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Donna M. Martin, MD, PhD

Yehoash Raphael, PhD

August 4, 2019

Departments of Pediatrics, Human

Genetics, and Otolaryngology

CHARGE Syndrome Research:The Past and The Future

Acknowledgements

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GeneDiscovery

Generation ofAnimal Models

Identification of Genetic Disease

Underlying Mechanisms

Drug Development and Treatment

Exploring Genetic Mechanisms in CHARGE

Martin, DM; Curr Med Genet Rep, 2014

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CHD7 Regulates DNA Accessibility

Yan, Matouk, and Marsden J Appl Physiol, (2010)

Timeline of CHARGE Knowledge

1979 1989 1999 2009 2019 2029

First clinical report

CHARGE “Syndrome”

iPS cells

ComprehensiveDiagnosis

Regenerative& Other Therapies

CHARGE “Association”

Discovery of CHD7

Animalmodels

Pathogenic Mechanisms

CSF PilotAwards

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Investigator Institution 2012 2013 2014 2015 2016 2017 2018Liz Hurd and Adam Stein University of Michigan xBob Hevner University of Washington xKelvin Kwan Rutgers xChing-Pin Chang Stanford, now at Indiana University xMichael Talkowski Harvard xMats Ljungman University of Michigan xPeter Scacheri Case Western Reserve University xRuchi Bajpai University of Southern California xFumiaki Imamura Penn State University xAllison Bardin Institut Curie xConny van Ravenswaaij-Arts Univ Gronigen xPhil Gage University of Michigan xFaith Liebl Southern Illinois University xKessen Patten Universite de Montreal xKai Jiao University of Alabama Birmingham xQ. Richard Lu University of Cincinnati xNicholas Pilon University of Quebec at Montreal xAlbert Basson King's College London xDan Marenda Drexel University xAnna Cariboni Univ Milan, Italy xJudith Yanowitz University of Pittsburgh xWeijun Feng and Haikun Liu University of Heidelberg xAnn Morris University of Kentucky xKurt Marsden North Carolina State University xStephanie Bielas University of Michigan x

Pilot Research Awardees 2012‐2018

Investigator Institution 2012 2013 2014 2015 2016 2017 2018Liz Hurd and Adam Stein University of Michigan xBob Hevner University of Washington xKelvin Kwan Rutgers xChing-Pin Chang Stanford, now at Indiana University xMichael Talkowski Harvard xMats Ljungman University of Michigan xPeter Scacheri Case Western Reserve University xRuchi Bajpai University of Southern California xFumiaki Imamura Penn State University xAllison Bardin Institut Curie xConny van Ravenswaaij-Arts Univ Gronigen xPhil Gage University of Michigan xFaith Liebl Southern Illinois University xKessen Patten Universite de Montreal xKai Jiao University of Alabama Birmingham xQ. Richard Lu University of Cincinnati xNicholas Pilon University of Quebec at Montreal xAlbert Basson King's College London xDan Marenda Drexel University xAnna Cariboni Univ Milan, Italy xJudith Yanowitz University of Pittsburgh xWeijun Feng and Haikun Liu University of Heidelberg xAnn Morris University of Kentucky xKurt Marsden North Carolina State University xStephanie Bielas University of Michigan x

Pilot Research Awardee Publications 2012‐2018

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How does research help people?

• Examples from sense organs that can be addressed experimentally:

• CHARGE involves deficient senses:

–Hearing, balance, smell, taste, vision

Mouse model avails research avenues

Cochlear implants can be improved using CHARGE mice

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Gene therapy procedure induces nerve sprouting

Cochlear Implants work in mice

Stimulus Current (µA)0 50 100 150 200 250 300 350 400 450 500

N1 t

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2 A

mp

litu

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( V

)

0

1

2

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1015303744525965

DPIM5332L1DTR MS

Injected w/DTA

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X

Make new hair cells

Cell replacement therapy by gene transfer

MyoVIIa / GFP (Atoh1)

OHC 1OHC 2

OHC 3

IHCIHC

Red cells with green nuclei are new hair cells

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Stem cell therapy

Create conditions that promote survival and integration of

injected stem cells

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Conclusions

Animal models are available to develop therapy for the senses and other organs and systems affected in CHARGE

Hearing can be enhanced by novel therapeutic technologies