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Genome-wide CRISPR screen to identify pro-myogenic factors for cell therapy of DMD

Award Information
Agency: Department of Health and Human Services
Branch: National Institutes of Health
Contract: 1R41AR074832-01
Agency Tracking Number: R41AR074832
Amount: $224,725.00
Phase: Phase I
Program: STTR
Solicitation Topic Code: NIAMS
Solicitation Number: PA18-575
Solicitation Year: 2018
Award Year: 2018
Award Start Date (Proposal Award Date): 2018-09-04
Award End Date (Contract End Date): 2019-08-31
Small Business Information
Montour Falls, NY 14865-9756
United States
DUNS: 081066380
HUBZone Owned: No
Woman Owned: No
Socially and Economically Disadvantaged: No
Principal Investigator
 (617) 355-6729
Business Contact
Phone: (607) 215-6401
Research Institution
BOSTON, MA 02115-5724
United States

 Domestic Nonprofit Research Organization

Project Abstract
Myos Incis developing a cell therapy treatment for patients with Duchenne muscular dystrophyDMDbased
on HLA matched donor cells that are pretreated with small molecule cocktails ex vivo to modify genes that will
enhance engraftment and fusion and enable muscle regenerationMyos is collaborating with DrLouis KunkelBoston Children s Hospitalto address the issues that led to low efficacy in previous clinical trialsGiven the
focus on DMDthis project is highly relevant to the mission of the NIH and the NIAMSThe long term goal is to develop efficient muscle cell therapy for all DMD patients of all agesThe objective of
this Phase I STTR project is to use genome wide screens to identify key factors that will promote myogenic
fusion and cell extravasationwhich are required for effective muscle cell engraftmentThe Aims areAimIdentify genes whose perturbation results in altered myogenic fusionThe project will utilize
genome wide screening libraries to generate gene edited myogenic cell populations with either single gene
knock outs or single gene over expressionGene edited cells will be switched to media that promotes
myogenic fusion into multinucleated myotubesNormal fused cells will be separated from abnormal un fusedmononuclearcells by filtration and analyzed by sequencing to identify CRISPR gene modifications that
distinguish fused vs un fused cellsMilestoneThe milestone is that the project will generate a validated list ofgenes pathways involved in cell fusionThese findings will be used in a Phase II STTR to test efficacy in
preclinical mice modelsAimIdentify genes whose perturbation results in increased efficiency of cellular extravasation and
homing to musclesUsing a human myogenic cell line expressing the molecular marker green fluorescence
proteinGFPthe project will separately transduce genome wide libraries to induce gene knock out or overexpressionGene edited cells will be intravenously injected into DBAJ mdx micea well characterized model
of human DMDMuscles will be harvested and digested for cell culture expansion and selection of human cells
that have successfully extravasated from the circulatory systemTheseengraftablecells will be expanded in
culture and sequenced to identify their gene modificationsMilestoneThe project will generate a validated list
ofgenes pathways involved in increased cell extravasation and muscle homingThe findings will be used in
a Phase II STTR to test efficacy in mice modelsThis is a fundamentally novel approach to identify genes that promote muscle recolonization and growth to
treat DMD regardless of disease mutationSuccessful completion of this project will lead to a future Phase II
STTR application to conduct preclinical animal testing of DMD cell therapy in preparation for clinical trials Project Narrative
This projectif successfulwill be the first step in developing a therapeutic that benefits the thousands of boys
and young men suffering from Duchenne muscular dystrophyDMDa rare and fatal disease that is
characterized by progressive muscle wastingThe critical research completed under the Phase I STTR will
enable Myos to begin to develop a cell therapy treatment that would allow patients suffering from DMD to not
only regain muscle butmore importantlyhave a significantly longer life expectancy than current projectionsThis therapeutic would have a significant return in that it would allow this group of patients to lead productive
lives while significantly reducing the annual cost to care for the disease

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

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