Novel Genome-editing Strategy for Familial Alzheimer’s Disease Therapy

Given that over 400 genetic mutations in the population can cause familial Alzheimer’s disease (FAD) and the pathologies affect multiple brain regions, developing effective genome-editing strategies for FAD requires tackling two key challenges: targeting different disease-causing mutations with a single tool and enabling efficient genome editing across various brain regions. Our novel genome-editing approach successfully addresses these challenges: the “one-for-many” feature allows targeting multiple mutations with one tool, while the “brain-wide” feature ensures widespread genome editing throughout the brain. With these advancements, this innovative genome-editing approach enables the development of a long-lasting, disease-modifying treatment for FAD.

• First-in-class solution: This genome-editing strategy represents a groundbreaking therapeutic approach, offering the first-in-class solution to address the unmet medical needs of familial Alzheimer’s disease (FAD).
• Novel “one-for-many” strategy: Traditional technologies require developing a custom genome-editing tool for each disease-causing mutation. With over 400 FAD-associated genetic mutations, this would necessitate the development of more than 400 tools, which is impractical. This groundbreaking “one-for-many” genome-editing strategy addresses this challenge by employing a single set of editing tool to cover distinct disease-causing mutations within a target gene across different patients.
• Brain-wide beneficial effects: Traditional genome-editing strategies for brain disorders are delivered via intraparenchymal injection, which affects limited brain regions. With the first engineered delivery vehicle, the new technology can effectively cross the blood-brain barrier, enabling efficient genome editing among the whole brain and hence generating beneficial therapeutic effects throughout the brain.

• “Once-for-all” treatment effect: This genome-editing therapy can tackle familial Alzheimer’s disease (FAD) at it root to provide long-lasting benefits.
• Broad applicability: The “one-for-many” strategy can be applied to many patients with distinct disease-causing mutations, achieving a practical and cost-effective approach to drug development for FAD.
• Targeted intervention: Precise gene-targeting technology is used to selectively edit only the mutated gene copy while keeping the normal gene copy intact in patients. This approach ensures safety by preserving physiological functions.
• Proven effectiveness: The “brain-wide” strategy has been validated in FAD mouse models, demonstrating significant efficacy with consistent reductions in Aβ levels, a hallmark of AD pathologies.

• Major Progress Award for Neuroscience in China (2021)
• Gold Medal, International Exhibition of Inventions Geneva (2024)

• This genome-editing strategy has implications beyond familial Alzheimer’s disease. It could potentially be applied to other autosomal dominant diseases that affect over 160 million patients worldwide.

• US Provisional 63/272689: Brain-Wide Genome Editing via an All-in-One AAV Vector and Treat Familial Alzheimer’s Mutations
• US Provisional 63/334650: CRISPR-Mediated Manipulation of APP Expression as a Therapeutic Approach for Alzheimer’s Disease
• US Provisional 63/582523: Mutation-independent allele-specific CRISPR targeting strategy for familial Alzheimer’s disease