+ Manuela Corti, PhD | Funding period: September 1, 2016 – March 1, 2019
Clinical outcome measures of efficacy in the treatment of Friedreich's ataxia
PI/Investigator: Manuela Corti, P.T., PhD
- University of Florida, FL, USA Award type:
General Research GrantGrant Title:
Clinical outcome measures of efficacy in the treatment of Friedreich's ataxia Lay summary:
The purpose of this multi-year longitudinal study is to identify the natural progression of Friedreich's Ataxia (FA), including disease phenotypes and their correlation with disease severity, current standard of care and adverse events. A key goal of this study is to develop and validate outcome measures that can be used in the development of future clinical trials for definitive treatment of FA. The development of a successful treatment is dependent not only on the understanding of the pathophysiological mechanisms of the disease and the attributes of the proposed therapeutic product, but also on the identification of sensitive and non-invasive, or minimally invasive outcome measures to demonstrate the potential effect of treatment. The identification of sensitive outcome measures evaluating both the cardiac, metabolic, and neuromuscular function in FA will be crucial to: 1) Evaluate the naturally-occurring changes in neural function as the result of growth, maturation, disease progression, or secondary consequences of the disease; and 2) Detect the effectiveness of potential therapeutic strategies. In this study, we will characterize measures of cardiac performance, neuromuscular physiology, speech and swallowing, as well as frataxin protein quantification in children and adults with FA. To achieve these objectives, we will use cutting edge techniques, including echocardiography and magnetic resonance imaging (MRI), metabolic exercise testing, neurophysiological and mass spectrometry measures. We are planning a 5-year, bi-annual, longitudinal study of 50 individuals with a confirmed diagnosis of Friedreich's Ataxia. Completion of this project will be an important milestone to advance the study of the natural history, discovery and validation of clinical outcome measures and biomarkers in FA. In addition, results of this study might be implemented in potential clinical trials to evaluate the effect of treatment. Publications
- Smith BK, Renno MS, Green MM, Sexton TM, Lawson LA, Martin AD, Corti M, and Byrne BJ. (2016) "Respiratory motor function in individuals with centronuclear myopathies." Muscle Nerve. 53:214-21.
- Doerfler P, Nayak S, Corti M, Morel L, Herzog R, and Byrne BJ. (2016) "Targeted Approaches to Induce Immune Tolerance for Pompe Disease Therapy." Molecular therapy. Methods & clinical development. 3:15053.
- Corti M, Cleaver B, Clément N, Conlon TJ, Faris KJ, Wang G, Benson J, Tarantal AF, Fuller D, Herzog RW, and Byrne BJ. (2015) "Evaluation of Readministration of a Recombinant Adeno-Associated Virus Vector Expressing Acid Alpha-Glucosidase in Pompe Disease: Preclinical to Clinical Planning. Hum Gene Ther Clin Dev. 26:185-93.
- Corti M, Elder M, Falk D, Lawson L, Smith B, Nayak S, Conlon T, Clement N, Erger K, Lavassani E, Green M, Doerfler P, Herzog R, and Byrne B. (2014) "B-Cell Depletion is Protective Against Anti-AAV Capsid Immune Response: A Human Subject Case Study." Mol Ther Methods Clin Dev. 1. pii: 14033.
+ Chad Heatwole, MD | Funding period: October 1, 2018 – September 30, 2020
Developing a Clinically Relevant Disease Specific Patient Reported Outcome Measures for use in Friedreich's Ataxia Therapeutic Trials and FDA Drug Labeling Claims
Chad Heatwole, MD
- University of Rochester Medical Center, NY Award type:
General Research GrantGrant Title:
Developing a Clinically Relevant Disease Specific Patient Reported Outcome Measures for use in Friedreich's Ataxia Therapeutic Trials and FDA Drug Labeling ClaimsLay summary:
This research will utilize existing methods and infrastructure to develop and validate disease-specific, patient-reported outcome measures for clinical trials of patients with Friedreich's ataxia. This proposal will shift and refine current research paradigms by producing instruments that will efficiently identify relevant changes in several areas of Friedreich's ataxia patient health. All instruments will be developed and validated in accordance with FDA guidelines for use in drug labeling claims. In addition, input will be obtained from the Friedreich's ataxia research community to optimize the acceptance and use of each of these instruments. These measures will provide researchers with valuable tools to use in clinical trials of pediatric and adult Friedreich's ataxia patients. Although the validation techniques proposed in this study are considered industry standard by many, they have never been implemented on this scale for pediatric and adult Friedreich's ataxia. At the completion of our work, the Friedreich's ataxia research community will have valid and highly responsive outcome measures to aid in therapeutic assessment and therapeutic development in Friedreich's ataxia.Publications
- Chad Heatwole, Rita Bode, Nicholas Johnson, Jeanne Dekdebrun, Nuran Dilek, Katy Eichinger, James E. Hilbert, Eric Logigian, Elizabeth Luebbe, William Martens, Michael P. McDermott, Shree Pandya, Araya Puwanant, Nan Rothrock, Charles Thornton, Barbara G. Vickrey, David Victorson, Richard T. Moxley, III (2017) The Myotonic Dystrophy Health Index: Correlations with Clinical Tests and Patient Function. Muscle Nerve. Author manuscript; available in PMC 2017 Feb 1
- Heatwole C, Bode R, Johnson N, et al. Patient-reported impact of symptoms in myotonic dystrophy type 1 (PRISM-1) (2012) . Neurology. 79(4):348-357
- Heatwole C, Bode R, Johnson N, et al. (2013) The myotonic dystrophy health index: Initial evaluation of a new outcome measure. Muscle Nerve.
