A 12.6% knockdown of ε4 gene expression was achieved in the mouse hippocampus using .
Focused ultrasound (FUS) successfully opened the blood-brain barrier to enhance gene editing delivery.
The knockdown of APOE ε4 was associated with over a 20% decrease in apoE4 protein levels.
Significant reductions in astrocyte and microglia levels were observed following the APOE ε4 knockdown.
No detectable gross toxicity was found after the FUS-mediated gene editing.
Simplified
INTRODUCTION: The apolipoprotein E () ε4 allele is widely recognized as the strongest genetic risk factor for late-onset Alzheimer's disease. Therapeutic strategies to reduce apoE4 expression in APOE ε4 carriers hold promise to mitigate neuroinflammatory and neurodegenerative processes driving disease progression.
METHODS: (FUS) was employed to transiently open the blood-brain barrier (BBB) for efficient knockdown of humanized APOE ε4 in the mouse brain via gene editing. The all-in-one clustered regularly interspaced short palindromic repeats (CRISPR)-based adeno-associated virus (AAV) vectors were administered intravenously at a dose of 1.5×10vg per mouse to determine the gene-editing efficacy within the hippocampus. 12
RESULTS: FUS-enhanced delivery of AAV resulted in a 12.6% knockdown of APOE ε4 gene expression in the targeted hippocampus, accompanied by an over 20% decrease in apoE4 protein levels and significant reductions in astrocyte and microglia levels.
DISCUSSION: Our findings demonstrate a noninvasive, targeted approach for APOE ε4 knockdown, highlighting FUS-mediated brain-directed interventions as a promising therapeutic strategy for Alzheimer's disease.
HIGHLIGHTS: Focused ultrasound (FUS) enables noninvasive, transient blood-brain barrier (BBB) opening for enhanced adeno-associated virus (AAV) delivery. FUS-mediated gene editing achieves a 12.6% knockdown in APOE ε4 expression within the hippocampus of mouse brain. APOE ε4 knockdown significantly reduces apoE4 protein levels and astrocyte and microglia levels. No detectable gross toxicity was observed following the FUS-mediated gene editing.
Key numbers
12.6%
ε4 Knockdown
Percentage reduction in ε4 gene expression in the hippocampus.
over 20%
Reduction in apoE4 Protein Levels
Percentage decrease in apoE4 protein levels following gene editing.
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Some of the work presented herein is supported by patents optioned to Delsona Therapeutics, Inc., where Elisa E. Konofagou serves as a co‐founder and scientific adviser. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Author disclosures are available in supporting information.
