Nonsense suppressor therapies rescue peroxisome lipid metabolism and assembly in cells from patients with specific PEX gene mutations
Patricia K. Dranchak,Erminia Di Pietro,Ann Snowden,Nathan Oesch,Nancy Braverman,Steven J. Steinberg,Joseph G. Hacia +6 more
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TLDR
The results support the continued development of safe and effective nonsense suppressor therapies that could benefit a significant subset of individuals with PBDs and suggest that the described cell culture assay systems could be useful for evaluating and screening for novel nonsense suppressionor therapies.Abstract:
Peroxisome biogenesis disorders (PBDs) are multisystemic autosomal recessive disorders resulting from mutations in PEX genes required for normal peroxisome assembly and metabolic activities. Here, we evaluated the potential effectiveness of aminoglycoside G418 (geneticin) and PTC124 (ataluren) nonsense suppression therapies for the treatment of PBD patients with disease-causing nonsense mutations. PBD patient skin fibroblasts producing stable PEX2 or PEX12 nonsense transcripts and Chinese hamster ovary (CHO) cells with a Pex2 nonsense allele all showed dramatic improvements in peroxisomal very long chain fatty acid catabolism and plasmalogen biosynthesis in response to G418 treatments. Cell imaging assays provided complementary confirmatory evidence of improved peroxisome assembly in G418-treated patient fibroblasts. In contrast, we observed no appreciable rescue of peroxisome lipid metabolism or assembly for any patient fibroblast or CHO cell culture treated with various doses of PTC124. Additionally, PTC124 did not show measurable nonsense suppression in immunoblot assays that directly evaluated the read-through of PEX7 nonsense alleles found in PBD patients with rhizomelic chondrodysplasia punctata type 1 (RCDP1). Overall, our results support the continued development of safe and effective nonsense suppressor therapies that could benefit a significant subset of individuals with PBDs. Furthermore, we suggest that the described cell culture assay systems could be useful for evaluating and screening for novel nonsense suppressor therapies.read more
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Journal ArticleDOI
Therapeutics Based on Stop Codon Readthrough
TL;DR: The current status of PTC suppression as a therapy for genetic diseases caused by nonsense mutations is examined, as well as therapeutic approaches under development to suppress PTCs.
Journal ArticleDOI
Peroxisome biogenesis disorders.
TL;DR: This poster presents a probabilistic procedure called a “naïve” cell reprograming procedure that is simple and straightforward to implement in the clinic and shows promising results in relation to Down’s syndrome.
Journal ArticleDOI
Ataluren as an Agent for Therapeutic Nonsense Suppression
TL;DR: Both translation termination and NMD are reviewed, and subsequent efforts over the past 15 years that led to the identification, characterization, and clinical testing of ataluren, a new therapeutic with the potential to treat a broad range of genetic disorders due to nonsense mutations.
Journal ArticleDOI
Nonsense-mediated decay in genetic disease: friend or foe?
Jake N. Miller,David A. Pearce +1 more
TL;DR: The normal function of this RNA surveillance pathway and how it is regulated is reviewed, current evidence for the role that it plays in modulating genetic disease phenotypes is provided, and how NMD can be used as a therapeutic target is provided.
Journal ArticleDOI
Rescue of nonsense mutations by amlexanox in human cells
Sara Gonzalez-Hilarion,Terence Beghyn,Jieshuang Jia,Jieshuang Jia,Jieshuang Jia,Nadège Debreuck,Gonzague Berte,Kamel Mamchaoui,Vincent Mouly,Dieter C. Gruenert,Dieter C. Gruenert,Benoit Deprez,Fabrice Lejeune,Fabrice Lejeune,Fabrice Lejeune +14 more
TL;DR: Amlexanox, a drug used for decades, not only induces an increase in nonsense-containing mRNAs amount in treated cells, but also leads to the synthesis of the full-length protein in an efficient manner and it is demonstrated that these full length proteins are functional.
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PTC124 targets genetic disorders caused by nonsense mutations
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