Antisense Oligonucleotide-Induced Amyloid Precursor Protein Splicing Modulation as a Therapeutic Approach for Dutch-Type Cerebral Amyloid Angiopathy

Nucleic Acid Therapeutics, vol. 31, pp. 351–363

Abstract

Dutch-type cerebral amyloid angiopathy (D-CAA) is a monogenic form of cerebral amyloid angiopathy and is inherited in an autosomal dominant manner. The disease is caused by a point mutation in exon 17 of the amyloid precursor protein ( APP ) gene that leads to an amino acid substitution at codon 693. The mutation is located within the amyloid beta (Aβ) domain of APP, and leads to accumulation of toxic Aβ peptide in and around the cerebral vasculature. We have designed an antisense oligonucleotide (AON) approach that results in skipping of exon 17, generating a shorter APP isoform that lacks part of the Aβ domain and the D-CAA mutation. We demonstrate efficient AON-induced skipping of exon 17 at RNA level and the occurrence of a shorter APP protein isoform in three different cell types. This resulted in a reduction of Aβ40 in neuronally differentiated, patient-derived induced pluripotent stem cells. AON-treated wild-type mice showed successful exon skipping on RNA and protein levels throughout the brain. These results illustrate APP splice modulation as a promising therapeutic approach for D-CAA.

Authors 9

1. Elena Daoutsali Aachen Department of Human Genetics

   Leiden University Medical Center

   Affiliation as printed

   Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands

2. Tsinatkeab T. Hailu
   Affiliation as printed

   Amylon Therapeutics, Leiden, the Netherlands

3. Ronald A.M. Buijsen Aachen Department of Human Genetics

   Leiden University Medical Center

   Affiliation as printed

   Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands

4. Barry A. Pepers Aachen Department of Human Genetics

   Leiden University Medical Center

   Affiliation as printed

   Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands

5. Linda M. van der Graaf Aachen Department of Human Genetics

   Leiden University Medical Center

   Affiliation as printed

   Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands

6. Marcel M. Verbeek

   Radboud University Nijmegen · Radboud University Medical Center · Donders Institute for Brain, Cognition and Behaviour

   Affiliation as printed

   Departments of Neurology and Laboratory Medicine, Radboud Alzheimer Centre, Radboud University Medical Center, Donders Institute for Brain, Cognition and Behaviour, Nijmegen, the Netherlands

7. Daniel Curtis
   Affiliation as printed

   Amylon Therapeutics, Leiden, the Netherlands

   Atalanta Therapeutics, Boston, Massachusetts, USA

8. Thomas de Vlaam
   Affiliation as printed

   Amylon Therapeutics, Leiden, the Netherlands

9. Willeke van Roon‐Mom corresponding Aachen Department of Human Genetics

   Leiden University Medical Center

   Affiliation as printed

   Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands