Prof. Michelle L. Hastings - Antisense Oligonucleotides for the Treatment of Disease
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Antisense oligonucleotides (ASOs) have proven to be an effective therapeutic platform for the treatment of disease. These short, single-stranded, modified nucleotides function by base-pairing with the complementary sequence of an RNA and modulating gene expression in a manner that is dependent on ASO design and targeting site. We have devised a number of approaches to alter splicing with ASOs to correct or improve gene expression and pathology in disease models. One of our approaches is under development for the treatment of CLN3 Batten disease, a fatal, pediatric lysosomal storage disease caused by mutations in a gene encoding the lysosomal membrane protein CLN3. The most common mutation associated with CLN3 Batten is a deletion of exons 7 and 8 (CLN3Δex78), which disrupts the mRNA open reading frame. We devised a therapeutic strategy for treating CLN3 Batten disease using an ASO that alters splicing CLN3 splicing to correct the open reading frame of the mutated transcript. Treatment of CLN3Δex78 neonatal mice with this ASO resulted in the desired splicing effect throughout the central nervous system, improved motor coordination, reduced histopathological features of the disease in the brain and extended life in a severe mouse model of the disease. Our results demonstrate that ASO-mediated reading frame correction is a promising therapeutic approach for CLN3 Batten disease.
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