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Development of mitochondrial disease mouse models

Award Number: R41OD026567
ORGANIZATION: OFFICE OF THE DIRECTOR, NIH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/15/2018
PERIOD OF PERFORMANCE END DATE: 06/14/2020

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Development of mitochondrial disease mouse models - Project Abstract Mitochondria are double membrane bound organelles that are found in all eukaryotic cells and carry a specialized circular 16.5kb genome. There is a group of devastating human genetic diseases caused by inherited or spontaneous mutation of genes encoded within the mitochondrial genome. These diseases can cause a wide array of medical problems from subtle muscular weakness to extreme neuromuscular problems such as loss of balance and coordination, seizures, stroke, dementia and death. Further, it is estimated that 1 in 10,000 children are diagnosed with a mitochondrial disease each year. Despite the importance of the mitochondrial genome in maintaining normal cellular function, as well as its role in promoting mitochondrial dysfunction when mutated, no method exists to alter the genome of mitochondria in a site-specific manner, until now. We have recently developed the first reliable method to introduce specific mutations into the mitochondrial genome of vertebrate animal cells. We have found that two pairs of site specific DNA-binding transcription activator-like (TAL) domain endo-nickases (mitoTALE-nicakses), can be directed to the mitochondria and that their activity results in generation of an intact mitochondrial genome, but with a deletion between the sites of the mtDNA nicks. Using a second pair of mitochondrial-targeted TAL endonucleases (mitoTALENs) to make a double strand DNA break in between the nick sites, we can induce the selective loss of wild-type mitochondrial genomes which did not undergo the deletion. Thus, we can seed mtDNA deletions using mitoTALE-nickases and enrich for edited mtDNA genomes using mitoTALENs. We have efficiently induced mtDNA deletions in zebrafish embryos and human and mouse cell lines. In this proposal, we will extend the innovations in mammalian cells by engineering targeted and precise mtDNA deletions systemically in mice. We will also develop inducible systems for expressing the mitoTALENs, which means we will make it possible to create “conditional” loss of function of mitochondrial genes in mice. This inducible mouse model system could be highly useful in settings in which the mitochondrial deletion would cause a selective disadvantage to such cells during early mouse development. We will create mice carrying an inducible deletion that causes Kearns Sayre syndrome (KSS) in humans, one of the most common mitochondrial genetic disease. The production of these novel mouse models will be useful for academic and pharmaceutical companies to test novel regenerative stem cell technologies.


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 = -$36,313 )
2023	2018	B-MOGEN BIOTECHNOLOGIES INC	1621 E HENNEPIN AVE SUITE B-15	MINNEAPOLIS	MN	55414	HENNEPIN	USA	Research Infrastructure Programs	000	1	3/17/2023	NEW	-$26,076
2023	2018	B-MOGEN BIOTECHNOLOGIES INC	1621 E HENNEPIN AVE SUITE B-15	MINNEAPOLIS	MN	55414	HENNEPIN	USA	Research Infrastructure Programs	001	1	3/17/2023	NEW	-$10,236
														Subtotal = -$36,313

Issue Date FY: 2019 ( Subtotal = $0 )
2019	2018	B-MOGEN BIOTECHNOLOGIES INC	1621 E HENNEPIN AVE SUITE B-15	MINNEAPOLIS	MN	55414	HENNEPIN	USA	Research Infrastructure Programs	000	1	1/2/2019	NEW	$0
														Subtotal = $0

Issue Date FY: 2018 ( Subtotal = $224,856 )
2018	2018	B-MOGEN BIOTECHNOLOGIES INC	614 MCKINLEY PL NE	MINNEAPOLIS	MN	55413	HENNEPIN	USA	Research Infrastructure Programs	000	1	8/8/2018	NEW	$224,856
														Subtotal = $224,856

Grand Total All Awards = $188,543

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Development of mitochondrial disease mouse models

Award Number: R41OD026567

ORGANIZATION: OFFICE OF THE DIRECTOR, NIH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/15/2018

PERIOD OF PERFORMANCE END DATE: 06/14/2020

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