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Optimizing Direct Delivery of Nucleic Acid Therapeutics

Award Number: R41MH119804
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/13/2019
PERIOD OF PERFORMANCE END DATE: 09/17/2019

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Optimizing Direct Delivery of Nucleic Acid Therapeutics - Project Summary While nucleic acid therapeutics have shown promise in rodent and nonhuman primate models of CNS diseases, all double blind clinical trials to date have failed. One likely explanation for this failure is poor therapeutic distribution in targeted brain regions. For example, post-mortem studies of patients with Parkinson's Disease receiving intraparenchymal injections of AAV-NTN demonstrated very limited protein expression. In this study, only 10-16% of the transgene was observable post-mortem using a standard injection approach with a maximum of 15% of TH up- regulation. Although the results of this study were disappointing, there is strong evidence that this gene therapy approach is valid and is capable of being highly effective. A primary difference between non-human primate studies and human trials has been that the monkeys receive a wide distribution of infection, while infection in humans is dramatically reduced due to the much larger brain volumes. Based on the results of the studies conducted by Ceregene (AAV-NTN), Sanofi-Genzyme (AAV-hAADC), and Neurologix (AAV-GAD), we conclude that the failure of these clinical trials was due in part to inadequate therapeutic delivery. Today, distribution of therapeutic to a brain region such as the striatum requires multiple trajectories per hemisphere using a large gauge cannula. Performing serial infusions using a straight cannula along multiple trajectories extends surgical time and increases the risk of hemorrhage and tissue trauma. A new system is needed to improve the efficiency and effectiveness of nucleic acid therapeutic delivery in the brain. We propose development of an MR-compatible stereotactic delivery device capable of achieving widespread nucleic acid therapeutic coverage of common CNS disease targets. The device will be tested in rats using a viral vector substitute. The proposed delivery technology is nonspecific and could be applied to the treatment of a wide range of CNS conditions where nucleic acid therapeutics are being investigated, including Huntington’s Disease (IONIS-HTT), Parkinson's Disease (VY-AADC), and Sanfilippo syndrome (LYS-SAF302).


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: 2023 ( Subtotal = -$12,183 )
2023	2019	FHC, INC.	1201 MAIN ST	WEST BOWDOIN	ME	04287	SAGADAHOC	USA	Mental Health Research Grants	000	1	10/24/2022	SUPPLEMENT FOR EXPANSION	-$12,183
														Subtotal = -$12,183

Issue Date FY: 2021 ( Subtotal = $0 )
2021	2018	FHC, INC.	1201 MAIN ST	WEST BOWDOIN	ME	04287	SAGADAHOC	USA	Mental Health Research Grants	000	1	12/22/2020	NEW	$0
														Subtotal = $0

Issue Date FY: 2019 ( Subtotal = $99,439 )
2019	2019	FHC, INC.	1201 MAIN ST	WEST BOWDOIN	ME	04287	SAGADAHOC	USA	Mental Health Research Grants	002	1	9/18/2019	SUPPLEMENT FOR EXPANSION	$99,439
2019	2018	FHC, INC.	1201 MAIN ST	WEST BOWDOIN	ME	04287	SAGADAHOC	USA	Mental Health Research Grants	000	1	2/19/2019	NEW	$0
2019	2018	FHC, INC.	1201 MAIN ST	WEST BOWDOIN	ME	04287	SAGADAHOC	USA	Mental Health Research Grants	001	1	6/4/2019	NEW	$0
														Subtotal = $99,439

Issue Date FY: 2018 ( Subtotal = $303,381 )
2018	2018	FHC, INC.	1201 MAIN ST	WEST BOWDOIN	ME	04287	SAGADAHOC	USA	Mental Health Research Grants	000	1	9/18/2018	NEW	$303,381
														Subtotal = $303,381

Grand Total All Awards = $390,637

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Optimizing Direct Delivery of Nucleic Acid Therapeutics

Award Number: R41MH119804

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/13/2019

PERIOD OF PERFORMANCE END DATE: 09/17/2019

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