+ David Herrmann, MD & Peter Creigh, MD | Funding period: September 1, 2018 – August 31, 2020
In-Vivo Confocal Imaging of Meissner's Corpuscles as a Biomarker in Friedreich's Ataxia (FA)
David Herrmann, MBBCh – University of Rochester Medical Center, NYPI/Investigator:
Peter Creigh, MD – University of Rochester Medical Center, NYAward type:
General Research GrantGrant Title:
In-Vivo Confocal Imaging of Meissner's Corpuscles as a Biomarker in Friedreich's Ataxia (FA) Lay summary:
This is an extension of an observational study designed to determine the potential role of Meissner Corpuscle (MC) Imaging as a biomarker in FA. In the first phase, 16 FA patients and 16 healthy controls were recruited and studied over 12 months with a series of potential biomarkers. Several of these biomarkers looked promising, and this study is being extended to include an additional 11 participants with FA, and the study will continue for up to 24 months. This is a two-part study. An initial cross-sectional phase assessed the utility of MC imaging, quantitative sensory testing (QST) (touch-pressure, vibration (timed and quantitative) and cold detection thresholds), as biomarkers in FA. These candidate biomarkers will now be assessed longitudinally in a larger cohort of patients and for a longer period in this extension phase. The study will include a screening and baseline visit on the same day and 3 subsequent visits, conducted 6, 12 and 24 months after the initial study visit. The original study included only screening, baseline 6 and 12 month visits, and in this extension a 24 month measurement will be added.Co-Sponsor: Voyager Therapeutics
+ Ian Harding, PhD | Funding period: October 1, 2018 – September 30, 2020
Neuroinflammation in Friedreich Ataxia: Mechanism, Biomarker, and Therapeutic Target
PI/Investigator: Ian Harding, PhD
- Monash University, AustraliaAward type:
General Research GrantGrant Title:
Neuroinflammation in Friedreich Ataxia: Mechanism, Biomarker, and Therapeutic TargetLay summary:
This study aims to establish if in vivo biomarkers of inflammation exist in the brain and spinal cord of individuals with Friedreich ataxia (FRDA). Although clinical presentation and progression are variable in individuals with FRDA, a universal feature is ataxia and loss of motor control secondary to the significant neuropathology that typifies FRDA. Sustained activation of immune-responsive cells in the brain – termed neuroinflammation – may represent one mechanism contributing to this progressive neuropathology. Recent preclinical and post-mortem studies in FRDA report increased inflammatory metabolites and gliosis in the nervous system. Importantly, cell line and animal studies indicate that blocking the inflammatory response in FRDA may ameliorate cell death. The link between chronic neuroinflammation and progressive neurodegeneration has also become increasingly well-establish in other degenerative disorders, including Alzheimer's and Parkinson's diseases. This project will be the first to evaluate in vivo neuroinflammation and its link with measures of neurodegeneration in individuals with FRDA using a novel combination of magnetic resonance imaging (MRI) and positron emission tomography (PET) brain imaging approaches. Given there are currently no treatments that are proven to alter the devastating natural history of FRDA, identifying markers of neuroinflammation and uncovering its role in driving or exacerbating neuropathology in FRDA will be key to improving the understanding of disease mechanisms, tracking disease progression, and identifying and monitoring novel treatment approaches.Co-sponsor: fara Australia and FARA Ireland
- Selvadurai LP, Harding IH, Corben LA, Georgiou-Karistianis N. (2018). Cerebral abnormalities in Friedreich Ataxia: A review. Neuroscience & Biobehavioral Reviews 84: 394-406.
