Wassmer, S. | bioRxiv Science

bioRxiv2023

Upregulation of steroidogenesis is associated with coma in human cerebral malaria

P. falciparum parasites manipulate host metabolic processes during malaria to ensure their survival and progression, causing the host and parasite metabolic pathways to become intertwined. We analyzed metabolites to evaluate their potential as biomarkers for cerebral malaria (CM). Our analysis of CM (with coma) and CM-like (without coma) patients identified 835 metabolites, including lipids, amino acids, xenobiotics, peptides, nucleotides, carbohydrates, cofactors, and vitamins. Principal component analysis revealed clear segregation between CM-like and CM patients. Metabolite-by-metabolite analysis identified 103 differentially abundant metabolites, 26 of which were significantly lower in CM-like patients (primarily lipids), while 71% of those higher in CM patients were amino acids and xenobiotics. The results revealed significant differences in circulating levels of long chain free fatty acids and catecholamine metabolism and identified steroid biosynthesis as the most enriched lipid metabolism pathway, with eight endogenous steroids showing significantly higher levels in CM patients compared to CM-like patients (FC > 2, B-H FDR-adjusted P < 0.05). These steroids include pregnenolone sulfate, pregnenediol sulfate, pregnenetriol sulfate, androsterone monosulfate, 16-OH-DHEA-S, DHEA-S, cortisol, and cortisone. High levels of pregnenolone and its downstream metabolic derivatives were significantly associated with coma in CM patients. Our findings suggest that monitoring circulating neurosteroid levels in patients could aid in the early identification of those at risk of coma, and may important implications for the clinical management of CM patients.

systems biology↗

bioRxiv2020

MCOLN1 gene-replacement therapy corrects neurologic dysfunction in the mouse model of mucolipidosis IV.

Mucolipidosis IV (MLIV, OMIM 252650) is an orphan disease leading to debilitating psychomotor deficits and vision loss. It is caused by loss-of-function mutations in the MCOLN1 gene that encodes thethe lysosomal transient receptor potential channel mucolipin 1 (TRPML1). With no existing therapy, the unmet need in this disease is very high. Here we show that AAV-mediated gene transfer of the human MCOLN1 gene rescues motor function and alleviates brain pathology in the Mcoln1-/- MLIV mouse model. Using the AAV-PHP.b vector for initial proof-of-principle experiments in symptomatic mice, we showed long-term reversal of declined motor function and significant delay of paralysis. Next, we designed self-complimentary AAV9 vector for clinical use and showed that its intracerebroventricular administration in post-natal day 1 mice significantly improved motor function and myelination and reduced lysosomal storage load in the MLIV mouse brain. We also showed that CNS targeted gene transfer is necessary to achieve therapeutic efficacy in this disease. Based on our data and general advancements in the gene therapy field, we propose scAAV9-mediated CSF-targeted MCOLN1 gene transfer as a therapeutic strategy in MLIV.

genetics↗