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Oligodendrocyte-focused rAAV gene therapy strategies for Canavan disease and Leukodystrophies

Award Number: R01NS076991
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2012
PERIOD OF PERFORMANCE END DATE: 01/31/2030

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Oligodendrocyte-focused rAAV gene therapy strategies for Canavan disease and Leukodystrophies - PROJECT SUMMARY Zolgensma, an FDA-approved gene therapy, employs recombinant adeno-associated virus (rAAV) to treat spinal muscular atrophy (SMA). However, toxicity and even death have been reported in patients, potentially due to widespread transgene expression caused by a constitutively active and ubiquitous promoter. Consequently, we have developed a second-generation therapy employing a cell type-specific promoter to enhance efficacy while mitigating toxicity. Similarly, Canavan disease (CD), a leukodystrophy linked to the aspartoacylase (ASPA) gene, is targeted with rAAV-based gene therapy using a constitutively active and ubiquitous promoter, which has generated off-target effects in mouse and human. To bolster safety and efficacy, we have devised a novel ASPA promoter derived from the endogenous ASPA regulatory elements to emulate endogenous ASPA expression. In addition, understanding the regulation of the ASPA promoter aims at further improving specificity and therapeutic efficacy of the novel ASPA promoter (Aim 2). While rAAV's efficacy in transducing neurons is well-documented—beneficial for disorders like SMA—the understanding of rAAV's transduction of oligodendrocytes, the target cells in CD, is sparse. These cells play pivotal roles in neurodegenerative diseases such as Leukodystrophies, multiple sclerosis, and Alzheimer’s; hence, understanding their transduction by rAAV is crucial and has the potential to benefit diseases with oligodendrocyte involvement. Furthermore, understanding the mechanism of AAV capsid-oligodendrocyte interaction could inform novel capsid design for oligodendrocyte targeting and, together with a transgene- specific promoter, improve specificity and safety of oligodendrocyte-targeted rAAV gene therapy for CD (Aim 1). In conclusion, the urgent need to comprehend oligodendrocyte transduction, along with the promising advancements in gene therapy, emphasizes the significance of our study. The outcomes will enhance treatment safety and efficacy and broaden the application of gene therapy to oligodendrocyte diseases currently considered challenging to treat.


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: 2026 ( Subtotal = $477,390 )
2026	2026	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	12	1/28/2026	NON-COMPETING CONTINUATION	$477,390
														Subtotal = $477,390

Issue Date FY: 2025 ( Subtotal = $533,982 )
2025	2025	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	11	1/22/2025	COMPETING CONTINUATION	$533,982
2025	2023	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	10	11/18/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $533,982

Issue Date FY: 2023 ( Subtotal = $422,442 )
2023	2023	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	10	1/27/2023	NON-COMPETING CONTINUATION	$422,442
														Subtotal = $422,442

Issue Date FY: 2022 ( Subtotal = $422,442 )
2022	2022	UNIVERSITY OF MASSACHUSETTS	55 LAKE AVE NORTH	WORCESTER	MA	01655	WORCESTER	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	9	2/2/2022	NON-COMPETING CONTINUATION	$380,197
2022	2022	UNIVERSITY OF MASSACHUSETTS	55 LAKE AVE NORTH	WORCESTER	MA	01655	WORCESTER	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	9	4/1/2022	NON-COMPETING CONTINUATION	$42,245
														Subtotal = $422,442

Issue Date FY: 2021 ( Subtotal = $459,292 )
2021	2021	UNIVERSITY OF MASSACHUSETTS	55 LAKE AVE NORTH	WORCESTER	MA	01655	WORCESTER	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	8	2/1/2021	NON-COMPETING CONTINUATION	$459,292
														Subtotal = $459,292

Issue Date FY: 2020 ( Subtotal = $459,292 )
2020	2020	UNIVERSITY OF MASSACHUSETTS	55 LAKE AVE NORTH	WORCESTER	MA	01655	WORCESTER	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	7	2/17/2020	NON-COMPETING CONTINUATION	$459,292
														Subtotal = $459,292

Issue Date FY: 2019 ( Subtotal = $459,292 )
2019	2019	UNIVERSITY OF MASSACHUSETTS	55 LAKE AVE NORTH	WORCESTER	MA	01655	WORCESTER	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	6	4/9/2019	COMPETING CONTINUATION	$459,292
2019	2016	UNIVERSITY OF MASSACHUSETTS	55 LAKE AVE NORTH	WORCESTER	MA	01655	WORCESTER	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	12/20/2018	EXTENSION WITH OR WITHOUT FUNDS	$0
														Subtotal = $459,292

Issue Date FY: 2017 ( Subtotal = $0 )
2017	2016	UNIVERSITY OF MASSACHUSETTS	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	5	1/29/2017	EXTENSION WITH OR WITHOUT FUNDS	$16,589
2017	2015	UNIVERSITY OF MASSACHUSETTS	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	1/29/2017	NON-COMPETING CONTINUATION	-$16,589
														Subtotal = $0

Issue Date FY: 2016 ( Subtotal = $472,725 )
2016	2016	UNIVERSITY OF MASSACHUSETTS	406 GOODELL BLDG, BOX 33210	AMHERST	MA	01003	HAMPSHIRE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	9/8/2016	EXTENSION WITH OR WITHOUT FUNDS	$472,725
														Subtotal = $472,725

Issue Date FY: 2015 ( Subtotal = $472,725 )
2015	2015	UNIVERSITY OF MASSACHUSETTS	406 GOODELL BLDG, BOX 33210	AMHERST	MA	01003	HAMPSHIRE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	9/17/2015	NON-COMPETING CONTINUATION	$472,725
														Subtotal = $472,725

Issue Date FY: 2014 ( Subtotal = $467,999 )
2014	2014	UNIVERSITY OF MASSACHUSETTS	406 GOODELL BLDG, BOX 33210	AMHERST	MA	01003	HAMPSHIRE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	8/27/2014	NON-COMPETING CONTINUATION	$467,999
														Subtotal = $467,999

Issue Date FY: 2013 ( Subtotal = $454,523 )
2013	2013	UNIVERSITY OF MASSACHUSETTS	406 GOODELL BLDG, BOX 33210	AMHERST	MA	01003	HAMPSHIRE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	9/6/2013	NON-COMPETING CONTINUATION	$454,523
														Subtotal = $454,523

Issue Date FY: 2012 ( Subtotal = $502,845 )
2012	2012	UNIVERSITY OF MASSACHUSETTS	406 GOODELL BLDG, BOX 33210	AMHERST	MA	01003	HAMPSHIRE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	8/24/2012	NEW	$502,845
														Subtotal = $502,845

Grand Total All Awards = $5,604,949

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Oligodendrocyte-focused rAAV gene therapy strategies for Canavan disease and Leukodystrophies

Award Number: R01NS076991

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/01/2012

PERIOD OF PERFORMANCE END DATE: 01/31/2030

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