While there has been tremendous progress in the identification of mutations underlying human disease, the translation of this knowledge into mutation-targeted therapies still represents a major challenge. Nakamura et al. (Hum Mutat 33:198–208, 2012) report on the targeted correction of specific mutations in ATM, the gene mutated in the neurodegenerative disorder ataxia-telangiectasia (A-T). ATM is ubiquitously expressed and regulates DNA double-strand break signalling in every known cell type, so its expression and function can be conveniently monitored in lymphoblastoid cell lines from A-T patients.
The authors first identified the disease-causing ATM gene mutations in eight Japanese A-T families, and then considered splicing and nonsense mutations for their potential correction. One deep-intronic mutation created a novel acceptor splice site that activated an aberrant exon. The authors achieved a remarkable restoration of ATM protein levels in the mutant cell line just by blocking the unwanted exon with a modified antisense morpholino oligonucleotide (AMO). It is the second example of a deep-intronic mutation in the ATM gene that has successfully been bypassed with sequence-specific AMO treatment, providing a proof-of-principle for this concept.
Nonsense mutations represent another mutation type that may be amenable to pharmacological correction. Building upon their previous work, the authors attempted to suppress a premature termination codon in the patient's cell line by treatment with a second-generation readthrough compound, RTC13. They detected increased pSer1981-ATM immunoreactivity posttreatment indicating that, at a low level, some correction might be achievable.
Although these approaches will need to be elaborated further in terms of efficacy and specificity, the present study represents a significant step toward the development of personalized therapies in the treatment of not only A-T but possibly other disorders. Targeted correction of splicing in model systems has also been reported for other diseases such as beta-thalassemia, cystic fibrosis, and Duchenne muscular dystrophy. With the relatively high frequency of nonsense and splicing mutations in several genetic disorders, such strategies hold the promise to potentially help many more patients in the future.