MDA Web MeetingJune 2017

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This webinar was funded through a Patient-Centered Outcomes Research Institute (PCORI) Eugene Washington PCORI Engagement Award EAIN-

2679

In support of A Foundation Building Strength (AFBS)

The Patient-Centered Outcomes Research Institute (PCORI) is an independent, nonprofit organization authorized by Congress in 2010. Its mission is to fund research that will provide patients, their caregivers, and clinicians with the evidence-based information needed to make better-informed healthcare decisions. PCORI is committed to continually seeking input from a broad range of stakeholders to guide its work.

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AFBS Founded 2008

Mission: Find effective treatments for nemaline

myopathy.

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Supporting families along the way

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Family gatheringsScientific Conferences

Travel & accommodation support

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Executive DirectorMarc Guillet

Other Board Members*

Willie Quinn, Jaqueline Wallach, Tom Unger Ph.D.,

Patty Mitchell, Sharon-Fiedler Shimanovsky,

and Boris Shimanovsky

*Combination of parents of children with NM and

experienced pharmaceutical industry executives

Nemaline Myopathy (NM)

• Congenital muscle disease affecting how muscles contract and function– Poor muscle tone & weakness, especially in the

face, neck, and trunk.

– Difficulty walking or inability to walk

– Respiratory insufficiency

– Feeding and aspiration concerns

– Speech difficulties or inability

– Curvature of the spine

– Severe form requires total life support from birth

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Consequences of untreated NM

• The common cold can be life-threatening, frequently requiring hospitalization.

• Life expectancy is significantly reduced and some never make it past the first year of life. The cause of death is usually related to respiratory failure.

• Many depend upon feeding tubes and ventilatory assistance to sustain life.

• Those affected are often unable to participate in everyday activities.

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Scientific Advisory Board

Research & Development Committee

Our goal is to find treatments by funding targeted research and supporting studies that pave the way for regulatory approval.

AFBS Making an Impact

AFBS raised well over $3M to fund research and development to find treatments for NM.

Treatments will improve quality of life for those individuals living with NM and their families:

– Fewer hospitalizations

– Improved ventilation and energy level

– Increased physical mobility

– Improved nutrition

– Ultimately, freeing people to live the lives they choose

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AFBS & MDA Intersecting Goals

• Live longer, healthier lives

• Family support

• Raise awareness

• Support Nemaline Myopathy related research

• Memorandum of Understanding – Partnership

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Live Longer, Healthier Lives

• Standard of Care established

• Preventive health care guidelines

• Chronic condition management

• Research opportunities and updates

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J Child Neurol 2012 27: 363

Ching H. Wang, James J. Dowling, Kathryn North, Mary K. Schroth, Thomas Sejersen, Frederic Shapiro, Jonathan Bellini, Hali Weiss, Marc Guillet, Kimberly Amburgey, Susan Apkon, Enrico Bertini, Carsten Bonnemann, Nigel Clarke, Anne M. Connolly, Brigitte Estournet-Mathiaud, Dominic Fitzgerald, Julaine M. Florence, Richard Gee, Juliana Gurgel-Giannetti, Allan M. Glanzman, Brittany Hofmeister, Heinz Jungbluth, Anastassios C. Koumbourlis, Nigel G. Laing, Marion Main, Leslie A. Morrison, Craig Munns, Kristy Rose, Pamela M. Schuler, Caroline Sewry, Kari Storhaug, Mariz Vainzof, and Nanci Yuan

Consensus Statement on Standard of Care for Congenital Myopathies

Family Support

• Help ease family & individual burdens

– Emotional and financial support

• Connecting people

– NM Welcome Flyer available at MDA clinics

• Education

– Congenital myopathy guide for families

• Sense of community & feel like family

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Core Writing Team:

Chamindra Konersman, Stacy Cossette, Sarah Foye, Kim Amburgey, Anne Rutkowski, Juliana Gurgel-Giannetti, Lucinda Lee

Available at:

