Myasthenia gravis is a life-long debilitating disease characterized by severe muscle weakness. To avoid debilitating weakness and potentially fatal respiratory failure, patients with autoimmune myasthenia gravis usually require long-term immunosuppression with oral drugs. The diagnosis of myasthenia gravis is difficult when autoantibodies, most commonly directed against the acetylcholine receptor, are negative. Other diagnostic tools require specialized training and equipment that is not widely available, and many patients are misdiagnosed and inappropriately managed. In addition, there is a long delay between onset of therapy and clinical response with oral immunosuppressive drugs and no clinical or laboratory methods predict response. Development of novel biomarkers to meet these unmet needs will improve outcomes for myasthenia gravis patients. In this proposal, Dr. Guptill will investigate potential immunological biomarkers to predict clinical response to immunosuppressive drugs and as a diagnostic tool for patients suspected to have myasthenia gravis but without detectable autoantibodies. This comprehensive approach will include: development of assays to quantify antigen specific T- and B-cell frequencies in seronegative myasthenia gravis patients (Aim 1); a study to identify candidate T- and B- cell biomarkers predictive of clinical response to immunosuppressive drugs (Aim 2); and an evaluation of B- and T-regulatory cell phenotypes and function after initiating immunosuppressive therapy (Aim 3). The candidate is a neuromuscular medicine specialist with a proven commitment to patient-oriented research and a desire to develop expertise in immunological assays and biomarkers. These skills will facilitate the candidate's long-term career goal to advance public health by incorporating biomarker approaches into the design and conduct of early-phase trials in neuromuscular diseases. During the course of this K23 proposal Dr. Guptill will 1) acquire knowledge and skills in clinical immunology, trial design, and analysis of complex data sets; 2) develop the professional skills to successfully lead an early phase clinical trial research team; and 3) produce preliminary data and publications to support an R01 grant application and establish an independent biomarker research program in myasthenia gravis. This proposal will capitalize on unique opportunities provided by the Duke Translational Research Institute Immune Monitoring Core (Weinhold, mentor), the Duke Clinical Research Institute (Laskowitz, co-mentor), and the Duke Myasthenia Gravis Clinic. Concomitant with this proposed research, the candidate will receive advanced immunology training through focused coursework, laboratory rotations, and expert mentorship. The mentorship team assembled is uniquely qualified, and strengths include: extensive clinical research experience; internationally recognized leadership in trial design, research methods, biomarkers, informatics and statistics, autoimmunity, and immunology; and a successful history of junior faculty mentorship. At the conclusion of this program, Dr. Guptill will be well positioned to be an independent physician-scientist leading a research team.

Public Health Relevance

Autoimmune myasthenia gravis is a potentially deadly disease that often requires chronic immunosuppressive therapy. Two significant clinical needs include: 1) novel diagnostic tools for patients with undetectable autoantibodies; and 2) efficacy surrogates (biomarkers) that predict a future response to immunosuppressive therapy. To address this knowledge gap, this proposal uses innovative immunologic techniques to identify biomarkers in patients with myasthenia gravis that will improve diagnosis and predict therapeutic responses.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
5K23NS085049-04
Application #
9346114
Study Section
NST-2 Subcommittee (NST)
Program Officer
Nuckolls, Glen H
Project Start
2014-09-01
Project End
2019-07-31
Budget Start
2017-08-01
Budget End
2018-07-31
Support Year
4
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Duke University
Department
Neurology
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
Ericson, Jessica E; Zimmerman, Kanecia O; Gonzalez, Daniel et al. (2017) A Systematic Literature Review Approach to Estimate the Therapeutic Index of Selected Immunosuppressant Drugs After Renal Transplantation. Ther Drug Monit 39:13-20
Gonzalez, Daniel; Chamberlain, James M; Guptill, Jeffrey T et al. (2017) Population Pharmacokinetics and Exploratory Pharmacodynamics of Lorazepam in Pediatric Status Epilepticus. Clin Pharmacokinet 56:941-951
Guptill, Jeffrey T; Raja, Shruti M; Boakye-Agyeman, Felix et al. (2017) Phase 1 Randomized, Double-Blind, Placebo-Controlled Study to Determine the Safety, Tolerability, and Pharmacokinetics of a Single Escalating Dose and Repeated Doses of CN-105 in Healthy Adult Subjects. J Clin Pharmacol 57:770-776
Juel, Vern C; Sanders, Donald B; Hobson-Webb, Lisa D et al. (2017) Marked clinical and jitter improvement after eculizumab in refractory myasthenia. Muscle Nerve 56:E16-E18
Thakkar, Nilay; Guptill, Jeffrey T; AleŇ°, Kathy et al. (2017) Population Pharmacokinetics/Pharmacodynamics of 3,4-Diaminopyridine Free Base in Patients With Lambert-Eaton Myasthenia. CPT Pharmacometrics Syst Pharmacol 6:625-634
Yi, John S; Russo, Melissa A; Massey, Janice M et al. (2017) B10 Cell Frequencies and Suppressive Capacity in Myasthenia Gravis Are Associated with Disease Severity. Front Neurol 8:34
Burns, Ted M; Sadjadi, Reza; Utsugisawa, Kimiaki et al. (2016) International clinimetric evaluation of the MG-QOL15, resulting in slight revision and subsequent validation of the MG-QOL15r. Muscle Nerve 54:1015-1022
Ku, Lawrence C; Wu, Huali; Greenberg, Rachel G et al. (2016) Use of Therapeutic Drug Monitoring, Electronic Health Record Data, and Pharmacokinetic Modeling to Determine the Therapeutic Index of Phenytoin and Lamotrigine. Ther Drug Monit 38:728-737
Yi, John S; Russo, Melissa A; Weinhold, Kent J et al. (2016) Adaptive immune response to therapy in hmgcr autoantibody myopathy. Muscle Nerve 53:313-7
Gwathmey, Kelly G; Conaway, Mark R; Sadjadi, Reza et al. (2016) Construction and validation of the chronic acquired polyneuropathy patient-reported index (CAP-PRI): A disease-specific, health-related quality-of-life instrument. Muscle Nerve 54:9-17

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