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Translational Research Studies in Exercise-Related Muscle Disorders

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Translational Research Studies in Exercise-Related Muscle Disorders Translational Research Studies in Exercise-related Muscle Disorders Renata Siciliani Scalco A thesis submitted to the University College London for the degree of Doctor of Philosophy (PhD) UCL Institute of Neurology, Queen Square, London 1 I, Renata S. Scalco, confirm that the work presented in this thesis is my own. Where information has been derived from other sources, I confirm that this has been indicated in the thesis. Signature Date 2 To all patients with rare neuromuscular diseases, who have inspired this work 3 1. Abstract Translational research is the process that transfers knowledge from basic sciences to the clinical setting. This PhD thesis translates knowledge gained from animal model research in hypokalaemic periodic paralysis (HypoPP) and McArdle disease to humans affected by these conditions to identify new treatment options for both diseases. The efficacy of two compounds, sodium valproate and bumetanide, were assessed for the first time in humans with McArdle disease and HypoPP, respectively. For HypoPP, the role of the McManis test as an outcome measure was explored in a randomised, double-blind, placebo-controlled phase II clinical trial with a cross-over design. For McArdle disease, several outcome measures were explored in an open-label proof-of-concept phase II study. 2 mg bumetanide was not effective to abort a focal attack of weakness in an immobilised hand in the majority of the trial participants with HypoPP, but data presented here supports further studies of bumetanide in this population of patients. Extending the isometric exercise period to 10 minutes increased the sensitivity of the McManis test, and frequent compound muscle action potential (CMAP) amplitude assessments were shown to be useful in assessing both efficacy and safety. 20 mg/kg/day sodium valproate was ineffective in stimulating the expression of the brain glycogen phosphorylase enzyme in skeletal muscle of people with McArdle disease. Based on these results, further research into VPA as a treatment for McArdle disease is discouraged. The combination of several outcome measures contributed to data interpretation and should be considered in future studies exploring treatment efficacy in McArdle disease. The results of this research should contribute to future clinical trials in the field of exercise-related muscle disorders and provide valuable insights for translational research. 4 2. Impact Statement Currently, there are few pharmacological treatments for rare neuromuscular diseases. This research comprised two investigator-initiated phase II clinical trials developed to address this limitation for two such conditions: hypokalaemic periodic paralysis (HypoPP) and McArdle disease. The first clinical trial provided Class 1 evidence that 2 mg bumetanide was not effective to abort a focal attack of weakness in an immobilised hand in the majority of the trial participants with HypoPP. However, data presented here show that a beneficial effect cannot be entirely excluded, supporting further studies of bumetanide in this population of patients. This study also provides safety data for 2 mg bumetanide in normokalaemic HypoPP patients for the first time. In addition, this clinical trial illustrates the role of the McManis test as an outcome measure in clinical trials for HypoPP. Extending the isometric exercise period to 10 minutes increased the sensitivity of this diagnostic tool in the assessed participants, and further studies should be performed to confirm the finding in a larger cohort of patients. Frequent compound muscle action potential (CMAP) amplitude assessments were shown to be useful in assessing safety. The second clinical trial showed that oral treatment with sodium valproate (valproic acid, VPA) was ineffective in stimulating the expression of the brain glycogen phosphorylase enzyme in skeletal muscle of people with McArdle disease. Based on these results, further research into VPA as a treatment for McArdle disease is discouraged. This project also includes data relating to the safety of VPA treatment for people affected by McArdle disease. Based on findings in this study, it is reasonable to say that McArdle disease should not be considered a formal contraindication for VPA use in patients with a strong clinical indication for its prescription, such as epilepsy. In terms of study assessments, this research shows that the combination of several outcome measures contributed to data interpretation and should be considered in future studies exploring treatment efficacy in McArdle disease. The combination of highly specialised clinical services, an academic institution, an international registry and a patients’ association generated a valuable partnership for the promotion of clinical research. This was one of the most important insights gained in this research. Such partnerships may be key to overcoming the lack of treatment options for patients with very rare diseases. 5 3. Contents 1. Abstract .................................................................................................................................... 4 2. Impact Statement ...................................................................................................................... 5 3. Contents ................................................................................................................................... 6 4. Tables ..................................................................................................................................... 12 5. Figures .................................................................................................................................... 14 6. List of Abbreviations ................................................................................................................ 15 7. Acknowledgements ................................................................................................................. 19 8. Acknowledgements Related to the PhD Projects ..................................................................... 20 Bumetanide Clinical Trial ............................................................................................................. 20 Sodium Valproate Clinical Trial .................................................................................................... 20 9. Contribution ............................................................................................................................ 21 10. Introduction .......................................................................................................................... 22 Introduction to Translational Research ......................................................................................... 22 Translational Research in Rare Diseases .................................................................................... 24 Regulatory Bodies – Orphan Drug Designation ........................................................................ 27 Drug Repurposing Studies ........................................................................................................... 28 Scope of Study ............................................................................................................................ 29 11. Translational Research in Periodic Paralysis ........................................................................ 30 Introduction to HypoPP ................................................................................................................ 30 Prevalence .............................................................................................................................. 31 Clinical Features ..................................................................................................................... 31 Diagnosis ................................................................................................................................ 32 6 Exercise-related Disease ......................................................................................................... 33 Management ........................................................................................................................... 34 Novel Frontiers of Therapy in HypoPP: Bumetanide .................................................................... 35 Pre-clinical Research .............................................................................................................. 35 Clinical Research .................................................................................................................... 36 Outcome Measures in Clinical Trials ............................................................................................ 37 Opportunities for Translational Research ................................................................................. 37 12. Translational Research in McArdle Disease ......................................................................... 39 Introduction to McArdle Disease .................................................................................................. 39 Exercise-related Disease ......................................................................................................... 41 Prevalence .............................................................................................................................. 43 Clinical Features ....................................................................................................................
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