Pyrimethamine Significantly Lowers CSF/SOD1 in ALS Patients With SOD1 Mutations

Dale J. Lange; Mona Shahbazi; Vincenzo Silani; Albert C Ludolph; Jochen H Weishaupt; Senda Ajroud-Driss; Kara G Fields; Rahul Remanan; Stanley H Appel; Claudia Morelli; Alberto Doretti; Luca Maderna; Stefano Messina; Ulrike Weiland; Stefan L Marklund; Peter M Andersen

doi:10.1002/ana.24950

Pyrimethamine Significantly Lowers CSF/SOD1 in ALS Patients With SOD1 Mutations

Dale J. Lange, Mona Shahbazi, Vincenzo Silani, Albert C Ludolph, Jochen H Weishaupt, Senda Ajroud-Driss, Kara G Fields, Rahul Remanan, Stanley H Appel, Claudia Morelli, Alberto Doretti, Luca Maderna, Stefano Messina, Ulrike Weiland, Stefan L Marklund, Peter M Andersen

Research output: Contribution to journal › Article › peer-review

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Abstract

BACKGROUND: Cu/Zn superoxide dismutase (SOD1) reduction prolongs survival in SOD1-transgenic animal models. Pyrimethamine produces dose dependent SOD1 reduction in cell culture systems. A previous phase-1 trial showed pyrimethamine lowers SOD1 levels in leucocytes in patients with SOD1 mutations. This study investigated whether pyrimethamine lowered SOD1 levels in the cerebrospinal fluid (CSF) in patients carrying SOD1 mutations linked to ALS (fALS/SOD1).

METHODS AND STUDY DESIGN: Multicenter (5 sites), open-label, 9-month duration, dose-ranging, to determine safety and efficacy of pyrimethamine to lower SOD1 levels in the CSF of FALS/SOD1. All participants underwent 3 lumbar punctures, blood draw, clinical assessment of strength, motor function, quality of life, and adverse effects assessments. SOD1 levels were measured in erythrocytes and CSF. Pyrimethamine was measured in plasma and CSF. Appel ALS, ALSFRS-R and single item McGill Quality of Life (SIS-MQoL) were measured at screening, visit 6 and 9.

RESULTS: We enrolled 32 patients; 24 completed 6 visits (18 weeks) and 21 completed all study visits. A linear mixed effects model showed a significant reduction in CSF SOD1 at visit 6 (p<0.001) with a mean reduction of 13.5% (95% CI: 8.4, 18.5) and at visit 9 (p<0.001) with a mean reduction of 10.5% (95% CI: 5.2, 15.8).

INTERPRETATION: Pyrimethamine is safe and well tolerated in ALS. Pyrimethamine is capable of producing a significant reduction in total CSF SOD1 protein content in patients with ALS caused by different SOD1 mutations. Further long-term studies are warranted to assess clinical efficacy. This article is protected by copyright. All rights reserved.

Original language	English (US)
Journal	Annals of Neurology
DOIs	https://doi.org/10.1002/ana.24950
State	E-pub ahead of print - May 8 2017

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Journal Article

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10.1002/ana.24950

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Lange, D. J., Shahbazi, M., Silani, V., Ludolph, A. C., Weishaupt, J. H., Ajroud-Driss, S., Fields, K. G., Remanan, R., Appel, S. H., Morelli, C., Doretti, A., Maderna, L., Messina, S., Weiland, U., Marklund, S. L., & Andersen, P. M. (2017). Pyrimethamine Significantly Lowers CSF/SOD1 in ALS Patients With SOD1 Mutations. Annals of Neurology. Advance online publication. https://doi.org/10.1002/ana.24950

@article{d2e2bb367e97458ea970c503acb53a59,

title = "Pyrimethamine Significantly Lowers CSF/SOD1 in ALS Patients With SOD1 Mutations",

abstract = "BACKGROUND: Cu/Zn superoxide dismutase (SOD1) reduction prolongs survival in SOD1-transgenic animal models. Pyrimethamine produces dose dependent SOD1 reduction in cell culture systems. A previous phase-1 trial showed pyrimethamine lowers SOD1 levels in leucocytes in patients with SOD1 mutations. This study investigated whether pyrimethamine lowered SOD1 levels in the cerebrospinal fluid (CSF) in patients carrying SOD1 mutations linked to ALS (fALS/SOD1).METHODS AND STUDY DESIGN: Multicenter (5 sites), open-label, 9-month duration, dose-ranging, to determine safety and efficacy of pyrimethamine to lower SOD1 levels in the CSF of FALS/SOD1. All participants underwent 3 lumbar punctures, blood draw, clinical assessment of strength, motor function, quality of life, and adverse effects assessments. SOD1 levels were measured in erythrocytes and CSF. Pyrimethamine was measured in plasma and CSF. Appel ALS, ALSFRS-R and single item McGill Quality of Life (SIS-MQoL) were measured at screening, visit 6 and 9.RESULTS: We enrolled 32 patients; 24 completed 6 visits (18 weeks) and 21 completed all study visits. A linear mixed effects model showed a significant reduction in CSF SOD1 at visit 6 (p<0.001) with a mean reduction of 13.5% (95% CI: 8.4, 18.5) and at visit 9 (p<0.001) with a mean reduction of 10.5% (95% CI: 5.2, 15.8).INTERPRETATION: Pyrimethamine is safe and well tolerated in ALS. Pyrimethamine is capable of producing a significant reduction in total CSF SOD1 protein content in patients with ALS caused by different SOD1 mutations. Further long-term studies are warranted to assess clinical efficacy. This article is protected by copyright. All rights reserved.",

