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Allopregnanolone Treatment Improves Plasma Metabolomic Profile Associated with GABA Metabolism in Fragile X-Associated Tremor/Ataxia Syndrome: a Pilot Study

Abstract

Currently, there is no effective treatment for the fragile X-associated tremor/ataxia syndrome (FXTAS), a late-onset neurodegenerative disorder. In this pilot study, we evaluated whether allopregnanolone, a natural neurosteroid that exerts beneficial effects in neurodegenerative diseases, nervous system injury, and peripheral neuropathies, could improve lymphocytic bioenergetics and plasma pharmacometabolomics in six males with FXTAS (68 ± 3 years old; FMR1 CGG repeats 94 ± 4; FXTAS stages ranging from 3 to 5) enrolled in a 12-week open-label intervention study conducted at the University of California Davis from December 2015 through July 2016. Plasma pharmacometabolomics and lymphocytic mitochondria function were assessed at baseline (on the day of the first infusion) and at follow-up (within 48 h from the last infusion). In parallel, quantitative measurements of tremor and ataxia and neuropsychological evaluations of mental state, executive function, learning, memory, and psychological symptoms were assessed at the same time points. Allopregnanolone treatment impacted significantly GABA metabolism, oxidative stress, and some of the mitochondria-related outcomes. Notably, the magnitude of the individual metabolic response, as well as the correlation with some of the behavioral tests, was overwhelmingly carrier-specific. Based on this pilot study, allopregnanolone treatment has the potential for improving cognitive and GABA metabolism in FXTAS aligned with the concept of precision medicine.

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Acknowledgments

We thank the carriers that participated in this study. We thank Drs. Roberta Brinton and Robert Irwin for their protocol guidance and expertise regarding allopregnanolone treatment and for providing the sulfobutylether-β-cyclodextrin for this study. We would like to thank Dr. Daniel Tancredi (Department of Pediatrics, UC Davis School of Medicine) for his excellent contribution to the statistical analysis of this study. We also thank Ms. Catherine Ross-Inta, Gyu Song, and Ilaria Marsilio for their valuable technical assistance and Dr. Gerhart Bauer for his expertise in preparing the allopregnanolone solutions. This study was made possible by private donations to FXTAS research, NICHD grant HD036071, and the MIND Institute IDDRC U54HD079125.

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EN assessed most of the mitochondrial outcomes and helped in drafting, edited, and approved the final version of the manuscript; AS carried out cognitive and psychological testing on the patients, revised the manuscript, and approved the final manuscript; JW acquired neuroimaging data, performed statistical analysis, interpreted the results, and reviewed and approved the final version of the manuscript; AT and NRC analyzed neuropsychiatric tests and reviewed and approved the final version of the manuscript; FT provided lymphocytes, performed the genotyping, and revised and approved the manuscript; MR provided expertise in intravenous injection of allopregnanolone, reviewed the manuscript, and approved its final version; RJH carried out clinical assessment of these subjects, wrote clinical findings, and revised and approved the final version of the manuscript; and CG conceptualized the study, designed the experiments, analyzed the metabolomics data, and wrote the manuscript.

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Correspondence to Cecilia Giulivi.

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Conflict of Interest

RJH has received funding from Novartis, Roche/Genentech, Alcobra, and Neuren for treatment trials in fragile X syndrome, autism, and Down syndrome. She has also consulted with Novartis, Fulcrum, Zynerba, and Roche/Genentech regarding treatment for fragile X syndrome. The other authors have no conflicts of financial interest relevant to this article to disclose.

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Napoli, E., Schneider, A., Wang, J.Y. et al. Allopregnanolone Treatment Improves Plasma Metabolomic Profile Associated with GABA Metabolism in Fragile X-Associated Tremor/Ataxia Syndrome: a Pilot Study. Mol Neurobiol 56, 3702–3713 (2019). https://doi.org/10.1007/s12035-018-1330-3

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Keywords

  • Allopregnanolone
  • Bioenergetics
  • FXTAS
  • GABA
  • Lymphocytes
  • Pharmacometabolomics