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Published on: October 3, 2011
Therapeutic efficacy of antisense oligonucleotides in mouse models of CLN3 Batten disease
Jessica L Centa1,2, Francine M Jodelka1, Anthony J Hinrich1
1Center for Genetic Diseases, Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL, USA.
Abstract:
CLN3 Batten disease is an autosomal recessive, neurodegenerative, lysosomal storage disease caused by mutations in CLN3, which encodes a lysosomal membrane protein1-3. There are no disease-modifying treatments for this disease that affects up to 1 in 25,000 births, has an onset of symptoms in early childhood and typically is fatal by 20-30 years of life4-7. Most patients with CLN3 Batten have a deletion encompassing exons 7 and 8 (CLN3∆ex7/8), creating a reading frameshift7,8. Here we demonstrate that mice with this deletion can be effectively treated using an antisense oligonucleotide (ASO) that induces exon skipping to restore the open reading frame. A single treatment of neonatal mice with an exon 5-targeted ASO-induced robust exon skipping for more than a year, improved motor coordination, reduced histopathology in Cln3∆ex7/8 mice and increased survival in a new mouse model of the disease. ASOs also induced exon skipping in cell lines derived from patients with CLN3 Batten disease. Our findings demonstrate the utility of ASO-based reading-frame correction as an approach to treat CLN3 Batten disease and broaden the therapeutic landscape for ASOs in the treatment of other diseases using a similar strategy.
Insights
Antisense oligonucleotides (ASOs) offer a promising new treatment for CLN3 Batten disease by correcting the genetic reading frame. This approach successfully improved symptoms and survival in mouse models and patient-derived cells.
Area of Science:
- Neuroscience
- Genetics
- Molecular Biology
Background:
- CLN3 Batten disease is a fatal neurodegenerative lysosomal storage disorder with no current disease-modifying treatments.
- Mutations in the CLN3 gene, particularly a common deletion (CLN3∆ex7/8), disrupt the lysosomal membrane protein and cause disease onset in early childhood.
- The genetic defect leads to a frameshift, preventing the production of functional CLN3 protein.
Purpose of the Study:
- To investigate the therapeutic potential of antisense oligonucleotides (ASOs) for CLN3 Batten disease.
- To determine if ASO-induced exon skipping can restore the open reading frame and ameliorate disease phenotypes.
- To evaluate ASO efficacy in preclinical models, including mouse models and patient-derived cell lines.
Main Methods:
- Development and application of an exon 5-targeted ASO in neonatal Cln3∆ex7/8 mice.
- Assessment of ASO-induced exon skipping, motor function, histopathology, and survival.
- Validation of ASO-induced exon skipping in cell lines derived from CLN3 Batten disease patients.
Main Results:
- A single ASO treatment in neonatal mice led to sustained exon skipping for over a year.
- Treated mice showed improved motor coordination and reduced neuropathology.
- The ASO treatment significantly increased survival in a novel mouse model of the disease.
- Exon skipping was also successfully induced in patient-derived cell lines.
Conclusions:
- ASO-mediated reading-frame correction is a viable therapeutic strategy for CLN3 Batten disease.
- This approach demonstrates significant preclinical efficacy, improving key disease markers and survival.
- The findings support the broader application of ASO-based strategies for treating genetic disorders caused by similar frameshift mutations.
