Protracted CLN3 Batten disease in mice that genetically model an exon-skipping therapeutic approach

Jessica L Centa; Matthew P Stratton; Melissa A Pratt; Jenna R Osterlund Oltmanns; Douglas G Wallace; Steven A Miller; Jill M Weimer; Michelle L Hastings

doi:10.1016/j.omtn.2023.05.025

Protracted CLN3 Batten disease in mice that genetically model an exon-skipping therapeutic approach

Mol Ther Nucleic Acids. 2023 Jun 3:33:15-27. doi: 10.1016/j.omtn.2023.05.025. eCollection 2023 Sep 12.

Authors

Jessica L Centa¹, Matthew P Stratton^{1

2}, Melissa A Pratt³, Jenna R Osterlund Oltmanns⁴, Douglas G Wallace⁴, Steven A Miller⁵, Jill M Weimer^{3

6}, Michelle L Hastings^{1

7}

Affiliations

¹ Center for Genetic Diseases, Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL 60064, USA.
² School of Graduate and Postdoctoral Studies, Rosalind Franklin University of Medicine and Science, North Chicago, IL 60064, USA.
³ Pediatrics and Rare Diseases Group, Sanford Research, Sioux Falls, SD 57104, USA.
⁴ Department of Psychology, Northern Illinois University, DeKalb, IL 60115, USA.
⁵ Psychology Department, College of Health Professionals, Rosalind Franklin University of Medicine and Science, North Chicago, IL 60064, USA.
⁶ Department of Pediatrics, Sanford School of Medicine, University of South Dakota, Sioux Falls, SD 57104, USA.
⁷ Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI 48109, 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.

Keywords: MT: Oligonucleotides: Therapies and Applications; antisense oligonucleotides/CLN3 Batten disease/exon skipping/lysosomal storage disease/pre-mRNA splicing.

Grants and funding

R01 NS113233/NS/NINDS NIH HHS/United States