Thursday, November 21, 2024 11/21/2024

Novel Lysosomal Enzyme Deficient in Batten Disease

Award Number: R01NS037918
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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View Award Abstract

The overall objective of this proposal is to develop improved methods for the treatment of the neurodegenerative lysosomal storage disorder (LSD) late infantile neuronal ceroid lipofuscinosis (LINCL). LINCL is an autosomal recessive disease due to mutations in gene encoding the lysosomal protease tripeptidyl peptidase 1 (TPP1). In the absence of effective treatment, LINCL is characterized by increasingly severe seizures, dementia, loss of vision and motor skills, and early death, typically at 8-15 years of age. Previous NIH-supported research from our group provided a firm underpinning for development of Brineura, the first FDA-approved enzyme replacement therapy for a neurodegenerative LSD. This was a breakthrough but there is considerable room for improvement. The current approved therapy involves intracerebroventricular administration of recombinant human TPP1 to the brain via the cerebrospinal fluid (CSF), a delivery method that is invasive and carries risk of infectious and non-infectious complications when used for chronic treatment. More importantly, animal studies in mouse, dog and monkey indicate that the distribution of recombinant TPP1 is not uniform throughout the brain when it is administered to the CSF, with regions proximal to the CSF receiving most TPP1 while regions distal receiving little or none. In LINCL patients, a failure to adequately treat specific brain regions that are distal to the site of administration remains a cause for concern and could have significant and possibly fatal long-term consequences. This proposal aims to continue the trajectory of our LINCL research with an integrated effort to use existing and novel animal models to develop improved therapies. In Aim 1, we will continue development of recombinant TPP1 derivatives that can cross the blood brain barrier. Given that the brain is highly vascularized, bloodstream- mediated delivery will likely provide the most uniform distribution of TPP1 throughout the brain. Promising candidates will initially be evaluated in our LINCL mouse model. In Aim 2, in which we will identify candidate CSF and blood biomarkers for LINCL that can be used for short-term monitoring of treatment efficacy. The previous aims will be integrated in Aim 3, in which chronic treatment studies will be conducted in the mouse model. These will provide proof-of-principle for effective IV-mediated treatment to be explored in larger animal models, and help validate candidate biomarkers. Convincing proof-of-principle for novel, improved treatment methods for LINCL will have significant translational implications for this disease. In addition, the majority of LSDs have a neurological component and are currently refractory to treatment. We envisage that any useful discoveries emerging from the proposed research will potentially also have a positive impact in these diseases.


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: 2024 ( Subtotal = $0 )
2024	2023	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	65 BERGEN ST	NEWARK	NJ	07107	ESSEX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	22	7/22/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2024	2022	RUTGERS, THE STATE UNIVERSITY	675 HOES LN	PISCATAWAY	NJ	08854	MIDDLESEX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	21	7/22/2024	NON-COMPETING CONTINUATION	$0
2024	2022	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	675 HOES LN	PISCATAWAY	NJ	08854	MIDDLESEX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	21	11/15/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $497,524 )
2023	2023	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	65 BERGEN ST	NEWARK	NJ	07107	ESSEX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	22	8/1/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$497,524
														Subtotal = $497,524

Issue Date FY: 2022 ( Subtotal = $497,524 )
2022	2022	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	675 HOES LN	PISCATAWAY	NJ	08854	MIDDLESEX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	21	5/18/2022	NON-COMPETING CONTINUATION	$497,524
														Subtotal = $497,524

Issue Date FY: 2021 ( Subtotal = $497,259 )
2021	2021	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	675 HOES LN	PISCATAWAY	NJ	08854	MIDDLESEX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	20	5/26/2021	NON-COMPETING CONTINUATION	$497,259
														Subtotal = $497,259

Issue Date FY: 2020 ( Subtotal = $494,355 )
2020	2020	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	675 HOES LN	PISCATAWAY	NJ	08854	MIDDLESEX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	19	8/31/2020	COMPETING CONTINUATION	$494,355
														Subtotal = $494,355

Issue Date FY: 2017 ( Subtotal = $0 )
2017	2016	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	675 HOES LN	PISCATAWAY	NJ	08854	MIDDLESEX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	18	4/4/2017	EXTENSION WITH OR WITHOUT FUNDS	$0
														Subtotal = $0

Issue Date FY: 2016 ( Subtotal = $313,031 )
2016	2016	Rutgers, The State Univ Biomedical & Health Sciences	65 Davidson Road	Piscataway	NJ	08854	MIDDLESEX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	18	12/8/2015	EXTENSION WITH OR WITHOUT FUNDS	$313,031
														Subtotal = $313,031

Issue Date FY: 2015 ( Subtotal = $347,813 )
2015	2015	Rutgers, The State Univ Biomedical & Health Sciences	65 Davidson Road	Piscataway	NJ	08854	MIDDLESEX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	17	1/13/2015	NON-COMPETING CONTINUATION	$34,782
2015	2015	Rutgers, The State Univ Biomedical & Health Sciences	65 Davidson Road	Piscataway	NJ	08854	MIDDLESEX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	17	11/19/2014	NON-COMPETING CONTINUATION	$313,031
														Subtotal = $347,813

Issue Date FY: 2014 ( Subtotal = $344,335 )
2014	2014	Rutgers, The State Univ Biomedical & Health Sciences	65 Davidson Road	Piscataway	NJ	08854	MIDDLESEX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	16	12/26/2013	NON-COMPETING CONTINUATION	$313,031
2014	2014	Rutgers, The State Univ Biomedical & Health Sciences	65 Davidson Road	Piscataway	NJ	08854	MIDDLESEX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	16	3/7/2014	NON-COMPETING CONTINUATION	$31,304
														Subtotal = $344,335