- Harding IH, Corben LA, Delatycki MB, Stagnitti MR, Storey E, Egan GF, Georgiou-Karistianis N. (2017). Cerebral compensation during motor function in Friedreich ataxia: The IMAGE-FRDA study. Movement Disorders 32(8): 1221-1229.
- Selvadurai LP*, Harding IH*, Corben LA, Stagnitti MR, Storey E, Egan GF, Delatycki MB, Georgiou- Karistianis N. (2016). Cerebral and cerebellar grey matter atrophy in Friedreich ataxia: The IMAGE-FRDA study. J Neurology 263(11): 2215-2223. *Equal Contribution
- Harding IH, Raniga P, Delatycki MB, Stagnitti MR, Corben LA, Storey E, Georgiou-Karistianis N, Egan GF. (2016). Tissue atrophy and elevated iron concentration in the extrapyramidal motor system in Friedreich ataxia: The IMAGE-FRDA study. J Neurology Neurosurgery and Psychiatry 87: 1261-1263.
- Harding IH, Corben LA, Storey E, Egan GF, Stagnitti MR, Poudel GR, Delatycki MB, Georgiou- Karistianis N. (2016). Fronto-cerebellar dysfunction and dysconnectivity underlying cognition in Friedreich ataxia: The IMAGE-FRDA study. Human Brain Mapping 37: 338-350.
+ Louise Corben, PhD | Funding period: July 1, 2018 - June 30, 2019
Developing a clinically meaningful instrumented measure of upper limb function in Friedreich ataxia
Louise Corben, PhD - Murdoch Children's Research Institute, Melbourne. AustraliaAward type: AFAF-FARA Ride Ataxia Europe Research AwardGrant Title:
Developing a clinically meaningful instrumented measure of upper limb function in Friedreich ataxiaLay summary:
This prospective longitudinal study aims to develop and evaluate the capacity of an upper limb measure to capture change in function over a 4.5 and 9 month period in 40 individuals with Friedreich ataxia (FRDA). We have developed an instrumented measure of upper limb function which has the potential to be a sensitive and clinically relevant biomarker for use in future clinical trials. This measure has arisen from a conceptual framework that has evaluated the strengths and limitations of current tools, identified specific motor components that contribute to upper limb impairment in FRDA as well as the upper limb activities that are meaningful and relevant to individuals with FRDA. Importantly the conceptual framework underlying this new measure has ensured the specific functional capacity as measured by this tool would enhance quality of life if it was maintained or improved by therapeutic intervention. Moreover, not only does this tool measure functional capacity it correlates with and detects upper limb ataxia as measured by clinical testing thus ensuring measurement of ataxia while completing a functional task, as well as overcoming assessor bias and skill. Our compelling preliminary data using this measure, a BioKin-WMS wireless motion capture device in the pre-oral phase of eating in individuals with FRDA, has demonstrated the face and discriminate validity of this tool, but indicates that a prospective longitudinal study with greater power is now required to evaluate both the reliability and capacity of the tool to measure change over time. This study has the potential to validate this novel clinically meaningful instrumented upper limb measure for FRDA as a biomarker for use in clinical trials. Importantly, if validity and reliability are established, this upper limb measure will provide a functionally meaningful outcome measure that will reflect the clinical trajectory of FRDA and enable inclusion in future clinical trials of those individuals who are currently unable to complete the traditional measures, in particular those that involve ambulation.Co-sponsor: Association Française de l'Ataxie de FriedreichPublications
- Milne SC, Corben LA, Roberts M, Murphy A, Tai G, Georgiou-Karistianis N, Yiu EM, Delatycki MB. (2018) Can rehabilitation improve the health and wellbeing in Friedreich's ataxia: a randomised controlled trial. Clinical Rehabilitation 32(5):630-643
- Milne SC, Murphy A, Georgiou-Karistianis N, Yiu EM, Delatycki MB, Corben LA (2018) Psychometric properties of outcome measures evaluating decline in gait in cerebellar ataxia: a systematic review. Gait and Posture, 61: 149-162
- Tai G, Yiu EM, Delatycki MB, Corben LA. (2017) How does performance of the Friedreich Ataxia Functional Composite compare to rating scales? Journal of Neurology, 264(8): 1768-1776.
- Corben LA, Klopper F, Stagnitti MM, Georgiou-Karistianis N, Bradshaw JL, Rance G, Delatycki MB. (2017) Measuring Inhibition and Cognitive Flexibility in Friedreich Ataxia. Cerebellum, 16(4):757-763.
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Center of Excellence in FA