keywords = "Journal Article",

author = "Lange, {Dale J.} and Mona Shahbazi and Vincenzo Silani and Ludolph, {Albert C} and Weishaupt, {Jochen H} and Senda Ajroud-Driss and Fields, {Kara G} and Rahul Remanan and Appel, {Stanley H} and Claudia Morelli and Alberto Doretti and Luca Maderna and Stefano Messina and Ulrike Weiland and Marklund, {Stefan L} and Andersen, {Peter M}",

note = "{\textcopyright} 2017 American Neurological Association.",

year = "2017",

month = may,

day = "8",

doi = "10.1002/ana.24950",

language = "English (US)",

journal = "Annals of Neurology",

issn = "0364-5134",

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TY - JOUR

T1 - Pyrimethamine Significantly Lowers CSF/SOD1 in ALS Patients With SOD1 Mutations

AU - Lange, Dale J.

AU - Shahbazi, Mona

AU - Silani, Vincenzo

AU - Ludolph, Albert C

AU - Weishaupt, Jochen H

AU - Ajroud-Driss, Senda

AU - Fields, Kara G

AU - Remanan, Rahul

AU - Appel, Stanley H

AU - Morelli, Claudia

AU - Doretti, Alberto

AU - Maderna, Luca

AU - Messina, Stefano

AU - Weiland, Ulrike

AU - Marklund, Stefan L

AU - Andersen, Peter M

PY - 2017/5/8

Y1 - 2017/5/8

N2 - BACKGROUND: Cu/Zn superoxide dismutase (SOD1) reduction prolongs survival in SOD1-transgenic animal models. Pyrimethamine produces dose dependent SOD1 reduction in cell culture systems. A previous phase-1 trial showed pyrimethamine lowers SOD1 levels in leucocytes in patients with SOD1 mutations. This study investigated whether pyrimethamine lowered SOD1 levels in the cerebrospinal fluid (CSF) in patients carrying SOD1 mutations linked to ALS (fALS/SOD1).METHODS AND STUDY DESIGN: Multicenter (5 sites), open-label, 9-month duration, dose-ranging, to determine safety and efficacy of pyrimethamine to lower SOD1 levels in the CSF of FALS/SOD1. All participants underwent 3 lumbar punctures, blood draw, clinical assessment of strength, motor function, quality of life, and adverse effects assessments. SOD1 levels were measured in erythrocytes and CSF. Pyrimethamine was measured in plasma and CSF. Appel ALS, ALSFRS-R and single item McGill Quality of Life (SIS-MQoL) were measured at screening, visit 6 and 9.RESULTS: We enrolled 32 patients; 24 completed 6 visits (18 weeks) and 21 completed all study visits. A linear mixed effects model showed a significant reduction in CSF SOD1 at visit 6 (p<0.001) with a mean reduction of 13.5% (95% CI: 8.4, 18.5) and at visit 9 (p<0.001) with a mean reduction of 10.5% (95% CI: 5.2, 15.8).INTERPRETATION: Pyrimethamine is safe and well tolerated in ALS. Pyrimethamine is capable of producing a significant reduction in total CSF SOD1 protein content in patients with ALS caused by different SOD1 mutations. Further long-term studies are warranted to assess clinical efficacy. This article is protected by copyright. All rights reserved.

AB - BACKGROUND: Cu/Zn superoxide dismutase (SOD1) reduction prolongs survival in SOD1-transgenic animal models. Pyrimethamine produces dose dependent SOD1 reduction in cell culture systems. A previous phase-1 trial showed pyrimethamine lowers SOD1 levels in leucocytes in patients with SOD1 mutations. This study investigated whether pyrimethamine lowered SOD1 levels in the cerebrospinal fluid (CSF) in patients carrying SOD1 mutations linked to ALS (fALS/SOD1).METHODS AND STUDY DESIGN: Multicenter (5 sites), open-label, 9-month duration, dose-ranging, to determine safety and efficacy of pyrimethamine to lower SOD1 levels in the CSF of FALS/SOD1. All participants underwent 3 lumbar punctures, blood draw, clinical assessment of strength, motor function, quality of life, and adverse effects assessments. SOD1 levels were measured in erythrocytes and CSF. Pyrimethamine was measured in plasma and CSF. Appel ALS, ALSFRS-R and single item McGill Quality of Life (SIS-MQoL) were measured at screening, visit 6 and 9.RESULTS: We enrolled 32 patients; 24 completed 6 visits (18 weeks) and 21 completed all study visits. A linear mixed effects model showed a significant reduction in CSF SOD1 at visit 6 (p<0.001) with a mean reduction of 13.5% (95% CI: 8.4, 18.5) and at visit 9 (p<0.001) with a mean reduction of 10.5% (95% CI: 5.2, 15.8).INTERPRETATION: Pyrimethamine is safe and well tolerated in ALS. Pyrimethamine is capable of producing a significant reduction in total CSF SOD1 protein content in patients with ALS caused by different SOD1 mutations. Further long-term studies are warranted to assess clinical efficacy. This article is protected by copyright. All rights reserved.

KW - Journal Article

U2 - 10.1002/ana.24950

DO - 10.1002/ana.24950

M3 - Article

C2 - 28480639

SN - 0364-5134

JO - Annals of Neurology

JF - Annals of Neurology

ER -

Pyrimethamine Significantly Lowers CSF/SOD1 in ALS Patients With SOD1 Mutations

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