Issue Date FY: 2013 ( Subtotal = $334,408 )
2013	2013	UMDNJ, ROBERT WOOD JOHNSON MED SCH	335 GEO ST LIBERTY PLAZA 4 FL	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	14	7/24/2013	NON-COMPETING CONTINUATION	-$130,000
2013	2013	UMDNJ, ROBERT WOOD JOHNSON MED SCH	335 GEO ST LIBERTY PLAZA 4 FL	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	14	5/16/2013	NON-COMPETING CONTINUATION	$22,525
2013	2013	UMDNJ, ROBERT WOOD JOHNSON MED SCH	335 GEO ST LIBERTY PLAZA 4 FL	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	14	11/2/2012	NON-COMPETING CONTINUATION	$311,883
2013	2013	Rutgers, The State Univ Biomedical & HEALTH Sciences	65 Davidson Road	Piscataway	NJ	08554		USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	003	15	7/25/2013	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$130,000
														Subtotal = $334,408

Issue Date FY: 2012 ( Subtotal = $367,817 )
2012	2012	UMDNJ, ROBERT WOOD JOHNSON MED SCH	335 GEO ST LIBERTY PLAZA 4 FL	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	13	7/6/2012	SUPPLEMENT FOR EXPANSION	$22,192
2012	2012	UMDNJ, ROBERT WOOD JOHNSON MED SCH	335 GEO ST LIBERTY PLAZA 4 FL	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	13	2/17/2012	COMPETING CONTINUATION	$341,250
2012	2012	UMDNJ, ROBERT WOOD JOHNSON MED SCH	335 GEO ST LIBERTY PLAZA 4 FL	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	13	4/26/2012	COMPETING CONTINUATION	$4,375
														Subtotal = $367,817

Issue Date FY: 2010 ( Subtotal = $429,000 )
2010	2010	UMDNJ, ROBERT WOOD JOHNSON MED SCH	335 GEO ST LIBERTY PLAZA 4 FL	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Trans-NIH Recovery Act Research Support	000	12	6/23/2010	NON-COMPETING CONTINUATION	$429,000
														Subtotal = $429,000

Issue Date FY: 2009 ( Subtotal = $429,000 )
2009	2009	UMDNJ, ROBERT WOOD JOHNSON MED SCH	335 GEO ST LIBERTY PLAZA 4 FL	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Trans-NIH Recovery Act Research Support	002	11	7/24/2009	COMPETING CONTINUATION	$429,000
2009	2009	UMDNJ, ROBERT WOOD JOHNSON MED SCH	335 GEO ST LIBERTY PLAZA 4 FL	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Trans-NIH Recovery Act Research Support	000	11	7/15/2009	COMPETING CONTINUATION	$429,000
2009	2009	UMDNJ, ROBERT WOOD JOHNSON MED SCH	335 GEO ST LIBERTY PLAZA 4 FL	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Trans-NIH Recovery Act Research Support	001	11	7/21/2009	COMPETING CONTINUATION	-$429,000
														Subtotal = $429,000

Issue Date FY: 2007 ( Subtotal = $350,175 )
2007	2007	UMDNJ, ROBERT WOOD JOHNSON MED SCH	335 GEO ST LIBERTY PLAZA 4 FL	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	10	5/1/2007	NON-COMPETING CONTINUATION	$350,175
														Subtotal = $350,175

Issue Date FY: 2006 ( Subtotal = $360,634 )
2006	2006	UMDNJ, ROBERT WOOD JOHNSON MED SCH	335 GEO ST LIBERTY PLAZA 4 FL	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	9	3/28/2006	NON-COMPETING CONTINUATION	$360,634
														Subtotal = $360,634

Issue Date FY: 2005 ( Subtotal = $399,313 )
2005	2005	UMDNJ, ROBERT WOOD JOHNSON MED SCH	335 GEO ST LIBERTY PLAZA 4 FL	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	7	12/16/2004	SUPPLEMENT FOR EXPANSION	$30,000
2005	2005	UMDNJ, ROBERT WOOD JOHNSON MED SCH	335 GEO ST LIBERTY PLAZA 4 FL	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	8	5/5/2005	NON-COMPETING CONTINUATION	$369,313
														Subtotal = $399,313

Issue Date FY: 2004 ( Subtotal = $369,313 )
2004	2004	UMDNJ, ROBERT WOOD JOHNSON MED SCH	335 GEO ST LIBERTY PLAZA 4 FL	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	7	4/23/2004	NON-COMPETING CONTINUATION	$369,313
														Subtotal = $369,313

Issue Date FY: 2003 ( Subtotal = $369,313 )
2003	2003	UMDNJ, ROBERT WOOD JOHNSON MED SCH	335 GEO ST LIBERTY PLAZA 4 FL	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	6		COMPETING CONTINUATION	$369,313
														Subtotal = $369,313

Issue Date FY: 2002 ( Subtotal = $275,073 )
2002	2002	UMDNJ, ROBERT WOOD JOHNSON MED SCH	335 GEO ST LIBERTY PLAZA 4 FL	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Biological Basis Research in the Neurosciences	000	5	3/28/2002	NON-COMPETING CONTINUATION	$275,073
														Subtotal = $275,073

Grand Total All Awards = $7,845,253

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Novel Lysosomal Enzyme Deficient in Batten Disease

Award Number: R01NS037918

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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