aminoglycoside NB54 improve readthrough efficiency and reduce toxicity compared to gentamicin in models of nonsense mutations?
The novel aminoglycoside NB54 demonstrates improved suppression of nonsense mutations with significantly reduced toxicity compared to gentamicin in preclinical models.
Nonsense mutations promote premature translational termination and represent the underlying cause of a large number of human genetic diseases. The aminoglycoside antibiotic gentamicin has the ability to allow the mammalian ribosome to read past a false-stop signal and generate full-length functional proteins. However, severe toxic side effects along with the reduced suppression efficiency at subtoxic doses limit the use of gentamicin for suppression therapy. We describe here the first systematic development of the novel aminoglycoside 2 (NB54) exhibiting superior in vitro readthrough efficiency to that of gentamicin in seven different DNA fragments derived from mutant genes carrying nonsense mutations representing the genetic diseases Usher syndrome, cystic fibrosis, Duchenne muscular dystrophy, and Hurler syndrome. Comparative acute lethal toxicity in mice, cell toxicity, and the assessment of hair cell toxicity in cochlear explants further indicated that 2 exhibits far lower toxicity than that of gentamicin.
Nudelman et al. (Mon,) conducted a other in Genetic diseases caused by nonsense mutations (Usher syndrome, cystic fibrosis, Duchenne muscular dystrophy, Hurler syndrome). Novel aminoglycoside 2 (NB54) vs. Gentamicin was evaluated on In vitro readthrough efficiency and toxicity (acute lethal toxicity in mice, cell toxicity, hair cell toxicity). The novel aminoglycoside NB54 exhibited superior in vitro readthrough efficiency of nonsense mutations and far lower toxicity in mice and cochlear explants compared to gentamicin.