Amazon.com

buildingstrength.org/resources/

Raise Awareness

• NM Welcome Flyer

• Ambassadors

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Graphic designers:Lucinda LeeShannon Welty

Raise Awareness: Continued

• Social media– AFBS social media coordinator May Shannon

– Quest feature story of NM or NM family

• AFBS Newsletters

• Webinars

• Scientific conferences

• Family gatherings

• Volunteer powered efforts

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Supporting Research

• AFBS annual RFP

• AFBS has been supporting prominent researchers around the world since 2009

• Research resources in partnership– Congenital Muscle Disease International Registry

(CMDIR)

– Congenital Muscle Disease Tissue Repository (CMD-TR)

– Congenital Muscle Disease Biobank (CMD BioBank)

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Memorandum of Understanding

• Public statement of partnership between AFBS and MDA

• Focus on shared objectives

• Roles and activities

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Follow-up

• Webinar for NM families about MDA services and supports (Oct 17th)

• In-person meeting (Chicago around Sept 22nd)

• Potential for co-sponsoring research studies

• Legislative action items

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THANK YOU for your dedication to finding treatments to help those with muscle

disease and the families who love them.

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Appendix

• Funded research 2009-2016

• Projected studies to fund 2017

• AFBS sponsored published work

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2009-2010 Research Funded

1. Standard of Care Protocol for NM & Other Congenital Myopathies: publish a consensus statement on caring for NM; Ching Wang MD, PhD, Stanford University ($200K)

2. Cardiac Actin Upregulation Therapy for Actin NM: using a mouse model to find a drug to increase cardiac actin in skeletal muscle; Nigel Laing, PhD, University of Western Australia, ($69K)

3. Dysregulation of Calcium Homeostasis in NM & Related Myopathies: seeking new targets for therapy by studying calcium handling proteins in muscle biopsies & primary cell lines from patients; Kathryn North, MD, University of Sydney ($44K)

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2011 Research Funded

4. Restoring Muscle Strength in NM: studying nebulin in mouse models & human biopsies to better understand NM & how to restore strength; Dr. Henk Granzier, University of Arizona

5. Viral therapy for ACTA1-based NM: studying viral delivery of actin in a mouse model; Nigel Laing, PhD, University of Western Australia

6. Whole Body Vibration Training for NM: studying the effect on strength & function in 10 patients ; Craig Munns, PhD, University of Sydney, Australia

7. Development of RNA-based therapies for NM: develop technique to correct mutations in the nebulin gene; Katarina Pelin, PhD, University of Helsinki, Finland

8. Drug Discovery in a Novel Vertebrate Model of Nemaline Myopathy; James Dowling, MD, PhD, University of Michigan

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2012-2015 Research Funded

9. Zebrafish models for drug discovery in congenital myopathy; Alan H. Beggs, PhD, Boston Children’s Hospital ($100K)

10. Myostatin inhibition in a nebulin mouse model, Mike Lawlor, MD, PhD, Medical College of Wisconsin ($50K)

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• Congenital Muscle Disease Tissue Repository

Michael Lawlor, MD, PhD

• Factors That Rescue Nebulin-Knockout Mice

Siegfried Labeit, MD, PhD

• Nebulin-NM Mechanisms and Treatment

Henk Grenzier, PhD

• Myofiblar Mechanics to Investigate Muscle Weakness in NM

Coen Ottenheijm, PhD

• ACTA1 NM Therapeutic Approaches

Kristen Nowak, PhD

• Gene Therapy for Nebulin-Based NM

Henk Grenzier, PhD, Jeff Chamberlain, PhD

2016 Funded Research Projects

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• CRISPR/Cas9 gene editing: a novel therapeutic strategy for nemaline

myopathy

James Dowling, MD, PhD and Hernan Gonorazky, MD

• Diaphragm Contractility in Patients with Nemaline Myopathy

Coen Ottenheijm, PhD,

• A chemical-biology approach to myofibril stress signaling

Siegfried Labeit, MD, Alan Beggs, PhD, Lee Sweeney, PhD

• Modulating myosin to improve muscle strength in nebulin-based

nemaline myopathy

Johan Lindqvist, PhD

• Improving myosin function to treat nemaline myopathy

Julien Ochala, PhD

• Use of Abnormal Protein Expression to Improve Prognostication and

Treatment Study

Michael Lawlor, MD, PhD

2017 AFBS Projected Research Projects to Fund

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• Pre-Clinical evaluation of FDA drug collection

