Gentamicin treatment of Duchenne and Becker muscular dystrophy due to nonsense mutations

Wagner, Kathryn R.; Hamed, Sherifa A.; Hadley, Donald W.; Gropman, Andrea; Burstein, Aaron H.; Escolar, Diana M.; Hoffman, Eric P.; Fischbeck, Kenneth H.

doi:10.1002/ana.1023

Cited by 238 publications

(99 citation statements)

References 27 publications

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“…Two clinical trials have shown that the administration of gentamicin to cystic fibrosis patients carrying nonsense mutations in the CFTR gene can produce a partial restoration of cystic fibrosis transmembrane conductance regulator protein and activity in nasal epithelia [28,29]. However, another trial carried out with Duchenne and Becker muscular dystrophy patients was unable to document a significant increase in full-length dystrophin in muscle biopsy specimens taken from patients following gentamicin treatment [30].…”

Section: Introductionmentioning

confidence: 97%

Clinically relevant aminoglycosides can suppress disease-associated premature stop mutations in the IDUA and P53 cDNAs in a mammalian translation system

2002

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Recent studies have suggested that the use of aminoglycosides to suppress disease-causing nonsense mutations may be a promising new therapy for a large number of genetic diseases. However, gentamicin is currently the only clinically relevant aminoglycoside shown to suppress premature stop mutations in a mammalian system. We compared the ability of the clinically approved aminoglycosides gentamicin, tobramycin, and amikacin to suppress premature stop mutations. Using readthrough reporter constructs as well as mammalian cDNAs containing naturally occurring premature stop mutations, we found that each of these aminoglycosides can suppress many premature stop mutations in a context-dependent manner in a mammalian translation system. Our results indicate that the tetranucleotide termination signal (the stop codon and the nucleotide 3' of the stop codon) is the primary determinant for aminoglycoside-mediated suppression. The levels of termination suppression achieved by tobramycin were substantially lower than those observed with gentamicin. In contrast, amikacin stimulated suppression in a manner that was generally similar to gentamicin. Amikacin produced higher levels of readthrough than gentamicin at some contexts, demonstrating a unique pattern of context dependence. Experiments with mammalian cDNAs confirmed these results and demonstrated that these aminoglycosides can also suppress disease-associated premature stop mutations previously identified in the IDUA gene (responsible for the lysosomal storage disease mucopolysaccharidosis I) and the P53 gene (associated with many forms of cancer). Taken together, these results suggest that amikacin represents an alternative to gentamicin for suppression therapy in certain contexts, thus providing a means of optimizing the efficacy of aminoglycoside-mediated suppression of premature stop mutations.

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Section: Introductionmentioning

confidence: 97%

Clinically relevant aminoglycosides can suppress disease-associated premature stop mutations in the IDUA and P53 cDNAs in a mammalian translation system

2002

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“…Based upon the apparent plasticity of the SMN exon 7 sequences, a panel of aminoglycosides was tested to determine whether these compounds could induce SMN expression in SMA Wbroblasts (Wolstencroft et al 2005). Since aminoglycosides have previously been shown to suppress stop codon recognition (Barton-Davis et al 1999;Du et al 2002;Howard et al 1996Howard et al , 2000Howard et al , 2004Keeling et al 2001;Lai et al 2004;Manuvakhova et al 2000;Sleat et al 2001;Wagner et al 2001), it was speculated that the inclusion of heterologous sequences at the C-terminus of the SMN 7 protein would stabilize this novel SMN protein. Consistent with this, tobramycin and amikacin were shown to elevate SMN levels in the cytoplasm and in nuclear gems in SMA cells (Wolstencroft et al 2005).…”

Section: Introductionmentioning

confidence: 99%

Novel aminoglycosides increase SMN levels in spinal muscular atrophy fibroblasts

et al. 2006

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Spinal muscular atrophy (SMA) is the leading genetic cause of infant mortality. SMA is caused by the homozygous absence of survival motor neuron-1 (SMN1). SMN2, a nearly identical copy gene, is retained in all SMA patients and encodes an identical protein as SMN1; however, SMN1 and SMN2 differ by a silent C to T transition which results in the production of an alternatively spliced isoform (SMNDelta7), which encodes a defective protein, demonstrating that the absence of the short peptide encoded by SMN exon 7 is critical in SMA development. Previously, we have shown that for some functions heterologous sequences can compensate for the exon 7 peptide, suggesting that the SMN C-terminus functions non-specifically. Consistent with this hypothesis, we now identify novel aminoglycosides that can induce SMN protein levels in patient fibroblasts. This hypothesis was supported, in part, by a novel fluorescent SMN read-through assay. Interestingly, however, through the development of a SMN exon 7-specific antibody, results suggested that levels of normal full-length SMN might also be elevated by aminoglycoside treatment. These results demonstrate that the compounds that promote read-through may provide an alternative platform for the discovery of compounds that induce SMN protein levels.

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“…Therefore, gene therapy research concentrates mainly on gene-delivery experiments (Xiao et al 2000) and gene-repair or correction (Bartlett et al 2000;Mann et al 2000;Rando et al 2000;Wagner et al 2001). But dystrophin interacts with several other gene products and the absence of the dystrophin protein is therefore associated with partly unknown complex pathophysiological cascades downstream of the dystrophin.…”

Section: Discussionmentioning

confidence: 99%

Identification of transcripts from a subtraction library which might be responsible for the mild phenotype in an intrafamilially variable course of Duchenne muscular dystrophy

et al. 2003

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While frame-shift mutations are usually found in Duchenne muscular dystrophy (DMD), in-frame mutations are associated with the less severe phenotype of Becker's muscular dystrophy. Exceptions have been reported in both directions suggesting the existence of modifying genes, which might be helpful for innovation of new therapeutic strategies. We report on the very rare case of an intrafamilially different course of DMD, with the younger brother being far less affected than the older one when compared at the same age. In this context, we constructed a subtraction library enriched for transcripts over-expressed in the patient with the milder phenotype. Twelve random clones were sequenced, followed by database analysis. Six of them, casein kinase 1 alpha 1, RAP2B, dynactin 3 light chain, core binding factor beta, myosin light polypeptide 2 and one hypothetical gene, were further analysed by real-time RT-PCR. All these genes were over-expressed 3-20 times in the less affected patient compared with the more severely affected one. Casein kinase 1 and the hypothetical gene showed even a slightly higher expression than the control. Up-regulation of myosin light polypeptide 2, one of the most sensitive markers of muscle fibre regeneration, obviously reflects the milder phenotype. Casein kinase 1, dynactin and core binding factor are supposed to be involved in cell cycle pathways. RAP is a component of the signalling network which controls fundamental cellular processes such as proliferation and differentiation. All four might be interesting candidates for a therapeutic approach to diminish progression of dystrophy in DMD.

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Gentamicin treatment of Duchenne and Becker muscular dystrophy due to nonsense mutations

Cited by 238 publications

References 27 publications

Clinically relevant aminoglycosides can suppress disease-associated premature stop mutations in the IDUA and P53 cDNAs in a mammalian translation system

Clinically relevant aminoglycosides can suppress disease-associated premature stop mutations in the IDUA and P53 cDNAs in a mammalian translation system

Novel aminoglycosides increase SMN levels in spinal muscular atrophy fibroblasts

Identification of transcripts from a subtraction library which might be responsible for the mild phenotype in an intrafamilially variable course of Duchenne muscular dystrophy

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