The pathogenic p.D1108N SORL1 variant is dominant-negative and suitable for an antisense-oligonucleotide-mediated splice-modulating therapy for Alzheimer’s disease

Variants in the SORL1 gene have been identified and associated with increased risk of developing Alzheimer’s disease (AD). However, there is an unmet need for an effective approach to verify pathogenicity and treat individuals carrying SORL1 variants causal of AD before the development of symptoms. We conducted a panel of biochemical and biological assays in cell lines and iPSC-derived neurons to evaluate the pathogenicity of the SORL1 p.D1108N variant and tested for a possible dominant-negative effect by analysis of its interaction and impact on intracellular trafficking of wild-type (WT)-SORL1. We investigated the effect of deletion of exon 23 using cell biological assays and screened a panel of splice-switching antisense oligonucleotides (SSO) for their ability to exclude exon 23. Here, we demonstrate how the SORL1 p.D1108N variant, which maps to a conserved sequence position within a complement-type repeat (CR)-domain and is involved in Calcium ion coordination, is pathogenic and acts through a dominant-negative mechanism by retaining WT-SORL1 in the endoplasmic reticulum ER. We next show how SORL1 protein that lacks the 38 amino acids that correspond to the CR1 domain, encoded by the 114-base-pair exon 23, has similar activity as the full-length receptor. Finally, we identify an SSO that can be used to efficiently exclude exon 23 from SORL1 transcripts. We provide evidence that the SORL1 p.D1108N variant is pathogenic and acts through a dominant-negative mechanism, while demonstrating that therapeutic exon 23 skipping preserves receptor activity. Accordingly, carriers of the p.D1108N variant are likely suitable for an early intervention. Our study thus represents the first step towards a personalized medicine therapy for a subpopulation of patients with SORL1-associated AD. People who have particular variants of the SORL1 gene are more likely to develop Alzheimer’s disease (AD) and dementia. We undertook a study to investigate why this is the case and developed a molecule that could be used to reduce the impact of these variants. This approach could potentially be used as a treatment for people with these variants to reduce the chances of their developing Alzheimer’s Disease. Rosenberg et al. compare the activity of the endosome sorting receptor SORL1 carrying a disease-associated variant with an isoform lacking the disease exon. p.D1108N is shown to be a pathogenic and dominant-negative variant, and ASO-induced exon-skipping represents a therapeutic strategy to avoid Alzheimer’s disease for carriers.