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Nonsense codons suppression. An acute toxicity study of three optimized TRIDs in murine model, safety and
Federica Corrao1, Maria Grazia Zizzo1, Marco Tutone1
1Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, University of Palermo, Palermo, Italy.
Abstract:
Stop mutations cause 11% of the genetic diseases, due to the introduction of a premature termination codon (PTC) in the mRNA, followed by the production of a truncated protein. A promising therapeutic approach is the suppression therapy by Translational Readthrough Inducing Drugs (TRIDs), restoring the expression of the protein. Recently, three new TRIDs (NV848, NV914, NV930) have been proposed, and validated by several in vitro assays, for the rescue of the CFTR protein, involved in Cystic Fibrosis disease. In this work, an acute toxicological study for the three TRIDs was conducted in vivo on mice, according to the OECD No.420 guidelines. Animals were divided into groups and treated with a single dose of TRIDs molecules or Ataluren, an FDA-approved TRID molecule, as control. Mice were observed continuously for the first day post-drugs administration and the behavioral changes were recorded. On the 15th day, animals were sacrificed for histological examinations. The results showed that acute administration of 2000 mg/kg of NV914 and Ataluren and 300 mg/kg of NV848 or NV930, did not induce any mortality within 14 days. Moreover, histopathological analysis of treated mice showed no differences when compared to the experimental controls. In summary, our results suggest a good tolerability for the three molecules, and include NV848 and NV930 in a category 4 and NV914 in a category 5 of the Globally Harmonized System (GHS) of Classification and Labeling of Chemicals, classifying these compounds in a low-risk scale for health.
Insights
Three new Translational Readthrough Inducing Drugs (TRIDs) show good tolerability in mice. These drugs, NV848, NV914, and NV930, are potential treatments for genetic diseases caused by stop mutations, with low health risks.
Area of Science:
- Pharmacology
- Toxicology
- Genetics
Background:
- Stop mutations leading to premature termination codons (PTCs) cause 11% of genetic diseases by producing truncated proteins.
- Translational Readthrough Inducing Drugs (TRIDs) offer a therapeutic strategy to restore full-length protein expression.
- Three novel TRIDs (NV848, NV914, NV930) have shown promise in vitro for rescuing CFTR protein expression, relevant to Cystic Fibrosis.
Purpose of the Study:
- To evaluate the acute toxicity of three novel TRIDs (NV848, NV914, NV930) in vivo using a mouse model.
- To assess the safety profile of these TRIDs compared to Ataluren, an established TRID, following OECD No.420 guidelines.
Main Methods:
- An acute toxicological study was performed on mice according to OECD No.420 guidelines.
- Animals received single high doses of NV848, NV914, NV930, or Ataluren.
- Mice were monitored for mortality and behavioral changes for 14 days, followed by histological examination.
Main Results:
- No mortality was observed within 14 days at doses up to 2000 mg/kg for NV914 and Ataluren, and 300 mg/kg for NV848 and NV930.
- Histopathological analysis revealed no significant differences between treated groups and control groups.
- The results indicate good tolerability and a low health risk profile for the tested TRIDs.
Conclusions:
- The novel TRIDs NV848, NV914, and NV930 demonstrate good acute tolerability in vivo.
- These findings support the classification of NV848 and NV930 under GHS Category 4, and NV914 under Category 5, indicating a low risk scale for health.
- The study provides crucial safety data for the further development of these TRIDs as potential therapeutics for genetic diseases.
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