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Protracted CLN3 Batten disease in mice that genetically model an exon-skipping therapeutic approach
Jessica L Centa1, Matthew P Stratton1,2, Melissa A Pratt3
1Center for Genetic Diseases, Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL 60064, USA.
Abstract:
Genetic mutations that disrupt open reading frames and cause translation termination are frequent causes of human disease and are difficult to treat due to protein truncation and mRNA degradation by nonsense-mediated decay, leaving few options for traditional drug targeting. Splice-switching antisense oligonucleotides offer a potential therapeutic solution for diseases caused by disrupted open reading frames by inducing exon skipping to correct the open reading frame. We have recently reported on an exon-skipping antisense oligonucleotide that has a therapeutic effect in a mouse model of CLN3 Batten disease, a fatal pediatric lysosomal storage disease. To validate this therapeutic approach, we generated a mouse model that constitutively expresses the Cln3 spliced isoform induced by the antisense molecule. Behavioral and pathological analyses of these mice demonstrate a less severe phenotype compared with the CLN3 disease mouse model, providing evidence that antisense oligonucleotide-induced exon skipping can have therapeutic efficacy in treating CLN3 Batten disease. This model highlights how protein engineering through RNA splicing modulation can be an effective therapeutic approach.
Insights
Antisense oligonucleotides can correct genetic mutations causing diseases like CLN3 Batten disease by inducing exon skipping. This approach shows therapeutic efficacy in a novel mouse model, offering new treatment possibilities.
Area of Science:
- Genetics
- Molecular Biology
- Therapeutics
Background:
- Genetic mutations causing premature translation termination lead to truncated proteins and mRNA degradation, posing challenges for disease treatment.
- Nonsense-mediated decay exacerbates disease severity by eliminating faulty mRNA transcripts.
- Splice-switching antisense oligonucleotides (ASOs) offer a novel therapeutic strategy by modulating RNA splicing.
Purpose of the Study:
- To validate the therapeutic potential of exon-skipping ASOs in CLN3 Batten disease.
- To generate and characterize a mouse model expressing a corrected CLN3 isoform.
- To assess the efficacy of ASO-induced splicing modulation in a disease context.
Main Methods:
- Development of an exon-skipping antisense oligonucleotide targeting CLN3.
- Generation of a mouse model constitutively expressing the ASO-induced CLN3 spliced isoform.
- Behavioral and pathological analysis of the generated mouse model and comparison with a CLN3 disease model.
Main Results:
- The generated mouse model exhibited a less severe phenotype compared to the CLN3 disease model.
- Antisense oligonucleotide-induced exon skipping demonstrated therapeutic efficacy in ameliorating disease characteristics.
- The study provides evidence for the effectiveness of RNA splicing modulation as a therapeutic strategy.
Conclusions:
- Antisense oligonucleotide-induced exon skipping is a viable therapeutic approach for CLN3 Batten disease.
- Protein engineering via RNA splicing modulation can effectively treat genetic disorders.
- This research validates ASOs as a promising therapeutic modality for diseases caused by genetic mutations affecting mRNA splicing.
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