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Development of mitochondrial disease mouse models

Award Information
Agency: Department of Health and Human Services
Branch: National Institutes of Health
Contract: 1R41OD026567-01
Agency Tracking Number: R41OD026567
Amount: $224,856.00
Phase: Phase I
Program: STTR
Solicitation Topic Code: OD
Solicitation Number: PA16-181
Solicitation Year: 2016
Award Year: 2018
Award Start Date (Proposal Award Date): 2018-08-15
Award End Date (Contract End Date): 2019-08-14
Small Business Information
Saint Paul, MN 55104-4179
United States
DUNS: 079960066
HUBZone Owned: No
Woman Owned: No
Socially and Economically Disadvantaged: No
Principal Investigator
 (800) 321-6467
Business Contact
Phone: (612) 309-7653
Research Institution
MINNEAPOLIS, MN 55455-0149
United States

 Nonprofit College or University

Project Abstract
Mitochondria are double membrane bound organelles that are found in all eukaryotic cells and carry a specialized
circularkb genomeThere is a group of devastating human genetic diseases caused by inherited or
spontaneous mutation of genes encoded within the mitochondrial genomeThese diseases can cause a wide
array of medical problems from subtle muscular weakness to extreme neuromuscular problems such as loss of
balance and coordinationseizuresstrokedementia and deathFurtherit is estimated thatinchildren
are diagnosed with a mitochondrial disease each yearDespite the importance of the mitochondrial genome in
maintaining normal cellular functionas well as its role in promoting mitochondrial dysfunction when mutatedno
method exists to alter the genome of mitochondria in a site specific manneruntil nowWe have recently
developed the first reliable method to introduce specific mutations into the mitochondrial genome of vertebrate
animal cellsWe have found that two pairs of site specific DNA binding transcription activator likeTALdomain
endo nickasesmitoTALE nicaksescan be directed to the mitochondria and that their activity results in
generation of an intact mitochondrial genomebut with a deletion between the sites of the mtDNA nicksUsing
a second pair of mitochondrial targeted TAL endonucleasesmitoTALENsto make a double strand DNA break
in between the nick siteswe can induce the selective loss of wild type mitochondrial genomes which did not
undergo the deletionThuswe can seed mtDNA deletions using mitoTALE nickases and enrich for edited
mtDNA genomes using mitoTALENsWe have efficiently induced mtDNA deletions in zebrafish embryos and
human and mouse cell linesIn this proposalwe will extend the innovations in mammalian cells by engineering
targeted and precise mtDNA deletions systemically in miceWe will also develop inducible systems for
expressing the mitoTALENswhich means we will make it possible to createconditionalloss of function of
mitochondrial genes in miceThis 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 developmentWe
will create mice carrying an inducible deletion that causes Kearns Sayre syndromeKSSin humansone of the
most common mitochondrial genetic diseaseThe production of these novel mouse models will be useful for
academic and pharmaceutical companies to test novel regenerative stem cell technologies Project Narrative
Although there have been significant advancements in gene editing over the past two decadesnone have been
able to precisely edit the mitochondrial genomeuntil nowThe goal of the proposed project is to use
mitochondrial gene editing technology to generate an inducible mouse model of mitochondrial genetic diseaseThis project will result in a set of mouse models necessary to identify and test novel therapeutics for the treatment
of mitochondrial disease

* Information listed above is at the time of submission. *

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