Readthrough compounds for nonsense mutations: bridging the translational gap

Spelier, Sacha; Doorn, Eveline P.M. van; Ent, Cornelis K. van der; Beekman, Jeffrey M.; Koppens, Martijn A.J.

doi:10.1016/j.molmed.2023.01.004

Cited by 24 publications

(13 citation statements)

References 104 publications

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“…As a large number of genetic diseases result from nonsense mutations [ 15 ], identifying and developing new therapeutic strategies by better understanding the mechanism that underlines induced nonsense mutation readthrough activity is of great interest.…”

Section: Introductionmentioning

confidence: 99%

Nonsense mutation suppression is enhanced by targeting different stages of the protein synthesis process

Wittenstein,

Caspi,

Rippin

et al. 2023

PLoS Biol

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The introduction of premature termination codons (PTCs), as a result of splicing defects, insertions, deletions, or point mutations (also termed nonsense mutations), lead to numerous genetic diseases, ranging from rare neuro-metabolic disorders to relatively common inheritable cancer syndromes and muscular dystrophies. Over the years, a large number of studies have demonstrated that certain antibiotics and other synthetic molecules can act as PTC suppressors by inducing readthrough of nonsense mutations, thereby restoring the expression of full-length proteins. Unfortunately, most PTC readthrough-inducing agents are toxic, have limited effects, and cannot be used for therapeutic purposes. Thus, further efforts are required to improve the clinical outcome of nonsense mutation suppressors. Here, by focusing on enhancing readthrough of pathogenic nonsense mutations in the adenomatous polyposis coli (APC) tumor suppressor gene, we show that disturbing the protein translation initiation complex, as well as targeting other stages of the protein translation machinery, enhances both antibiotic and non-antibiotic-mediated readthrough of nonsense mutations. These findings strongly increase our understanding of the mechanisms involved in nonsense mutation readthrough and facilitate the development of novel therapeutic targets for nonsense suppression to restore protein expression from a large variety of disease-causing mutated transcripts.

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Section: Introductionmentioning

confidence: 99%

Nonsense mutation suppression is enhanced by targeting different stages of the protein synthesis process

Wittenstein,

Caspi,

Rippin

et al. 2023

PLoS Biol

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“…48 Nonsense variants, which result in negligible full-length protein expression, can be targeted by nonsense suppression therapy, which uses small molecules that target the translational machinery to restore translation of full-length, functional protein. 49,50 Finally, proteins can be replaced, and modifier compounds can be utilized to translocate, stabilize, or otherwise help restore defective function. We consider each modality in detail and elaborate on advantages and disadvantages, their status for NF1/SWN, and examples of clinical success in Table 1.…”

Section: Currently Investigated Gene-targeted Treatment Modalities In...mentioning

confidence: 99%

Gene-targeted therapy for neurofibromatosis and schwannomatosis: The path to clinical trials

Staedtke,

Anstett,

Bedwell

et al. 2023

Clinical Trials

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Numerous successful gene-targeted therapies are arising for the treatment of a variety of rare diseases. At the same time, current treatment options for neurofibromatosis 1 and schwannomatosis are limited and do not directly address loss of gene/protein function. In addition, treatments have mostly focused on symptomatic tumors, but have failed to address multisystem involvement in these conditions. Gene-targeted therapies hold promise to address these limitations. However, despite intense interest over decades, multiple preclinical and clinical issues need to be resolved before they become a reality. The optimal approaches to gene-, mRNA-, or protein restoration and to delivery to the appropriate cell types remain elusive. Preclinical models that recapitulate manifestations of neurofibromatosis 1 and schwannomatosis need to be refined. The development of validated assays for measuring neurofibromin and merlin activity in animal and human tissues will be critical for early-stage trials, as will the selection of appropriate patients, based on their individual genotypes and risk/benefit balance. Once the safety of gene-targeted therapy for symptomatic tumors has been established, the possibility of addressing a wide range of symptoms, including non-tumor manifestations, should be explored. As preclinical efforts are underway, it will be essential to educate both clinicians and those affected by neurofibromatosis 1/schwannomatosis about the risks and benefits of gene-targeted therapy for these conditions.

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“…5) In recent years, a new therapeutic strategy, called nonsense suppression or premature termination codon (PTC) readthrough, which promotes the insertion of an amino acid at the PTC, resulting in the production of the full-length, functional proteins, has attracted attention for genetic diseases caused by a nonsense mutation. [6][7][8][9] Several small molecules with readthrough-inducing activity have been reported (Fig. 1).…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Evaluation of Novel Triaryl Derivatives with Readthrough-Inducing Activity

Kawai,

Takashima,

Ando

et al. 2023

CHEMICAL & PHARMACEUTICAL BULLETIN

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The readthrough mechanism, which skips the premature termination codon and restores the biosynthesis of the defective enzyme, is an emerging therapeutic tactic for nonsense mutation-related diseases, such as Hurler syndrome, a type of mucopolysaccharidosis. In the present study, novel triaryl derivatives were synthesized and their readthrough-inducing activities were evaluated by a luciferase reporter assay with a partial α-L-iduronidase (IDUA) DNA sequence containing the Q70X nonsense mutation found in Hurler syndrome and by measuring the enzyme activity of IDUA knockout cells transfected with the mutant IDUA gene. KY-516, a representative compound in which the meta position carboxyl group of the left ring of the clinically used ataluren was converted to the para position sulfamoylamino group, the central ring to triazole, and the right ring to cyanobenzene, exhibited the most potent readthrough-inducing activity in the Q70X/luciferase reporter assay. In Q70X mutant IDUA transgenic cells, KY-516 significantly increased enzyme activity at 0.1 µM. After the oral administration of KY-516 (10 mg/kg), the highest plasma concentration of KY-516 was above 5 µM in rats. These results indicate that KY-516, a novel triaryl derivative, exhibits potent readthrough-inducing activity and has potential as a therapeutic agent for Hurler syndrome.

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Readthrough compounds for nonsense mutations: bridging the translational gap

Cited by 24 publications

References 104 publications

Nonsense mutation suppression is enhanced by targeting different stages of the protein synthesis process

Nonsense mutation suppression is enhanced by targeting different stages of the protein synthesis process

Gene-targeted therapy for neurofibromatosis and schwannomatosis: The path to clinical trials

Synthesis and Evaluation of Novel Triaryl Derivatives with Readthrough-Inducing Activity

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