OMB No. 0925-0001 and 0925-0002 (Rev. 10/15 Approved Through 10/31/2018)

BIOGRAPHICAL SKETCH Provide the following information for the Senior/key personnel and other significant contributors. Follow this format for each person. DO NOT EXCEED FIVE PAGES. NAME: Tawil, Rabi eRA COMMONS USER NAME (credential, e.g., agency login): RTawil POSITION TITLE: Professor of , Pathology and Lab Medicine EDUCATION/TRAINING (Begin with baccalaureate or other initial professional education, such as nursing, include postdoctoral training and residency training if applicable.) INSTITUTION AND LOCATION DEGREE Completion Date FIELD OF STUDY (if applicable) MM/YYYY Emory University, Atlanta, GA BS 06/1979 Biology American University of Beirut, Beirut MS 06/1981 Physiology American University of Beirut, Beirut MD 06/1985 Medicine

A. Personal Statement

My academic career is centered on clinical and translational research with the ultimate aim of developing treatments for inherited neuromuscular diseases. My particular focus is on FSHD (Facioscapulohumeral ) since 1991. I contributed to the clinical and genetic characterization of the disease and was the co-PI of the first FSHD randomized controlled trial. In 2007 I established a successful collaborative team to understand the underlying molecular pathophysiology of FSHD (Fields Center for FSHD and Neuromuscular Research: http://www.urmc.rochester.edu/fields-center/). The identification of a unifying hypothesis for FSHD in 2010 shifted my focus to trial readiness as the potential for targeted treatments in FSHD became a reality. I organized two international trial readiness workshops and contributed in the development of new outcome measures and a better understanding of factors that influence disease severity in FSHD. This has led in 2015 to creation of an FSHD Clinical Trial Network to help validate outcome measures and streamline the conduct of future therapeutic trials in FSHD. B. Positions and Honors Positions and Employment 1991 - 1993 Fellow in Neuromuscular Science, University of Rochester Medical Center, Rochester, NY 1991 - 1993 Instructor in Neurology, University of Rochester Medical Center, Rochester, NY 1993 - 1998 Assistant Professor of Neurology, Pathology & Lab Medicine, University of Rochester Medical Center, Rochester, NY 1998 - 2005 Associate Professor of Neurology, Pathology and Lab Medicine, University of Rochester Medical Center, Rochester, NY 2005 – 2016 Professor of Neurology, Pathology and Lab Medicine, University of Rochester Medical Center, Rochester, NY 2016- Present Richard Fields Endowed Professor of Neurology, Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY

Other Experience and Professional Memberships 1992 - Member, American Academy of Neurology 2001 - Member, American Neurological Association 2007 - Fellow, American Academy of Neurology 2011 - 2012 Committee Member of NINDS Common Data Element Initiative on cardiac and respiratory involvement in neuromuscular diseases, NINDS 2011 - 2014 Co-chair, AAN Standards of Care Committee for Facioscapulohumeral Muscular dystrophy, American Academy of Neurology 2014 - 2015 Committee Member of NINDS Common Data Elements for Facioscapulohumeral muscular dystrophy, NINDS

Honors 1979 Associate Member: Sigma Xi, Emory University Chapter 1994 Buswell Fellowship Award, University of Rochester

C. Contribution to Science

1. Understanding the Clinical manifestations and natural history of Facioscapulohumeral muscular dystrophy (FSHD). A long-standing commitment to studying FSHD has resulted in the largest comprehensive natural history study of FSHD, the correlation between the clinical phenotype and genotype in relation to disease severity and non-muscular manifestations. This has allowed for improved clinical guidelines as well as providing critical information that is vital for the design of upcoming clinical trials.

