D-amino acid substitution of peptide-mediated NF-κB suppression in mdx mice preserves therapeutic benefit in skeletal muscle, but causes kidney toxicity

Daniel P. Reay, Sheldon I. Bastacky, Kathryn E. Wack, Donna B. Stolz, Paul D. Robbins, Paula R. Clemens

Research output: Contribution to journalArticle

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Abstract

In Duchenne muscular dystrophy (DMD) patients and the mdxmouse model of DMD, chronic activation of the classical nuclear factor-kB (NF-κB) pathway contributes to the pathogenesis that causes degeneration of muscle fibers, inflammation and fibrosis. Prior studies demonstrate that inhibition of inhibitor of κB kinase (IKK)-mediated NF-κB activation using L-isomer NF-κB essential modulator (NEMO)-binding domain (NBD) peptide-based approaches reduce muscle pathology in the mdxmouse. For our studies, the NBD peptide is synthesized as a fusion peptide with an eight-lysine (8K) protein transduction domain to facilitate intracellular delivery. We hypothesized that the D-isoform peptide could have a greater effect than the naturally occurring L-isoform peptide due to the longer persistence of the D-isoform peptide in vivo. In this study, we compared systemic treatment with low (1 mg/kg) and high (10 mg/kg) doses of L- and D-isomer 8K-wild-type-NBD peptide in mdx mice. Treatment with both L- or D-isoform 8K-wild-type-NBD peptide resulted in decreased activation of NF-κB and improved histology in skeletal muscle of the mdxmouse. However, we observed kidney toxicity (characterized by proteinuria), increased serum creatinine, activation of NF-kB and pathological changes in kidney cortex that were most severe with treatment with the D-isoform of 8K-wild-type-NBD peptide. The observed toxicity was also seen in normal mice.

Original languageEnglish (US)
Pages (from-to)442-452
Number of pages11
JournalMolecular Medicine
Volume21
DOIs
StatePublished - Jan 1 2015
Externally publishedYes

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Inbred mdx Mouse
Amino Acid Substitution
Skeletal Muscle
Protein Isoforms
Kidney
Peptides
Duchenne Muscular Dystrophy
Therapeutics
Kidney Cortex
Muscles
NF-kappa B
Proteinuria
Lysine
Protein Domains
Creatinine
Histology
Fibrosis
Phosphotransferases
Pathology
Inflammation

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D-amino acid substitution of peptide-mediated NF-κB suppression in mdx mice preserves therapeutic benefit in skeletal muscle, but causes kidney toxicity. / Reay, Daniel P.; Bastacky, Sheldon I.; Wack, Kathryn E.; Stolz, Donna B.; Robbins, Paul D.; Clemens, Paula R.

In: Molecular Medicine, Vol. 21, 01.01.2015, p. 442-452.

Research output: Contribution to journalArticle

Reay, Daniel P. ; Bastacky, Sheldon I. ; Wack, Kathryn E. ; Stolz, Donna B. ; Robbins, Paul D. ; Clemens, Paula R. / D-amino acid substitution of peptide-mediated NF-κB suppression in mdx mice preserves therapeutic benefit in skeletal muscle, but causes kidney toxicity. In: Molecular Medicine. 2015 ; Vol. 21. pp. 442-452.
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