Yvonne Naegelin1,2, Jens Kuhle3, Sabine Schädelin4, Alexandre N Datta5, Stefano Magon3, Michael Amann6,7, Christian Barro3, Gian Paolo Ramelli8, Kate Heesom9, Yves-Alain Barde10, Peter Weber5, Ludwig Kappos3. 1. Neurologic Clinic and Policlinic, Departments of Medicine, Clinical Research, Biomedicine and Biomedical Engineering, University Hospital Basel and University of Basel, Petersgraben 4, 4031, Basel, Switzerland. yvonne.naegelin@usb.ch. 2. School of Biosciences, Cardiff University, Cardiff, CF10 3AX, UK. yvonne.naegelin@usb.ch. 3. Neurologic Clinic and Policlinic, Departments of Medicine, Clinical Research, Biomedicine and Biomedical Engineering, University Hospital Basel and University of Basel, Petersgraben 4, 4031, Basel, Switzerland. 4. Clinical Trial Unit, Department of Clinical Research, University Hospital Basel, 4031, Basel, Switzerland. 5. Department of Pediatric Neurology and Developmental Medicine, University of Basel Children's Hospital, 4056, Basel, Switzerland. 6. Medical Image Analysis Center (MIAC) AG, 4051, Basel, Switzerland. 7. Department of Biomedical Engineering, University of Basel, 4123, Allschwil, Switzerland. 8. Neuropediatric Unit, Pediatric Institute of Southern Switzerland, 6500, Bellinzona, Switzerland. 9. University of Bristol Proteomics Facility, Bristol, BS8 1TD, UK. 10. School of Biosciences, Cardiff University, Cardiff, CF10 3AX, UK.
Abstract
BACKGROUND: Rett syndrome (RS) is a severe neurodevelopmental disorder for which there is no approved therapy. This study aimed to assess safety and efficacy of oral fingolimod in children with RS using a pre-post and case-control design. METHODS: At the University of Basel Children's Hospital, Basel, Switzerland, children with RS were included if they were older than 6 years and met the established diagnostic criteria of RS, including a positive MeCP2 mutation. Participants were observed 6 months before and after treatment and received 12 months of fingolimod treatment. Serum samples of 50 children without RS served as reference for brain-derived neurotrophic factor (BDNF) measurements. Primary outcome measures were safety and efficacy, the latter measured by change in levels of BDNF in serum/CSF (cerebrospinal fluid) and change in deep gray matter volumes measured by magnetic resonance imaging (MRI). Secondary outcome measure was efficacy measured by change in clinical scores [Vineland Adaptive Behaviour Scale (VABS), Rett Severity Scale (RSSS) and Hand Apraxia Scale (HAS)]. RESULTS: Six children with RS (all girls, mean and SD age 11.3 ± 3.1 years) were included. Serum samples of 50 children without RS (25 females, mean and SD age 13.5 ± 3.9 years) served as reference for BDNF measurements. No serious adverse events occurred. Primary and secondary outcome measures were not met. CSF BDNF levels were associated with all clinical scores: RSSS (estimate - 0.04, mult.effect 0.96, CI [0.94; 0.98], p = 0.03), HAS (estimate - 0.09, mult.effect 0.91, CI [0.89; 0.94], p < 0.01) and VABS (communication: estimate 0.03, mult.effect 1.03, CI [1.02; 1.04], p < 0.01/daily living: estimate 0.03, mult.effect 1.03, CI [1.02; 1.04], p < 0.01/social skills: estimate 0.07, mult.effect 1.08, CI [1.05; 1.11], p < 0.01/motoric skills: estimate 0.04, mult.effect 1.04, CI [1.03; 1.06], p = 0.02). CONCLUSIONS: In children with RS, treatment with fingolimod was safe. The study did not provide supportive evidence for an effect of fingolimod on clinical, laboratory, and imaging measures. CSF BDNF levels were associated with clinical scores, indicating a need to further evaluate its potential as a biomarker for RS. This finding should be further validated in independent patient groups. TRIAL REGISTRATION: Clinical Trials.gov NCT02061137, registered on August 27th 2013, https://clinicaltrials.gov/ct2/show/study/NCT02061137 .
