The designer aminoglycoside NB84 significantly reduces glycosaminoglycan accumulation associated with MPS I-H in the Idua-W392X mouse.

Abstract

Suppression therapy utilizes compounds that suppress translation termination at in-frame premature termination codons (PTCs) to restore full-length, functional protein. This approach may provide a treatment for diseases caused by nonsense mutations such as mucopolysaccharidosis type I-Hurler (MPS I-H). MPS I-H is a lysosomal storage disease caused by severe α-L-iduronidase deficiency and subsequent lysosomal glycosaminoglycan (GAG) accumulation. MPS I-H represents a good target for suppression therapy because the majority of MPS I-H patients carry nonsense mutations, and restoration of even a small amount of functional α-L-iduronidase may attenuate the MPS I-H phenotype. In this study, we investigated the efficiency of suppression therapy agents to suppress the Idua-W392X nonsense mutation in an MPS I-H mouse model. The drugs tested included the conventional aminoglycosides gentamicin, G418, amikacin, and paromomycin. In addition, the designer aminoglycosides NB54 and NB84, two compounds previously designed to mediate efficient PTC suppression with reduced toxicity, were also examined. Overall, NB84 suppressed the Idua-W392X nonsense mutation much more efficiently than any of the other compounds tested. NB84 treatment restored enough functional α-L-iduronidase activity to partially reverse abnormal GAG accumulation and lysosomal abundance in mouse embryonic fibroblasts derived from the Idua-W392X mouse. Finally, in vivo administration of NB84 to Idua-W392X mice significantly reduced urine GAG excretion and tissue GAG storage. Together, these results suggest that NB84-mediated suppression therapy has the potential to attenuate the MPS I-H disease phenotype.

• Authors: Dan Wang, Valery Belakhov, Jeyakumar Kandasamy, Timor Baasov, Su-Chen Li, Yu-Teh Li, David M Bedwell, Kim M Keeling
• Journal: Molecular genetics and metabolism (Mol Genet Metab) Vol. 105 Issue 1 Pg. 116-25 (Jan 2012) ISSN: 1096-7206 [Electronic] United States
• PMID: 22056610 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 Elsevier Inc. All rights reserved.

Chemical References

• Aminoglycosides
• Codon, Nonsense
• Designer Drugs
• Glycosaminoglycans
• Trisaccharides
• aminoglycoside NB84
• Iduronidase

Topics

• Aminoglycosides (chemistry, pharmacology, therapeutic use)
• Animals
• Base Sequence
• Biological Assay
• Codon, Nonsense (genetics)
• Designer Drugs (chemistry, pharmacology, therapeutic use)
• Disease Models, Animal
• Embryo, Mammalian (pathology)
• Fibroblasts (drug effects, metabolism)
• Genes, Reporter
• Glycosaminoglycans (metabolism, urine)
• Iduronidase (metabolism)
• Lysosomes (drug effects, metabolism)
• Mice
• Mice, Inbred C57BL
• Molecular Sequence Data
• Mucopolysaccharidosis I (drug therapy, metabolism)
• Trisaccharides (chemistry, pharmacology, therapeutic use)