Quanto può essere efficace un approccio di read-through per le patologie legate al gene CDKL5?
Mutations in the X-linked cyclin dependent kinase-like gene (CDKL5) cause a broad spectrum of neuropsychiatric disorders that affect both genders and generally share the common features of severe intellectual disability and early drug-resistant epilepsy. One group of patients is represented by those harboring PTCs (Premature Termination Codons) that collectively account for roughly 15% of CDKL5 cases and that might benefit from the treatment with “read-through” drugs, permitting to suppress specific nonsense mutations. We believe that there are many “unknowns” that must become “knowns” before read-through drugs can be applied to treat CDKL5 patients. The administration of the best “read-through” drug for each specific PTC is certainly an important consideration. Further, since the amino acid substituted at each nonsense codon by read-through might lead to a missense mutation, it becomes imperative testing whether the full-length “read-through” CDKL5 protein retains proper functions.
Our study demonstrates for the first time that read-through occurs quite efficiently on CDKL5 and that several nonsense mutations, independently from the type of stop codon, can be suppressed by aminoglycosides. However, the functional characterization of the restored full-length CDKL5 causes some concerns on the potential efficacy of a CDKL5 nonsense suppression therapy. Indeed, our results demonstrate that although all the analyzed read-through CDKL5 proteins manifest a full-recovery of the subcellular distribution, they are unable to rescue the catalytic activity that remains significantly hypomorphic. To conclude, our results suggest that read-through therapy might be an opportunity for a selected cohort of CDKL5 patients, although indicating some limitations. We believe that further studies involving genetically modified human cells and mouse models will be fundamental to understand whether read-through therapy permits to obtain sufficient levels of functional CDKL5 to induce relevant neurological rescue.
RNA Biol. 2019 Jun 23:1-10. doi: 10.1080/15476286.2019.1632633. [Epub ahead of print]
Aminoglycoside drugs induce efficient read-through of CDKL5 nonsense mutations, slightly restoring its kinase activity.
Fazzari M, Frasca A, Bifari F, Landsberger N
Prof. Nicoletta Landsberger
Dr.ssa Maria Fazzari
Dr.ssa Angelisa Frasca
Dip. di Biotecnologie Mediche e Medicina Traslazionale
Università degli Studi di Milano
Via F.lli Cervi, 93
20090 Segrate (MI)