BACKGROUND:Rett syndrome (RS) is a severe neurodevelopmental disorder for which there is no approved therapy. This study aimed to assess safety and efficacy of oral fingolimod in children with RS using a pre-post and case-control design. METHODS: At the University of Basel Children's Hospital, Basel, Switzerland, children with RS were included if they were older than 6 years and met the established diagnostic criteria of RS, including a positive MeCP2 mutation. Participants were observed 6 months before and after treatment and received 12 months of fingolimod treatment. Serum samples of 50 children without RS served as reference for brain-derived neurotrophic factor (BDNF) measurements. Primary outcome measures were safety and efficacy, the latter measured by change in levels of BDNF in serum/CSF (cerebrospinal fluid) and change in deep gray matter volumes measured by magnetic resonance imaging (MRI). Secondary outcome measure was efficacy measured by change in clinical scores [Vineland Adaptive Behaviour Scale (VABS), Rett Severity Scale (RSSS) and Hand Apraxia Scale (HAS)]. RESULTS: Six children with RS (all girls, mean and SD age 11.3 ± 3.1 years) were included. Serum samples of 50 children without RS (25 females, mean and SD age 13.5 ± 3.9 years) served as reference for BDNF measurements. No serious adverse events occurred. Primary and secondary outcome measures were not met. CSF BDNF levels were associated with all clinical scores: RSSS (estimate - 0.04, mult.effect 0.96, CI [0.94; 0.98], p = 0.03), HAS (estimate - 0.09, mult.effect 0.91, CI [0.89; 0.94], p < 0.01) and VABS (communication: estimate 0.03, mult.effect 1.03, CI [1.02; 1.04], p < 0.01/daily living: estimate 0.03, mult.effect 1.03, CI [1.02; 1.04], p < 0.01/social skills: estimate 0.07, mult.effect 1.08, CI [1.05; 1.11], p < 0.01/motoric skills: estimate 0.04, mult.effect 1.04, CI [1.03; 1.06], p = 0.02). CONCLUSIONS: In children with RS, treatment with fingolimod was safe. The study did not provide supportive evidence for an effect of fingolimod on clinical, laboratory, and imaging measures. CSF BDNF levels were associated with clinical scores, indicating a need to further evaluate its potential as a biomarker for RS. This finding should be further validated in independent patient groups. TRIAL REGISTRATION: Clinical Trials.gov NCT02061137, registered on August 27th 2013, https://clinicaltrials.gov/ct2/show/study/NCT02061137 .
Authors: Volker Brinkmann; Michael D Davis; Christopher E Heise; Rainer Albert; Sylvain Cottens; Robert Hof; Christian Bruns; Eva Prieschl; Thomas Baumruker; Peter Hiestand; Carolyn A Foster; Markus Zollinger; Kevin R Lynch Journal: J Biol Chem Date: 2002-04-19 Impact factor: 5.157
Authors: Arie R Gafson; Nicolas R Barthélemy; Pascale Bomont; Roxana O Carare; Heather D Durham; Jean-Pierre Julien; Jens Kuhle; David Leppert; Ralph A Nixon; Roy O Weller; Henrik Zetterberg; Paul M Matthews Journal: Brain Date: 2020-07-01 Impact factor: 13.501
Authors: Martina Zandl-Lang; Thomas Züllig; Martin Trötzmüller; Yvonne Naegelin; Lucia Abela; Bernd Wilken; Sabine Scholl-Buergi; Daniela Karall; Ludwig Kappos; Harald Köfeler; Barbara Plecko Journal: Metabolites Date: 2022-03-25