Robert Bryson-Richardson, PhD, Tamar Sztal, PhD, Nigel Laing, PhD,

Kristen Nowak, PhD

• Targeting Kelch-regulated pathways to develop therapies in Nemaline

Myopathy

Vandana Gupta, PhD

• A stem cell-derived muscle model of Nemaline Myopathy

Uli Schmidt, PhD, Alex Kiselyov, PhD, Monica Hayhurst Bennett, PhD,

Anabel S. de la Garza-Rodea, MD, PhD

• An actin isoform gene switching small-molecule for nemaline myopathy

Jay Schneider, MD, PhD

• Congenital Muscle Disease Tissue Repository

Michael Lawlor, MD, PhD

2017 AFBS Projected Research Projects: Continued

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Troponin activator augments muscle force in nemaline myopathy patients with nebulin mutations

Josine Marieke de Winter, Danielle Buck, Carlos Hidalgo, Jeffrey R. Jasper, Fady I. Malik, Nigel F.

Clarke, Ger J. M. Stienen, Michael W. Lawlor, Alan H. Beggs, Coen A. C. Ottenheijm, and

Henk Granzier

J Med Genet. Author manuscript; available in PMC 2014 Jun 1. Published online 2013 Apr 9.

doi:10.1136/jmedgenet-2012-101470 PMCID: PMC3865762 NIHMSID: NIHMS535765

Deleting exon 55 from the nebulin gene induces severe muscle weakness in a mouse model for nemaline

myopathy

Coen A. C. Ottenheijm, Danielle Buck, Josine M. de Winter, Claudia Ferrara, Nicoletta Piroddi, Chiara

Tesi, Jeffrey R. Jasper, Fady I. Malik, Hui Meng, Ger J. M. Stienen, Alan H. Beggs, Siegfried Labeit,

Corrado Poggesi, Michael W. Lawlor, and Henk Granzier corresponding author

Brain. 2013 Jun; 136(6): 1718–1731. Published online 2013 May 28. doi: 0.1093/brain/awt113 PMCID:

PMC3673460

Fast Skeletal Muscle Troponin Activation Increases Force of Mouse Fast Skeletal Muscle and Ameliorates

Weakness Due to Nebulin Deficiency

Eun-Jeong Lee, Josine M. De Winter , Danielle Buck, Jeffrey R. Jasper, Fady I. Malik, Siegfried Labeit,

Coen A. Ottenheijm, Henk Granzier

PLOS ONE · FEBRUARY 2013 Impact Factor: 3.53 · DOI: 0.1371/journal.pone.0055861 Source:PubMed

K7del is a common TPM2 gene mutation associated with nemaline myopathy and raised myofibre calcium

sensitivity

Nancy Mokbel, Biljana Ilkovski, Michaela Kreissl, Massimiliano Memo, Cy M. Jeffries, Minttu Marttila,

Vilma-Lotta Lehtokari, Elina Lemola, Mikaela Gronholm, Nan Yang, Dominique Menard, Pascale

Marcorelles, Andoni Echaniz-Laguna, Jens Reimann, Mariz Vainzof, Nicole Monnier, Gianina

Ravenscroft, Elyshia McNamara, Kristen J. Nowak, Nigel G. Laing, Carina Wallgren-Pettersson, Jill

Trewhella, Steve Marston, Coen Ottenheijm, Kathryn N. North, and Nigel F. Clarke

Brain 2013: Page 1 of 14

Published Work Sponsored by AFBS