Summary: According to researchers, a drug that has been used for decades to help treat malaria can lower levels of a biomarker associated with ALS.
Source: Hospital for Special Surgery.
Decades-old drug used to treat malaria targets genetic mutation in ALS patients.
A new study finds that a decades-old drug used to treat malaria lowers levels of a biomarker linked to the inherited form of amyotrophic lateral sclerosis, also known as ALS and Lou Gehrig’s Disease. The research, conducted by investigators at Hospital for Special Surgery (HSS) and other centers, was published online in the Annals of Neurology, in advance of the June print edition of the journal.
Some people with the inherited form of ALS have a mutation in the SOD1 gene. Researchers set out to determine if pyrimethamine, a drug that has been around for decades, could safely and effectively lower levels of the toxic protein produced by the gene mutation.
“Our multi-center international study found that pyrimethamine reduced levels of SOD1 in the cerebrospinal fluid of patients with familial ALS, and the amount of lowering was related to the dose of pyrimethamine,” noted Dale J. Lange, MD, principal investigator and neurologist-in-chief at HSS. “There is currently no cure for this devastating disease, but our study represents the first time a drug lowered a protein known to be relevant to disease progression; as such, a slowing of disease progression would be expected.”
Amyotrophic lateral sclerosis is a relentless disease that progressively attacks nerve cells in the brain and the spinal cord. As time goes on, patients lose the ability to initiate and control muscle movement, their speech is affected and they become paralyzed. Swallowing and breathing become increasingly difficult, and ALS is often fatal within three to five years. In addition to Lou Gehrig, acclaimed physicist Steven Hawkings is a well-known person with ALS.
The study, supported by a grant from the Muscular Dystrophy Association of America, enrolled 32 patients with various SOD1 genetic mutations linked to ALS. Participants had three lumbar punctures, blood studies, and a clinical assessment of strength, motor function, quality of life, and potential adverse effects. Out of the patients enrolled, 24 completed six visits over 18 weeks, and 21 completed all study visits.
The researchers noted that their study represents the largest prospective clinical and biological investigation of patients with familial ALS in the literature to date. “To our knowledge, this is the first study in humans with ALS that targeted and achieved a significant reduction of a disease-relevant biomarker in the cerebrospinal fluid. We found that pyrimethamine was safe and well tolerated in patients with ALS caused by different SOD1 mutations,” Dr. Lange noted.
“Although not proven by this study, a slowing of disease progression was observed. A larger study is needed, and is being planned, to determine if pyrimethamine does indeed influence the disease course in ALS patients.”
No significant change in quality of life was observed over the nine-month study period. Study limitations included the fact that patients had varying levels of disease severity, and those with the worst symptoms were more likely to drop out, according to the investigators.
Funding: The research was funded by the Muscular Dystrophy Association.
Source: Robin Frank – Hospital for Special Surgery
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Original Research: Full open access research for “Pyrimethamine significantly lowers cerebrospinal fluid Cu/Zn superoxide dismutase in amyotrophic lateral sclerosis patients with SOD1 mutations” by Dale J. Lange MD, Mona Shahbazi MSN, NP, BC-NP, OCNCNP, Vincenzo Silani MD, Albert C. Ludolph MD, PhD, Jochen H. Weishaupt MD, Senda Ajroud-Driss MD, Kara G. Fields MS, Rahul Remanan MB, Stanley H. Appel MD, Claudia Morelli MD, Alberto Doretti MD, Luca Maderna MD, Stefano Messina MD, Ulrike Weiland MD, Stefan L. Marklund MD, PhD, Peter M. Andersen MD, PhD in Annals of Neurology. Published online June 9 2017 doi:10.1002/ana.24950
Pyrimethamine significantly lowers cerebrospinal fluid Cu/Zn superoxide dismutase in amyotrophic lateral sclerosis patients with SOD1 mutations
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 leukocytes 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 familial amyotrophic lateral sclerosis (fALS/SOD1).
A multicenter (5 sites), open-label, 9-month-duration, dose-ranging study was undertaken to determine the safety and efficacy of pyrimethamine to lower SOD1 levels in the CSF in fALS/SOD1. All participants underwent 3 lumbar punctures, blood draw, clinical assessment of strength, motor function, quality of life, and adverse effect assessments. SOD1 levels were measured in erythrocytes and CSF. Pyrimethamine was measured in plasma and CSF. Appel ALS score, ALS Functional Rating Scale–Revised, and McGill Quality of Life Single-Item Scale were measured at screening, visit 6, and visit 9.
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% confidence interval [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).
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.
“Pyrimethamine significantly lowers cerebrospinal fluid Cu/Zn superoxide dismutase in amyotrophic lateral sclerosis patients with SOD1 mutations” by Dale J. Lange MD, Mona Shahbazi MSN, NP, BC-NP, OCNCNP, Vincenzo Silani MD, Albert C. Ludolph MD, PhD, Jochen H. Weishaupt MD, Senda Ajroud-Driss MD, Kara G. Fields MS, Rahul Remanan MB, Stanley H. Appel MD, Claudia Morelli MD, Alberto Doretti MD, Luca Maderna MD, Stefano Messina MD, Ulrike Weiland MD, Stefan L. Marklund MD, PhD, Peter M. Andersen MD, PhD in Annals of Neurology. Published online June 9 2017 doi:10.1002/ana.24950