ANTISENSE OLIGONUCLEOTIDE THERAPY FOR D-CAA AND ALZHEIMER'S DISEASE
Summary
Leiden University Medical Center's NeuroD research group has developed an innovative antisense oligonucleotide (ASO) therapy targeting APP gene mutations, applicable to D-CAA and Alzheimer's Disease (AD). This therapy is designed to modulate APP pre-mRNA splicing, reducing harmful amyloid-beta production.
Background
D-CAA, (Dutch type cerebral amyloid angiopathy (CAA), also known as HCHWA-D or Katwijk’s disease), is caused by a point mutation in the APP gene, leading to brain bleeds and early fatality. Similarly, certain APP mutations and increased production of the harmful amyloid-beta peptide are implicated in AD. Current treatment options are limited, emphasizing the need for targeted genetic therapies.
Technology
The ASO therapy focuses on splice modulation, specifically targeting APP exon 17. This results in an APP protein lacking part of the amyloid-beta peptide sequence, thereby reducing the formation of harmful amyloid peptides.
In vitro studies and Molecular Mechanism
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Initial in vitro studies in human cell lines demonstrated the ASO therapy’s ability to induce exon 17 skipping in the APP gene, leading to an APP protein variant without the amyloid-beta peptide, a key factor in plaque formation.
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Molecular analysis confirmed the ASO's targeted action in altering APP mRNA, showcasing its precision and specificity.
Preclinical Studies in iPSC Models
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Preclinical research in patient-derived human induced pluripotent stem cells (iPSC) showed the ASO therapy's effectiveness in reducing amyloid-beta levels in vitro, a major pathological marker in D-CAA and Alzheimer's Disease, suggesting the therapy’s potential to counteract neurodegeneration.
Safety and Efficacy
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The ASO therapy maintained a favorable safety profile throughout preclinical studies, with no significant adverse effects in treated models showing no overt toxicity at the highest delivered dose.
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This ASO therapy targets APP and is applicable to all diseases with harmful amyloid-beta peptide accumulation, such as D-CAA and Alzheimer's Disease, potentially reducing amyloid-beta formation and altering disease progression. Its application extends beyond these conditions, addressing significant unmet needs in various neurodegenerative diseases.
The Alzheimer's disease market alone is expected to grow significantly, with a projected compound annual growth rate of 20.0%, increasing from $2.2 billion in 2020 to $13.7 billion by 2030 (Global Data).
The development of this therapy is led by Prof. Dr. Willeke van Roon-Mom and her team of the NeuroD research group in the LUMC. The team combines expertise in molecular neuroscience, genetic therapies, and clinical neurology.
The technology has patent applications in the national phase in the US, CA, EP, NZ and AU – (WO2017064308A1).
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Targets APP mutations in Alzheimer's Disease and D-CAA, aiming to reduce amyloid-beta formation and potentially slow disease progression.
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Demonstrated efficacy in reducing amyloid-beta in patient cell lines, indicating potential for disease modification.
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