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Exploring Antisense Oligonucleotides as a potential therapy for Autosomal Dominant Leukodystrophy

Award Number: R33NS104384
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: 09/30/2018
PERIOD OF PERFORMANCE END DATE: 01/31/2023

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Exploring Antisense Oligonucleotides as a potential therapy for Autosomal Dominant Leukodystrophy - Autosomal dominant leukodystrophy (ADLD) is a fatal, progressive adult-onset disease characterized by autonomic and motor dysfunction with widespread CNS demyelination. We have previously shown that ADLD is caused by duplications of the lamin b1 gene and that increased expression of lamin B1 underlies the disease process. In eukaryotic cells, lamin B1 is a major constituent of the nuclear lamina, a fibrous meshwork adjacent to the inner nuclear membrane. The nuclear lamina maintains the structural integrity of the nucleus and has roles in essential cellular processes including transcription, DNA replication, DNA repair, and epigenetic regulation. We have recently demonstrated that transgenic (TG) mice with oligodendrocyte specific over-expression of lamin B1 exhibit severe vacuolar demyelination of the spinal cord that result in age-dependent degenerative phenotypes reminiscent of ADLD. The late age of onset together with the relatively slow progression of the disease provides a large therapeutic window for the disorder. However, no treatment exits for ADLD, representing an urgent and unmet clinical need. This proposal aims to test the potential of antisense oligonucleotides (ASOs) to delay or reverse the progression of the disease in a mouse model of ADLD. ASOs are synthetic single stranded nucleic acids with a modified backbone that bind to RNA and thereby reduce expression of the target RNA or alter protein expression through interference of pre-mRNA splicing. Their mechanism of actions thus makes them ideally suited for a disease such as ADLD that is caused by an overexpression of a protein. ASOs also have tremendous translational potential and some of these molecules have demonstrated efficacy in clinical trials for neurological disorders such as spinal muscular atrophy (SMA).


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 = -$1 )
2024	2021	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	11/30/2023	NON-COMPETING CONTINUATION	-$1
														Subtotal = -$1

Issue Date FY: 2022 ( Subtotal = $2,513 )
2022	2020	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	7/5/2022	EXTENSION WITH OR WITHOUT FUNDS	$2,513
														Subtotal = $2,513

Issue Date FY: 2021 ( Subtotal = $373,796 )
2021	2021	UNIVERSITY OF PITTSBURGH THE	3520 FIFTH AVE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	1/27/2021	NON-COMPETING CONTINUATION	$373,796
														Subtotal = $373,796

Issue Date FY: 2020 ( Subtotal = $373,797 )
2020	2020	UNIVERSITY OF PITTSBURGH THE	3520 FIFTH AVE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	4/2/2020	EXTENSION WITH OR WITHOUT FUNDS	$1
2020	2020	UNIVERSITY OF PITTSBURGH THE	3520 FIFTH AVE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	1/27/2020	EXTENSION WITH OR WITHOUT FUNDS	$373,796
														Subtotal = $373,797

Grand Total All Awards = $750,105

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Exploring Antisense Oligonucleotides as a potential therapy for Autosomal Dominant Leukodystrophy

Award Number: R33NS104384

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: 09/30/2018

PERIOD OF PERFORMANCE END DATE: 01/31/2023

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