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Improved Delivery of Gene Therapies to the Central Nervous System by Focused Ultrasound-Mediated Disruption of the Blood-Brain Barrier

Award Number: R01NS123557
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Improved Delivery of Gene Therapies to the Central Nervous System by Focused Ultrasound-Mediated Disruption of the Blood-Brain Barrier - Project Summary: A major challenge faced by all gene therapies directed to the central nervous system is delivering the therapy across the blood-brain barrier (BBB) in a way that achieves adequate central exposure while minimizing toxicity in non-targeted tissues. The two most common routes of administration for delivering adeno-associated viral (AAV) vectors, the only FDA-approved gene transfer platform for neurological applications, suffer from complimentary limitations. Intravenous (IV) injection can achieve widespread distribution throughout the brain but only at low concentration levels, while intraparenchymal (IPa) injections supply a high concentration of therapy but only near the site of injection. As most neurological disorders manifest in multiple brain regions, successful gene therapy treatments will require an improved approach to AAV delivery that can achieve high therapy concentration and large volume coverage. To address this critical bottleneck, we aim to develop and validate delivery strategies using the technology of focused ultrasound (FUS)-mediated disruption of the BBB to significantly improve the concentration and brain coverage of AAV-packaged gene therapies. In this project we will investigate the application of delivering an AAV-packaged micro-RNA therapy targeting suppression of mutant Huntingtin, the gene implicated in Huntington’s disease (HD). Our preliminary work demonstrates that FUS-BBB opening enhances the delivery of IV-injected AAV1 and AAV9 vectors to targeted brain regions in wild-type and HD model mice. We additionally have experience using our human clinical FUS system to achieve large-volume BBB disruption in rats, monkeys and humans. Building off this preliminary data, Aim 1 will determine the optimal FUS parameters and AAV dose for maximizing AAV concentration at the FUS-targeted site in HD model mice. The safety profile of each treatment will be characterized in terms of markers of neuroinflammation and signs of trauma-like damage to tissue. To maximize brain coverage, we will characterize the safety profile and AAV delivery efficacy as a function of BBB opening volume in HD model mice. Aim 2 will incorporate the information gained in Aim 1 to devise an optimal treatment strategy that balances high AAV concentration, large volume coverage and safety. We will assess the safety and therapeutic efficacy of delivering an AAV-packaged microRNA to HD model mice at 1-, 3- , 6- and 12-month time points in terms of mHTT lowering and functional markers of disease progression. In Aim 3, all of the mice data will be used to devise a treatment strategy for AAV delivery in rhesus macaque monkeys. A safety and biodistribution study will be carried out in these non-human primates using our human clinical FUS system. If successful, the strategies developed here would enable AAV delivery to the brain with a more favorable safety and efficacy profile than existing alternatives and unlock the clinical promise of these transformative therapies.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $524,739 )
2025	2025	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	3/18/2025	NON-COMPETING CONTINUATION	$524,739
														Subtotal = $524,739

Issue Date FY: 2024 ( Subtotal = $393,815 )
2024	2024	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	4/1/2024	NON-COMPETING CONTINUATION	$393,815
														Subtotal = $393,815

Issue Date FY: 2023 ( Subtotal = $403,573 )
2023	2023	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	3/29/2023	NON-COMPETING CONTINUATION	$403,573
														Subtotal = $403,573

Issue Date FY: 2022 ( Subtotal = $469,441 )
2022	2022	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	4/25/2022	NEW	$469,441
2022	2022	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	1	5/6/2022	NEW	$0
														Subtotal = $469,441

Grand Total All Awards = $1,791,568

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Improved Delivery of Gene Therapies to the Central Nervous System by Focused Ultrasound-Mediated Disruption of the Blood-Brain Barrier

Award Number: R01NS123557

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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