Stanford University

Noninvasive Focused Ultrasound Accelerates Glymphatic Transport to Bypass the Blood-Brain Barrier

Muna Aryal, PhDPostdoctoral Fellow

Department of Radiology

Mentors: Drs. Raag Airan & Jeremy Dahl

SCIT SeminarJanuary 29, 2020

Stanford University

Outline

q Introduction • Meningeal Lymphatic• Glymphatic Pathway

q Ultrasonic Glymphatic Control

q Conclusions

q Future Work

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A Garbage Truck of The Brain: Meningeal Lymphatic

Louveau et al., Nature 2015.

• Immune cells• Cerebral spinal fluid• Macromolecules

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Stanford UniversityNedergaard et al., Science 2013.

A Garbage Truck of The Brain: Glymphatic PathwayProteins (Amyloid-beta (Ab), Tau oligomers

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Glymphatic Dysfunction and Therapeuticsq Clearance efficacy can decay

• Healthy aging• Alzheimer• Traumatic brain injury, • Subarachnoid hemorrhage • Strokes (Hemorrhagic, Ischemic)• Idiopathic normal pressure

hydrocephalus• Diabetes Mellitus Type 2

Nedergaard et al., Science 2013. Meng et al, Ann Neurol. 2019. 4/25

Stanford UniversityNedergaard et al., Science 2013. Meng et al, Ann Neurol. 2019.

Glymphatic Dysfunction and Therapeuticsq Clearance efficacy can decay

• Healthy aging• Alzheimer• Traumatic brain injury, • Subarachnoid hemorrhage • Strokes (Hemorrhagic, Ischemic)• Idiopathic normal pressure

hydrocephalus• Diabetes Mellitus Type 2

q Glymphatic Transport: novel therapeutic target to optimize and maintain the brain health

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Approaches to Accelerates Glymphatic Flow

• Physical exercise• Changes in body posture• Intake of omega-3

polyunsaturated fatty acids• Low dose alcohol (0.5 g/kg)

Nedergaard et al., Science 2013. Meng et al, Ann Neurol. 2019. 5/25

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Approaches to Accelerates Glymphatic Flow

• Physical exercise• Changes in body posture• Intake of omega-3

polyunsaturated fatty acids• Low dose alcohol (0.5 g/kg)

• FUS-BBBO clearing the Ab in alzhiemer’s disease model

Nedergaard et al., Science 2013. Meng et al, Ann Neurol. 2019. 5/25

Stanford University

Approaches to Accelerates Glymphatic Flow

• Physical exercise• Changes in body posture• Intake of omega-3

polyunsaturated fatty acids• Low dose alcohol (0.5 g/kg)

• FUS-BBBO clearing the Ab in alzhiemer’s disease model

Nedergaard et al., Science 2013. Meng et al, Ann Neurol. 2019. 5/25

Stanford University

Limitations of BBBO

• Spatial Resolution is limited for neurodegenerative diseases that needs global treatment like Alzheimer’s and infiltrating/metastatic tumor and for other

• Disrupting the BBB by FUS induces sterile inflammation, Kovacs et al. PNAS 2017

• BBB breakdown is an early biomarker of human cognitive dysfunction, Nation et al. Nature medicine 2019

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Supportive Data

• BBBO helps to distribute drug homogeneously in tumor

• Ultrasound is accelerating the bulk flow of interstitial fluid

N+F

T+FT-F

N-F

Segmentation map of MALDI-MS imaging

BBBOTumor

No BBBOTumor

(Drug: Maroon color in map)BBBOTumor

No BBBOTumor

Hematoxylin and Eosin Staining

Aryal et al., Under Preparation.8/25

Stanford UniversityJung B, et al. J Control Release. 2019

Supportive Data

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Supportive Data

Hersh et al., PLoS One. 2018, 10/25

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Supportive Data

Nicodemus et al. Alzheimers Dement (N Y). 201911/25

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Biological Agent Delivery via BBBO

• Panitumumumab: Epidermal growth factor receptor inhibitor cancer drug (biological therapy)

• Optically-labeled Panitumumumab: Pan800

• Test: BBBO-based drug delivery efficacy

TumorBBBO

Tumor No BBBO

HealthyBBBO

Preliminary Results22/25

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Thank you