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Therapeutic antisense oligonucleotide mitigates retinal dysfunction in a pig model of CLN3 Batten disease
Journal article   Peer reviewed

Therapeutic antisense oligonucleotide mitigates retinal dysfunction in a pig model of CLN3 Batten disease

Matthew P Stratton, Jessica L Centa, Vicki J Swier, Wanda L Pfeifer, Clarissa D Booth, Karlee Albert, John L Hunyara, Mitchell J Rechtzigel, Fox J Duelli, Hannah G Leppert, …
Nucleic acids research, Vol.53(20), gkaf1141
10/28/2025
DOI: 10.1093/nar/gkaf1141
PMCID: PMC12585909
PMID: 41189054

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Abstract

CLN3 Batten disease is a lethal pediatric neurodegenerative disease caused by mutations in the CLN3 gene. Typically, the disease manifests as vision loss in early childhood and progresses to neurological dysfunction and death in young adulthood. Most therapeutic developments have focused on treating the brain and may not protect against vision loss, which greatly affects quality of life. We have previously shown that a splice-switching antisense oligonucleotide (ASO) delivered to the central nervous system can reduce neurological disease burden in mouse models of CLN3 disease. Here, we apply a similar ASO approach for treating retinal dysfunction in a pig model of CLN3 Batten disease, which is more representative of human vision. A single intravitreal injection of ASO induces robust exon skipping in the retina for up to 12 months. The ASO treatment resulted in higher amplitudes on electroretinograms, suggesting mitigation of retinal dysfunction at early timepoints of disease. One ASO that efficiently induces exon skipping in vivo was well-tolerated and targets a region conserved in humans, making it a promising candidate for clinical translation. Our findings demonstrate the utility of an ASO-based approach to treat retinal dysfunction in CLN3 Batten disease and support broader ASO applications for treating ocular diseases.
 Animals Disease Models, Animal Electroretinography Exons Humans Intravitreal Injections Membrane Glycoproteins - genetics Molecular Chaperones - genetics Neuronal Ceroid-Lipofuscinoses - drug therapy Neuronal Ceroid-Lipofuscinoses - genetics Neuronal Ceroid-Lipofuscinoses - pathology Neuronal Ceroid-Lipofuscinoses - physiopathology Neuronal Ceroid-Lipofuscinoses - therapy Oligonucleotides, Antisense - administration & dosage Oligonucleotides, Antisense - genetics Oligonucleotides, Antisense - therapeutic use Retina - drug effects Retina - metabolism Retina - pathology Retina - physiopathology Swine

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