a. Tawil R, Kissel JT, Heatwole C, Pandya S, Gronseth G, Benatar M. Evidence-based guideline summary: Evaluation, diagnosis, and management of facioscapulohumeral muscular dystrophy: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology and the Practice Issues Review Panel of the American Association of Neuromuscular & Electrodiagnostic Medicine. Neurology. 2015 Jul 28;85(4):357-64. PubMed PMID: 26215877; PubMed Central PMCID: PMC4520817. b. A prospective, quantitative study of the natural history of facioscapulohumeral muscular dystrophy (FSHD): implications for therapeutic trials. The FSH-DY Group. Neurology. 1997 Jan;48(1):38-46. PubMed PMID: 9008491. c. Tawil R, Forrester J, Griggs RC, Mendell J, Kissel J, McDermott M, King W, Weiffenbach B, Figlewicz D. Evidence for anticipation and association of deletion size with severity in facioscapulohumeral muscular dystrophy. The FSH-DY Group. Ann Neurol. 1996 Jun;39(6):744-8. PubMed PMID: 8651646. d. Personius KE, Pandya S, King WM, Tawil R, McDermott MP. Facioscapulohumeral dystrophy natural history study: standardization of testing procedures and reliability of measurements. The FSH DY Group. Phys Ther. 1994 Mar;74(3):253-63. PubMed PMID: 8115459.

2. As a clinical translational researcher, I was acutely aware of the importance of biological resources generated from carefully characterized patients in helping understand underlying disease mechanisms. This was especially true in a disease like FSHD with a unique genetic mechanism the consequences of which remained unexplained for over a decade. In 2007, with private resources, I formed a collaborative group that included a molecular geneticist and cellular biologist at two other institutions to tackle the seemingly unsolvable riddle of FSHD. Within three years this collaboration resulted in a major breakthrough in our understanding of FSHD. The identification of the derepression of DUX4 as the cause of FSHD1 and FSHD2 has provided a therapeutic target for FSHD. The biological resources generated at our institution which proved vital in uncovering the molecular mechanism of FSHD are now actively being used by researchers and industry for drug screening.

a. Lemmers RJ, van der Vliet PJ, Klooster R, Sacconi S, Camaño P, Dauwerse JG, Snider L, Straasheijm KR, van Ommen GJ, Padberg GW, Miller DG, Tapscott SJ, Tawil R, Frants RR, van der Maarel SM. A unifying genetic model for facioscapulohumeral muscular dystrophy. Science. 2010 Sep 24;329(5999):1650-3. PubMed PMID: 20724583; PubMed Central PMCID: PMC4677822. b. de Greef JC, Lemmers RJ, Camaño P, Day JW, Sacconi S, Dunand M, van Engelen BG, Kiuru-Enari S, Padberg GW, Rosa AL, Desnuelle C, Spuler S, Tarnopolsky M, Venance SL, Frants RR, van der Maarel SM, Tawil R. Clinical features of facioscapulohumeral muscular dystrophy 2. Neurology. 2010 Oct 26;75(17):1548-54. PubMed PMID: 20975055; PubMed Central PMCID: PMC2974464. c. Geng LN, Yao Z, Snider L, Fong AP, Cech JN, Young JM, van der Maarel SM, Ruzzo WL, Gentleman RC, Tawil R, Tapscott SJ. DUX4 activates germline genes, retroelements, and immune mediators: implications for facioscapulohumeral dystrophy. Dev Cell. 2012 Jan 17;22(1):38-51. PubMed PMID: 22209328; PubMed Central PMCID: PMC3264808. d. Lemmers RJ, Tawil R, Petek LM, Balog J, Block GJ, Santen GW, Amell AM, van der Vliet PJ, Almomani R, Straasheijm KR, Krom YD, Klooster R, Sun Y, den Dunnen JT, Helmer Q, Donlin-Smith CM, Padberg GW, van Engelen BG, de Greef JC, Aartsma-Rus AM, Frants RR, de Visser M, Desnuelle C, Sacconi S, Filippova GN, Bakker B, Bamshad MJ, Tapscott SJ, Miller DG, van der Maarel SM. Digenic inheritance of an SMCHD1 mutation and an FSHD-permissive D4Z4 allele causes facioscapulohumeral muscular dystrophy type 2. Nat Genet. 2012 Dec;44(12):1370-4. PubMed PMID: 23143600; PubMed Central PMCID: PMC3671095.

