Focused-ultrasound mediated anti-alpha-synuclein antibody delivery for the treatment of Parkinson’s disease

Identification: Zhang, Hairong


Description

Focused-ultrasound mediated anti-alpha-synuclein antibody delivery for the treatment of Parkinson's disease
 
Hairong Zhang1, Carlos Sierra1, Nancy Kwon1, Maria Eleni Karakatsani1, Vernice R. Jackson-Lewis2, Serge Przedborski2,4, Elisa Konofagou1,3
1Ultrasound Elasticity Imaging Laboratory, Department of Biomedical Engineering, Columbia University, New York, NY, USA; 2Department of Neurology, Columbia University, New York, NY, USA; 3Department of Radiology, Columbia University, New York, NY, USA; 4Department of Pathology & Cell Biology, Columbia University, New York, NY, USA
 
Parkinson's disease (PD) results from the selective death of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc). While the specific cause of this neuronal loss remains elusive, the abnormal accumulation of alpha-synuclein (α-syn), a major constituent of Lewy bodies, is thought to play a central role in the pathology of PD. Previous studies have demonstrated the potential of immunotherapy with antibodies against α-syn, but such treatments remain ineffective due to the presence of the blood-brain barrier (BBB), which can hinder the passage of most therapeutic agents through to the brain parenchyma. Therefore, in this study, we explored the potential of focused ultrasound (FUS)-mediated delivery of anti-α-syn monoclonal antibodies to targeted brain areas for the reduction of α-syn in the A53T transgenic mice. We used an initial cohort of 10 mice (2 control, 3 FUS-only, and 5 with both FUS and antibody), where the treated mice (5-6 months old) received 3 weekly sonications on their left hippocampus, left caudate putamen, and left substantia nigra (either with or without intravenous injection of antibody). Mice were sacrificed one month after the last treatment and were double-stained for NeuN and α-syn. Quantification using a minimum error thresholding technique demonstrated reduced α-syn load in mice treated with both FUS and antibody compared to the control mice (p<0.05 by student's t-test), without a significant change in neuronal cell counts. Reduction of α-syn aggregation was detected bilaterally in the treated brain, indicating a possible bilateral effect of unilateral FUS treatment. The FUS treatment was found to be safe as assessed by both MRI and TUNEL staining. These findings indicate that weekly treatments with FUS and anti-α-syn antibodies can successfully reduce α-syn load in transgenic mice models of PD.
 

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