Potential Disease-Modifying Effects of Lithium Carbonate in Niemann-Pick Disease, Type C1

Shiqian Han, Huiwen Zhang, Mengni Yi, Xiaoqing Liu, Gustavo H B Maegawa, Yunding Zou, Qijun Wang, Dianqing Wu, Zhijia Ye, Shiqian Han, Huiwen Zhang, Mengni Yi, Xiaoqing Liu, Gustavo H B Maegawa, Yunding Zou, Qijun Wang, Dianqing Wu, Zhijia Ye

Abstract

Background: Niemann-Pick disease type C1 (NP-C1) is a rare, autosomal-recessive neurodegenerative disorder with no United States Food and Drug Administration (FDA)-approved drug. Lithium has been shown to have considerable neuroprotective effects for neurological disorders such as bipolar disorder, Alzheimer's disease and stroke and has been tested in many clinical trials. However, the pharmacological effect of lithium on NP-C1 neurodegenerative processes has not been investigated. The aim of this study was to provide an initial evaluation of the safety and feasibility of lithium carbonate in patients with NP-C1. Methods: A total of 13 patients diagnosed with NP-C1 who met the inclusion criteria received lithium orally at doses of 300, 600, 900, or 1,200 mg daily. The dose was reduced based on tolerance or safety observations. Plasma 7-ketocholesterol (7-KC), an emerging biomarker of NP-C1, was the primary endpoint. Secondary endpoints included NPC Neurological Severity Scores (NNSS) and safety. Results: Of the 13 patients with NP-C1 (12-33 years) enrolled, three withdrew (discontinuation of follow-up outpatient visits). The last observed post-treatment values of 7-KC concentrations (128 ng/ml, SEM 20) were significantly lower than pretreatment baselines values (185 ng/ml, SEM 29; p = 0.001). The mean NNSS was improved after lithium treatment at 12 months (p = 0.005). Improvement in swallowing capacity was observed in treated patients (p = 0.014). No serious adverse events were recorded in the patients receiving lithium. Conclusion: Lithium is a potential therapeutic option for NP-C1 patients. Larger randomized and double-blind clinical trials are needed to further support this finding. Clinical Trial Registration: ClinicalTrials.gov, NCT03201627.

Keywords: 7-ketocholesterol; NNSS; clinical trial; lithium; niemann-pick disease.

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2021 Han, Zhang, Yi, Liu, Maegawa, Zou, Wang, Wu and Ye.

Figures

FIGURE 1
FIGURE 1
CONSORT flow diagram of patient recruitment until the 12-months follow-up.
FIGURE 2
FIGURE 2
Plasma lithium levels after receiving lithium carbonate. Every point represents that plasma lithium levels were detected after receiving lithium at doses of 300, 600, 900, or 1,200 mg. The first month was the dose adjustment period. and plasma lithium levels were measured by IC-MS once a week. The plasma lithium levels were then examined approximately every 3 months after the first month. Therefore, the lithium plasma levels of one patient were detected several times at one dose. conc, concentration.
FIGURE 3
FIGURE 3
Effect of lithium on 7-KC. (A) Plasma 7-KC concentration measured before and at the last follow-up after lithium administration in 13 patients. (B) The association of plasma 7-KC at baseline with changes in 7-KC. Concentration change of plasma 7-KC after oral doses of 300 mg (C), 600 mg (D) or 900 mg (E) of lithium carbonate. Each paired set of pre- and post-values represent an individual dose: 10 doses among four patients for 300 mg, five doses among three patients for 600 mg and 12 doses among six patients for 900 mg r is the Pearson correlation coefficient.
FIGURE 4
FIGURE 4
Effect of lithium on NNSS. The total NNSS of 13 patients who accepted lithium treatment obtained at multiple time points within 12 months.
FIGURE 5
FIGURE 5
The total NNSS (A) and swallowing (B) domain score recorded at the pre-study and 12-months visits. Change in total score and swallowing domain score from the pre-study to the final visit assessment.

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