3. The identification of a therapeutic target for FSHD has shifted the focus of clinical research towards trial preparedness. To that end, we have and continue to develop new outcome measures with an emphasis on development of measures that are more sensitive to change for the more efficient conduct of future clinical trials.

a. Statland JM, Heatwole C, Eichinger K, Dilek N, Martens WB, Tawil R. Electrical impedance myography in facioscapulohumeral muscular dystrophy. Muscle Nerve. 2016 Feb 3;PubMed PMID: 26840230. b. Tawil R, Padberg GW, Shaw DW, van der Maarel SM, Tapscott SJ. Clinical trial preparedness in facioscapulohumeral muscular dystrophy: Clinical, tissue, and imaging outcome measures 29-30 May 2015, Rochester, New York. Neuromuscul Disord. 2016 Feb;26(2):181-6. PubMed PMID: 26627872. c. Statland J, Donlin-Smith CM, Tapscott SJ, van der Maarel S, Tawil R. Multiplex Screen of Serum Biomarkers in Facioscapulohumeral Muscular Dystrophy. J Neuromuscul Dis. 2014;1(2):181-190. PubMed PMID: 25705588; PubMed Central PMCID: PMC4332410. d. Statland JM, McDermott MP, Heatwole C, Martens WB, Pandya S, van der Kooi EL, Kissel JT, Wagner KR, Tawil R. Reevaluating measures of disease progression in facioscapulohumeral muscular dystrophy. Neuromuscul Disord. 2013 Apr;23(4):306-12. PubMed PMID: 23406877; PubMed Central PMCID: PMC3602208.

4. At time of rapid genetic characterization of muscle , I identified several families with a unique form of periodic , known at the under the eponym Andersen syndrome. These families allowed for a better and more complete characterization of this condition. Additionally, unlike other muscle channelopathies associated with channels expressed only in , Andersen syndrome patients had predilection for ventricular arrhythmias. This led me to focus exam more carefully their ECGs and discover that a long QT interval is an integral feature of condition and was what predisposed these patients to potential fatal ventricular arrhythmias. In collaboration with Dr. Louis Ptacek, the gene for this condition was identified. The condition is now knows as Andersen Tawil syndrome or LQT7.

a. Zhang L, Benson DW, Tristani-Firouzi M, Ptacek LJ, Tawil R, Schwartz PJ, George AL, Horie M, Andelfinger G, Snow GL, Fu YH, Ackerman MJ, Vincent GM. Electrocardiographic features in Andersen-Tawil syndrome patients with KCNJ2 mutations: characteristic T-U-wave patterns predict the KCNJ2 genotype. Circulation. 2005 May 31;111(21):2720-6. PubMed PMID: 15911703. b. Plaster NM, Tawil R, Tristani-Firouzi M, Canún S, Bendahhou S, Tsunoda A, Donaldson MR, Iannaccone ST, Brunt E, Barohn R, Clark J, Deymeer F, George AL Jr, Fish FA, Hahn A, Nitu A, Ozdemir C, Serdaroglu P, Subramony SH, Wolfe G, Fu YH, Ptácek LJ. Mutations in Kir2.1 cause the developmental and episodic electrical phenotypes of Andersen's syndrome. Cell. 2001 May 18;105(4):511-9. PubMed PMID: 11371347. c. Sansone V, Griggs RC, Meola G, Ptácek LJ, Barohn R, Iannaccone S, Bryan W, Baker N, Janas SJ, Scott W, Ririe D, Tawil R. Andersen's syndrome: a distinct periodic paralysis. Ann Neurol. 1997 Sep;42(3):305-12. PubMed PMID: 9307251.

5. Development of an FDA-approved treatment for periodic paralysis.Treatment of the periodic paralyses was based on anecdotal evidence and case series. Anecdotal evidence suggested dichlorphenamide was more effective than the more commonly used , we therefor conducted a randomized controlled study demonstrating the efficacy of this medication. A recently completed second study of dichlorphenamide, spearheaded by Dr. Robert Griggs confirmed our initial study. Based on the two studies, FDA registration was successfully obtained for dichlorphenamide as the first FDA-approved treatment for this condition.Subsequently, another study recently completed, spearheaded by Dr. Robert Griggs confirmed our initial study. Based on the two studies, a drug company is now seeking FDA approval to produce and market dichlorphenamide. This will be the first FDA approved drug for this condition. a. Sansone VA, Burge J, McDermott MP, Smith PC, Herr B, Tawil R, Pandya S, Kissel J, Ciafaloni E, Shieh P, Ralph JW, Amato A, Cannon SC, Trivedi J, Barohn R, Crum B, Mitsumoto H, Pestronk A, Meola G, Conwit R, Hanna MG, Griggs RC. Randomized, placebo-controlled trials of dichlorphenamide in periodic paralysis. Neurology. 2016 Apr 12;86(15):1408-16. PubMed PMID: 26865514; PubMed Central PMCID: PMC4831040. b. Tawil R, McDermott MP, Brown R Jr, Shapiro BC, Ptacek LJ, McManis PG, Dalakas MC, Spector SA, Mendell JR, Hahn AF, Griggs RC. Randomized trials of dichlorphenamide in the periodic paralyses. Working Group on Periodic Paralysis. Ann Neurol. 2000 Jan;47(1):46-53. PubMed PMID: 10632100.

