Nonsense mutations

Question

Hello,

I am a mother of a child who has a nonsense mutation and I would like to know whether, apart from Ataluren, there were other current researchs on these mutations.

Thank you in advance.

Answer

Despite several contacts to search for information I could not, Ataluren aside, get accurate information on ongoing clinical trials targeting CFTR stop mutations. Stop mutations (also called nonsense mutations), further to cellular mechanisms of control, result in the rapid degradation of messenger RNA (mRNA) carrying the mutation.
Research for this type of mutations is the matter of three strategies:
- a first strategy is to block the mechanism of control and destruction of this mRNA to enable its translation into a truncated CFTR. This truncated protein corresponds to the reading of the gene between the initiation codon (which controls the start of synthesis) and the stop codon mutation (which controls the premature termination of the synthesis). If it is not destroyed, this truncated protein retains indeed, in a number of cases, part or all of the function of the CFTR protein. This approach has not yet reached the stage of clinical trials.
- a second strategy is to force the stop in order to continue the translation of mRNA into a complete CFTR mostly functional. This strategy, called"readthrough", was used in the case of Ataluren. The results of this Phase III clinical trial were presented at the last congress of the European society in Dublin (see answer to the question posted on ECORN "Results of studies on the project Ataluren").
- Finally, the third strategy is to modify the splicing * of pre-messenger RNA carrying the nonsense mutation in order to not include in the mRNA the part (exon) carrying the mutation. This results in a truncated protein of an inner part which may not always be required for the function of the protein. This approach called "exon skipping" is currently in Phase III clinical trials in patients with Duchenne muscular dystrophy.

Hope that answers your question.

Gilles RAULT (CRCM de Roscoff)
Fabrice LEJEUNE (Inserm, Institut Pasteur Lille)

* Splicing is the cellular process of extracting portions of the pre-messenger RNA and joining up the remaining portions to form messenger RNA

13.11.2012