Abstract
GDF-15 is a biomarker for mitochondrial diseases. We investigated the application of GDF-15 as biomarker of disease severity and response to deoxynucleoside treatment in patients with thymidine kinase 2 (TK2) deficiency and compared it to FGF-21. GDF-15 and FGF-21 were measured in serum from 24 patients with TK2 deficiency treated 1–49 months with oral deoxynucleosides. Patients were grouped according to age at treatment and biomarkers were analyzed at baseline and various time points after treatment initiation. GDF-15 was elevated on average 30-fold in children and 6-fold in adults before the start of treatment. There was a significant correlation between basal GDF-15 and severity based on pretreatment distance walked (6MWT) and weight (BMI). During treatment, GDF-15 significantly declined, and the decrease was accompanied by relevant clinical improvements. The decline was greater in the paediatric group, which included the most severe patients and showed the greatest clinical benefit, than in the adult patients. The decline of FGF-21 was less prominent and consistent. GDF-15 is a potential biomarker of severity and of therapeutic response for patients with TK2 deficiency. In addition, we show evidence of clinical benefit of deoxynucleoside treatment, especially when treatment is initiated at an early age.
Highlights
Our group described the global gene expression profile of skeletal muscle from patients with thymidine kinase 2 (TK2) deficiency and identified the main molecular pathways implicated in the disease including the induction of Growth Differentiation Factor 15 (GDF-15) expression partly under the control of p53
We demonstrated that GDF-15 outperformed other diagnostic biomarkers for mitochondrial diseases and postulated that it may serve to monitor response to treatment based on preliminary data of one patient with TK2 deficiency that was treated with deoxynucleotides replacement therapy[14,15]
An expanded access program has shown a favorable side-effect profile and clinical efficacy of dNMP and deoxynucleoside therapies in patients with TK2 deficiency, some of them included in this study
Summary
Department, Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen del Rocío, Consejo Superior de Investigaciones Científicas, University of Seville, Seville, Spain. 6Neuropediatrics Department, Hospital Universitario Donostia, San Sebastian, Spain. 7Neuromuscular Disorders Unit, Neurology Department, Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen del Rocío, Consejo Superior de Investigaciones Científicas, University of Seville, Seville, Spain. 8Biomedical Network Research Centre on Neurodegenerative Diseases (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain. 9Neuromuscular Diseases Unit, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain. 10Department of Neurology, Columbia University Medical Center, New York, USA. 11Statistics Unit, Fundación Sant Joan de Déu, Barcelona, Spain. 12Moebius Research Ltd, Systems Biomedicine, London, UK. 13Research group on Neuromuscular and Mitochondrial Diseases, Vall d’Hebron Institut de Recerca, Universitat Autònoma de Barcelona, Barcelona, Spain. 14Departmento de Bioquímica y Biología. Department, Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen del Rocío, Consejo Superior de Investigaciones Científicas, University of Seville, Seville, Spain. In addition to contributing to a better understanding of diseases, biomarkers provide more sensitive and specific means of diagnosing and ways to determine responses to new treatments. In this way, they help to streamline clinical trial efficacy and reduce uncertainty in regulatory decision-making, accelerating drug approval and drug access for patients. A pharmacodynamics/response biomarker is used to show that a biological response has occurred in an individual who has been exposed to a medical product
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