Complete List of Published Work in My Bibliography: https://www.ncbi.nlm.nih.gov/pubmed?cmd=historysearch&querykey=3 D. Additional Information: Research Support and/or Scholastic Performance Ongoing Research Support

1 U01 NS101944-01, NIH/NINDS Tawil, Rabi (PI) 06/2017-06/2022 Clinical Trial Readiness to Solve Barriers to Drug Development in FSHD The overall aim of this study is to hasten drug development for facioscapulohumeral muscular dystrophy (FSHD). This proposal will develop novel outcome measures for use in both early phase studies (EIM) and in late phase registration studies (FSH-COM), and will determine genetic or demographic predictors of progression important for defining key eligibility criteria.

005872, Kenneth Cole Foundation Tawil, Rabi (PI) 01/01/16-12/31/19 FSHD Clinical Trials Network The overall, long term aim of this project is to expedite the development of new therapies for FSHD by building a core FSHD Clinical Trial Network composed of 4 institutions (University of Rochester; Kennedy Krieger Institute, Baltimore; Ohio State University, Columbus; and Kansas University, Kansas City) Role: PI

1P01 NS069539, Fred Hutchinson Cancer Ctr/NIH Tapscott, Stephen (PI) 04/15/10-09/29/20 The Pathogenesis of Facioscapulohumeral Muscular Dystrophy Following the initial PPG grant, we now have a greater understanding of the genetic and epigenetic changes in FSHD. This new grant seeks to expand our understanding of the underlying mechanisms in FSHD, focus on development of drugs that target the epigenetic de-repression of DUX4. The specific aim of the Rochester core is to continue to provide essential biological samples for the other PPG projects and develop clinical and molecular biomarkers. Role: Co-Investigator

059067-002, Friends of FSH Research and FSH Society Tawil, Rabi (PI) 06/01/16-05/31/19 Optimizing the Utility of the National FSHD Registry and Trial Recruitment The aim of this project is to offer present and future National FSHD Registry participants, who have not been genetically confirmed, the change to get detailed genetic testing for both FSHD1 and FSHD2. Role: PI

2U54NS048843, NIH Moxley, Richard T. III (PI) 09/30/18-08/31/18 Paul D. Wellstone Muscular Dystrophy Cooperative Research Center The goal of this program project is to establish optimal methods to assess treatment efficacy in DM1 patients and to identify potential new therapies. Role: Co-Investigator

1U54AR065139, University of Washington/NIH Chamberlain, Jeffrey (PI) 05/07/14-04/30/18 Senator Paul D. Wellstone Muscular Dystrophy Cooperative Research Center The goal of this program project is to leverage the collaborative research programs on FSHD to establish cooperative clinical protocols and advance biomarker assessment of disease mechanisms in FSHD and treatment response. Project 2 is an observational study in FSHD of the correlation between muscle MRI, pathology and biomarkers. Role: Co-Investigator

005584 Acceleron Pharma Inc. 05/01/17-4/30/19 0.24 calendar months per subject reimbursement A Phase 1b/2 Randomized, Double-Blind, Placebo-Controlled Study of ACE-083 in Patients with Facioscapulohumeral Muscular Dystrophy (FSHD) The primary objective of this study is to evaluate the safety and tolerability of ACE-083 in patients with facioscapulohumeral muscular dystrophy (FSHD) Role: Site PI Completed Research Support U01 NS061795-05 McDermott, Michael P (PI) 07/01/10-06/30/16 Biostatistics and Data Management for a Trial of Corticosteroid Regimens in DMD Role: PI

FSHS-22013-01, FSH Society Statland, Jeffrey (PI) 08/01/13-06/30/16 Pilot Study of Electrical Myography in Facioscapulohumeral Muscular Dystrophy The goal of this project is to test the reliability of electrical impedance myography in facioscapulohumeral muscular dystrophy Role: Co-Investigator