The most common form of congenital muscular dystrophy (CMD), caused by mutations in the LAMA2 gene encoding the α2 chain of laminin-211, is characterized by clinical manifestations mainly affecting skeletal muscle. Numerous nonsense mutations identified in the LAMA2 gene lead to premature termination codons (PTCs). The ability of aminoglycoside antibiotics to promote read-through of nonsense mutations has attracted interest in these drugs as potential therapeutic agents in genetic diseases. However, the toxicity of aminoglycoside antibiotics such as gentamicin may result in severe side effects during long-term treatment. In this paper, Dr. Valérie Allamand and colleagues analyzed the effect of two other compounds with antibiotic activities, negamycin, a dipeptide antibiotic and amikacin, another member of the aminoglycoside family, on a PTC in the LAMA2 gene in vitro and ex vivo using a dual reporter assay. Their results show that in NIH3T3 cells, amikacin leads to a 2.5-fold increase in readthrough whereas negamycin readthrough was increased up to 19-fold. Similar results were obtained for negamycin in vivo. Furthermore, negamycin treatment strongly sustained the stabilization of the LAMA2 transcripts in patient-derived myotubes up to 77% of control levels. However, neither gentamicin nor negamycin enabled re-expression of the laminin α2 chain in the patients’ myotubes at the protein level. This study demonstrates that negamycin, a compound less toxic and more efficient for premature termination readthrough than gentamicin, appears to be an alternative for treatment of patients carrying a PTC mutation.



Références : J Gene Med. 2008 Feb;10(2):217-24.