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Article

Characterization of Fluid Biomarkers Reveals Lysosome Dysfunction and Neurodegeneration in Neuronopathic MPS II Patients

1
Denali Therapeutics Inc., South San Francisco, CA 94080, USA
2
Department of Neuroscience, University of California, San Francisco, San Francisco, CA 94158, USA
3
Department of Pediatrics, Children’s Hospital of Pittsburgh, Pittsburgh, PA 15224, USA
*
Authors to whom correspondence should be addressed.
Equal contribution.
Int. J. Mol. Sci. 2020, 21(15), 5188; https://doi.org/10.3390/ijms21155188
Received: 28 June 2020 / Revised: 19 July 2020 / Accepted: 19 July 2020 / Published: 22 July 2020
(This article belongs to the Special Issue Mucopolysaccharidoses: Diagnosis, Treatment, and Management)
Mucopolysaccharidosis type II is a lysosomal storage disorder caused by a deficiency of iduronate-2-sulfatase (IDS) and characterized by the accumulation of the primary storage substrate, glycosaminoglycans (GAGs). Understanding central nervous system (CNS) pathophysiology in neuronopathic MPS II (nMPS II) has been hindered by the lack of CNS biomarkers. Characterization of fluid biomarkers has been largely focused on evaluating GAGs in cerebrospinal fluid (CSF) and the periphery; however, GAG levels alone do not accurately reflect the broad cellular dysfunction in the brains of MPS II patients. We utilized a preclinical mouse model of MPS II, treated with a brain penetrant form of IDS (ETV:IDS) to establish the relationship between markers of primary storage and downstream pathway biomarkers in the brain and CSF. We extended the characterization of pathway and neurodegeneration biomarkers to nMPS II patient samples. In addition to the accumulation of CSF GAGs, nMPS II patients show elevated levels of lysosomal lipids, neurofilament light chain, and other biomarkers of neuronal damage and degeneration. Furthermore, we find that these biomarkers of downstream pathology are tightly correlated with heparan sulfate. Exploration of the responsiveness of not only CSF GAGs but also pathway and disease-relevant biomarkers during drug development will be crucial for monitoring disease progression, and the development of effective therapies for nMPS II. View Full-Text
Keywords: mucopolysaccharidosis type II; Hunter syndrome; biomarkers; ETV:IDS; glycosaminoglycans (GAGs); heparan sulfate (HS); dermatan sulfate (DS); inflammation; lysosome dysfunction; neurodegeneration; neurofilament light chain (Nf-L); cerebrospinal fluid; GM3; gangliosides mucopolysaccharidosis type II; Hunter syndrome; biomarkers; ETV:IDS; glycosaminoglycans (GAGs); heparan sulfate (HS); dermatan sulfate (DS); inflammation; lysosome dysfunction; neurodegeneration; neurofilament light chain (Nf-L); cerebrospinal fluid; GM3; gangliosides
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MDPI and ACS Style

Bhalla, A.; Ravi, R.; Fang, M.; Arguello, A.; Davis, S.S.; Chiu, C.-L.; Blumenfeld, J.R.; Nguyen, H.N.; Earr, T.K.; Wang, J.; Astarita, G.; Zhu, Y.; Fiore, D.; Scearce-Levie, K.; Diaz, D.; Cahan, H.; Troyer, M.D.; Harris, J.M.; Escolar, M.L. Characterization of Fluid Biomarkers Reveals Lysosome Dysfunction and Neurodegeneration in Neuronopathic MPS II Patients. Int. J. Mol. Sci. 2020, 21, 5188. https://doi.org/10.3390/ijms21155188

AMA Style

Bhalla A, Ravi R, Fang M, Arguello A, Davis SS, Chiu C-L, Blumenfeld JR, Nguyen HN, Earr TK, Wang J, Astarita G, Zhu Y, Fiore D, Scearce-Levie K, Diaz D, Cahan H, Troyer MD, Harris JM, Escolar ML. Characterization of Fluid Biomarkers Reveals Lysosome Dysfunction and Neurodegeneration in Neuronopathic MPS II Patients. International Journal of Molecular Sciences. 2020; 21(15):5188. https://doi.org/10.3390/ijms21155188

Chicago/Turabian Style

Bhalla, Akhil, Ritesh Ravi, Meng Fang, Annie Arguello, Sonnet S. Davis, Chi-Lu Chiu, Jessica R. Blumenfeld, Hoang N. Nguyen, Timothy K. Earr, Junhua Wang, Giuseppe Astarita, Yuda Zhu, Damian Fiore, Kimberly Scearce-Levie, Dolores Diaz, Heather Cahan, Matthew D. Troyer, Jeffrey M. Harris, and Maria L. Escolar 2020. "Characterization of Fluid Biomarkers Reveals Lysosome Dysfunction and Neurodegeneration in Neuronopathic MPS II Patients" International Journal of Molecular Sciences 21, no. 15: 5188. https://doi.org/10.3390/ijms21155188

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