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ANTISENSE OLIGONUCLEOTIDE SUPPRESSION OF NON-DELETION DMD CAUSING MUTATIONS

Award Number: R01NS044146
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: 07/01/2002
PERIOD OF PERFORMANCE END DATE: 03/31/2013

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ANTISENSE OLIGONUCLEOTIDE SUPPRESSION OF NON-DELETION DMD CAUSING MUTATIONS - DESCRIPTION (provided by applicant): Duchenne muscular dystrophy (DMD) is a fatal X-linked muscle-wasting disorder caused by protein truncating mutations in the dystrophin gene. Antisense oligomer induced removal of an exon carrying a nonsense mutation, or exons flanking frame-shifting deletions, the most common type of DMD mutation, has been shown to generate an in-frame message and an internally deleted, but functional protein. Becker muscular dystrophy (BMD) is an allelic disorder typically caused by in-frame deletions of one or more exons, most commonly in the first two thirds of the gene. The severity of BMD varies from borderline DMD to asymptomatic, and the dystrophin genes in mildly affected BMD patients provide an indication of functional exon combinations. At least one third of DMD cases result from duplications, micro-insertions/deletions and single base changes that alter splice site recognition or cause premature termination of translation. This project will address the design and application of antisense oligomers for induced exon skipping, for those DMD cases caused by non-deletion mutations. Patient cell lines will be transfected with test compounds and exon skipping assessed. Exon skipping strategies will be modified to maximize induced dystrophin quality and quantity, as permitted by the context of each particular dystrophin gene lesion. The specific aims are to: 7 Optimise antisense oligomers to remove exons carrying sequence variations (disease-causing or neutral polymorphims) that would otherwise compromise exon skipping. 7 Develop exon skipping strategies appropriate to DMD cases caused by pseudo-exon incorporation or duplications of one or more exons. 7 Develop transient animal models to identify functionally significant dystrophin domains, according to exon boundaries, to facilitate design of optimal exon skipping strategies. PUBLIC HEALTH RELEVANCE: Duchenne muscular dystrophy is a relentlessly progressive, fatal disease for which there is no effective treatment. Specific exon removal has the potential to greatly reduce the severity of DMD, and restoration of dystrophin expression, even of partial function in a DMD patient is expected to result in a BMD-like phenotype, and reduce morbidity and extend life expectancy. This application seeks to develop personalised exon skipping therapies for the one third of DMD patients who have non-deletion mutations. Exon skipping should be made available to all patients who could benefit, not only those with the more common exon deletion mutations.


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: 2012 ( Subtotal = $235,110 )
2012	2012	TVW TELETHON INSTITUTE FOR CHILD HEALTH RESEARCH	POST OFFICE BOX 855	PERTH				AUS	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	8	5/2/2012	NON-COMPETING CONTINUATION	$235,110
2012	2011	TVW TELETHON INSTITUTE FOR CHILD HEALTH RESEARCH	POST OFFICE BOX 855	PERTH				AUS	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	7	10/25/2011	NON-COMPETING CONTINUATION	$0
														Subtotal = $235,110

Issue Date FY: 2011 ( Subtotal = $228,316 )
2011	2011	TVW TELETHON INSTITUTE FOR CHILD HEALTH RESEARCH	POST OFFICE BOX 855	PERTH				AUS	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	7	10/25/2011	NON-COMPETING CONTINUATION	$0
2011	2011	TVW TELETHON INSTITUTE FOR CHILD HEALTH RESEARCH	POST OFFICE BOX 855	PERTH				AUS	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	7	6/8/2011	NON-COMPETING CONTINUATION	$228,316
														Subtotal = $228,316

Issue Date FY: 2010 ( Subtotal = $223,984 )
2010	2010	TVW TELETHON INSTITUTE FOR CHILD HEALTH RESEARCH	POST OFFICE BOX 855	PERTH				AUS	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	6	3/12/2010	NON-COMPETING CONTINUATION	$223,984
														Subtotal = $223,984

Issue Date FY: 2009 ( Subtotal = $232,837 )
2009	2009	TVW TELETHON INSTITUTE FOR CHILD HEALTH RESEARCH	POST OFFICE BOX 855	PERTH				AUS	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	4/6/2009	COMPETING CONTINUATION	$232,837
														Subtotal = $232,837

Issue Date FY: 2007 ( Subtotal = $142,085 )
2007	2007	UNIVERSITY OF WESTERN AUSTRALIA	**	NEDLANDS		00000		AUS	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	2/23/2007	NON-COMPETING CONTINUATION	$142,085
														Subtotal = $142,085

Issue Date FY: 2006 ( Subtotal = $146,328 )
2006	2006	UNIVERSITY OF WESTERN AUSTRALIA	**	NEDLANDS		00000		AUS	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	3/17/2006	NON-COMPETING CONTINUATION	$146,328
														Subtotal = $146,328

Issue Date FY: 2005 ( Subtotal = $149,850 )
2005	2005	UNIVERSITY OF WESTERN AUSTRALIA	**	NEDLANDS		00000		AUS	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	3/1/2005	NON-COMPETING CONTINUATION	$149,850
														Subtotal = $149,850

Issue Date FY: 2004 ( Subtotal = $149,850 )
2004	2004	UNIVERSITY OF WESTERN AUSTRALIA	**	NEDLANDS		00000		AUS	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	12/19/2003	NEW	$149,850
														Subtotal = $149,850

Grand Total All Awards = $1,508,360

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ANTISENSE OLIGONUCLEOTIDE SUPPRESSION OF NON-DELETION DMD CAUSING MUTATIONS

Award Number: R01NS044146

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: 07/01/2002

PERIOD OF PERFORMANCE END DATE: 03/31/2013

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