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

Autor: Bhalla A; Denali Therapeutics Inc., South San Francisco, CA 94080, USA., Ravi R; Denali Therapeutics Inc., South San Francisco, CA 94080, USA., Fang M; Denali Therapeutics Inc., South San Francisco, CA 94080, USA., Arguello A; Denali Therapeutics Inc., South San Francisco, CA 94080, USA., Davis SS; Denali Therapeutics Inc., South San Francisco, CA 94080, USA., Chiu CL; Denali Therapeutics Inc., South San Francisco, CA 94080, USA., Blumenfeld JR; Denali Therapeutics Inc., South San Francisco, CA 94080, USA.; Department of Neuroscience, University of California, San Francisco, San Francisco, CA 94158, USA., Nguyen HN; Denali Therapeutics Inc., South San Francisco, CA 94080, USA., Earr TK; Denali Therapeutics Inc., South San Francisco, CA 94080, USA., Wang J; Denali Therapeutics Inc., South San Francisco, CA 94080, USA., Astarita G; Denali Therapeutics Inc., South San Francisco, CA 94080, USA., Zhu Y; Denali Therapeutics Inc., South San Francisco, CA 94080, USA., Fiore D; Denali Therapeutics Inc., South San Francisco, CA 94080, USA., Scearce-Levie K; Denali Therapeutics Inc., South San Francisco, CA 94080, USA., Diaz D; Denali Therapeutics Inc., South San Francisco, CA 94080, USA., Cahan H; Denali Therapeutics Inc., South San Francisco, CA 94080, USA., Troyer MD; Denali Therapeutics Inc., South San Francisco, CA 94080, USA., Harris JM; Denali Therapeutics Inc., South San Francisco, CA 94080, USA., Escolar ML; Department of Pediatrics, Children's Hospital of Pittsburgh, Pittsburgh, PA 15224, USA.
Jazyk: angličtina
Zdroj: International journal of molecular sciences [Int J Mol Sci] 2020 Jul 22; Vol. 21 (15). Date of Electronic Publication: 2020 Jul 22.
DOI: 10.3390/ijms21155188
Abstrakt: 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.
Databáze: MEDLINE
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