TY - JOUR
T1 - Brain-enriched microRNAs circulating in plasma as novel biomarkers for Rett syndrome
AU - Sheinerman, Kira
AU - Djukic, Aleksandra
AU - Tsivinsky, Vladimir G.
AU - Umansky, Samuil R.
N1 - Funding Information:
SU, KS, and VT are employees of DiamiR, LLC. DiamiR received an award from the Rett Syndrome Research Trust (RSRT) for the animal work reported here. The RSRT (reverserett.org) contributed to the animal study design by participating in the initial discussions; introducing us to Dr. D. Katz, who provided the Mecp2tm1.1Jae animal model used in the studies described in this manuscript; and encouraging the making of the study results available to the research community. The RSRT had no role in data collection and analysis or in the preparation of the manuscript. The authors would like to thank Dr. D. Katz and his laboratory for providing the Mecp2tm1.1Jae mouse model and Dr. B. Martinez for providing helpful comments and editing the manuscript.
Publisher Copyright:
© 2019 Sheinerman et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
PY - 2019/6/1
Y1 - 2019/6/1
N2 - Rett syndrome (RTT) is a severe neurodevelopmental disorder caused by mutations in the X-linked gene MECP2 (methyl-CpG-binding protein 2). Minimally invasive and accurate biomarkers of disease progression and treatment response could facilitate screening of therapeutic compounds in animal models, enrollment of better-defined participants into clinical trials, and treatment monitoring. In this study, we used a targeted approach based on analysis of brain-enriched microRNAs (miRNAs) circulating in plasma to identify miRNA biomarkers of RTT using Mecp2-mutant mice as a model system and human plasma samples. An “miRNA pair” approach, i.e. the ratio between two miRNAs, was used for data normalization. Specific miRNA pairs and their combinations (classifiers) analyzed in plasma differentiated wild-type from Mecp2 male and female mice with >90% accuracy. Individual miRNA pairs were more effective in distinguishing male (homozygous) animals than female (heterozygous) animals, suggesting that disease severity correlated with the levels of the miRNA biomarkers. In the human study, 30 RTT patients were compared with age-matched controls. The results of this study showed that miRNA classifiers were able to differentiate RTT patients from controls with 85–100% sensitivity. In addition, a comparison of various age groups demonstrated that the dynamics in levels of miRNAs appear to be associated with disease development (involvement of liver, muscle and lipid metabolism in the pathology). Importantly, certain miRNA biomarker pairs were common to both the animal models and human subjects, indicating the similarity between the underlying pathological processes. The data generated in this feasibility study suggest that circulating miRNAs have the potential to be developed as markers of RTT progression and treatment response. Larger clinical studies are needed to further evaluate the findings presented here.
AB - Rett syndrome (RTT) is a severe neurodevelopmental disorder caused by mutations in the X-linked gene MECP2 (methyl-CpG-binding protein 2). Minimally invasive and accurate biomarkers of disease progression and treatment response could facilitate screening of therapeutic compounds in animal models, enrollment of better-defined participants into clinical trials, and treatment monitoring. In this study, we used a targeted approach based on analysis of brain-enriched microRNAs (miRNAs) circulating in plasma to identify miRNA biomarkers of RTT using Mecp2-mutant mice as a model system and human plasma samples. An “miRNA pair” approach, i.e. the ratio between two miRNAs, was used for data normalization. Specific miRNA pairs and their combinations (classifiers) analyzed in plasma differentiated wild-type from Mecp2 male and female mice with >90% accuracy. Individual miRNA pairs were more effective in distinguishing male (homozygous) animals than female (heterozygous) animals, suggesting that disease severity correlated with the levels of the miRNA biomarkers. In the human study, 30 RTT patients were compared with age-matched controls. The results of this study showed that miRNA classifiers were able to differentiate RTT patients from controls with 85–100% sensitivity. In addition, a comparison of various age groups demonstrated that the dynamics in levels of miRNAs appear to be associated with disease development (involvement of liver, muscle and lipid metabolism in the pathology). Importantly, certain miRNA biomarker pairs were common to both the animal models and human subjects, indicating the similarity between the underlying pathological processes. The data generated in this feasibility study suggest that circulating miRNAs have the potential to be developed as markers of RTT progression and treatment response. Larger clinical studies are needed to further evaluate the findings presented here.
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U2 - 10.1371/journal.pone.0218623
DO - 10.1371/journal.pone.0218623
M3 - Article
C2 - 31291284
AN - SCOPUS:85069608873
SN - 1932-6203
VL - 14
JO - PLoS One
JF - PLoS One
IS - 7
M1 - e0218623
ER -
