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. 2020 Jun 22;10(1):10111.
doi: 10.1038/s41598-020-66940-8.

Growth Differentiation Factor 15 is a potential biomarker of therapeutic response for TK2 deficient myopathy

Cristina Dominguez-Gonzalez  1   2   3 , Carmen Badosa  4 , Marcos Madruga-Garrido  5 , Itxaso Martí  6 , Carmen Paradas  7   8 , Carlos Ortez  4 , Jordi Diaz-Manera  3   9 , Andres Berardo  10 , Jorge Alonso-Pérez  9 , Selena Trifunov  4 , Daniel Cuadras  11 , Susana G Kalko  12 , Cora Blázquez-Bermejo  3   13 , Yolanda Cámara  3   13 , Ramon Martí  3   13 , Fabiola Mavillard  7   8 , Miguel A Martin  2   3 , Julio Montoya  3   14 , Eduardo Ruiz-Pesini  3   14 , Joan Villarroya  15   16 , Raquel Montero  3   17 , Francesc Villarroya  15   16 , Rafael Artuch  3   17 , Michio Hirano  10 , Andrés Nascimento  3   4 , Cecilia Jimenez-Mallebrera  18   19   20
Affiliations

Growth Differentiation Factor 15 is a potential biomarker of therapeutic response for TK2 deficient myopathy

Cristina Dominguez-Gonzalez et al. Sci Rep. .

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.

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Conflict of interest statement

MH, RM, Columbia University Medical Center (CUMC), and the Vall d’Hebron Research Institute (VHIR) have filed patent applications for deoxynucleoside and deoxynucleotide therapies for human mitochondrial DNA depletion and deletions syndrome including TK2 deficiency. RM, YC, CB, VHIR, and The Biomedical Network Research Centre on Rare Diseases (CIBERER) have filed patent applications covering potential use of deoxynucleoside treatment for POLG deficiency and other mtDNA replication defects in humans. CUMC, VHIR, and CIBERER have licensed pending patent applications related to these technologies to Modis Therapeutics, Inc. CUMC, VHIR, and CIBERER may be eligible to receive payments related to the development and commercialization of the technologies. Any potential licensing fees earned will be paid to CUMC, VHIR, and CIBERER and are shared with all inventors mentioned above through VHIR and CIBERER policies on distribution and objectivity in research. MH and RM serve as paid consultants to Modis Therapeutics, Inc. and RM has equity in this company. RM, YC, CB, VHIR, and The Biomedical Network Research Centre on Rare Diseases (CIBERER) have filed patent applications covering the potential use of deoxynucleoside treatment as a way to increase mtDNA copy number.

Figures

Figure 1
Figure 1
Pre-treatment GDF-15 and FGF-21 serum levels are associated with disease severity. Histograms representing the basal (before treatment) serum levels (mean and SEM) of GDF-15, FGF-21 and creatine kinase (CK) in patients from Group 1 (G1), those patients from Group 1 with the early onset and the most severe phenotype (G1-EO) and patients in Group 2 (G2). Dotted lines represent control values.
Figure 2
Figure 2
GDF-15 levels decreased during treatment with deoxynucleosides. Development of GDF-15 (A,B) and FGF-21 (C,D) circulating concentrations (pg/mL) over time in group 1 (left) and group 2 (right) patients.
Figure 3
Figure 3
GDF-15 levels do not decrease over time in the absence of treatment. Development of serum GDF-15 over 28 months in treated patients (black lines) from group 2 versus untreated patients (P25 and P26, red lines).
Figure 4
Figure 4
GDF-15 decrease was accompanied by improvement of several clinical outcome measures in treated patients. Development of selected functional tests for patients in group 1: 6MWT (A), HMFS (B), HMFSE (C), and % FVC (D) and for patients in group 2: 6MWT (E), NSAA (F), and % FVC (G) during treatment with deoxynucleosides. Correlation between basal levels of GDF-15 and FGF-21 in serum for group 1 (black) and group 2 (red) patients together (H).
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References

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