Lithium carbonate in amyotrophic lateral sclerosis patients homozygous for the C-allele at SNP rs12608932 in UNC13A: protocol for a confirmatory, randomized, group-sequential, event-driven, double-blind, placebo-controlled trial

Willemse, Sean W.; Roes, Kit C. B.; Damme, Philip Van; Hardiman, Orla; Ingre, Caroline; Povedano, Mònica; Wray, Naomi R.; Gijzen, Marleen; Pagter, Mirjam S. de; Demaegd, Koen C.; Janse, Annemarie F. C.; Vink, Roel; Sleutjes, Boudewijn T.H.M.; Chiò, Adriano; Corcia, Philippe; Reviers, Evy; Al‐Chalabi, Ammar; Kiernan, Matthew C.; Berg, Leonard H van den; Es, Michael A. van; Eijk, Ruben P A van

doi:10.1186/s13063-022-06906-5

Cited by 16 publications

(11 citation statements)

References 62 publications

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“…We note that lithium carbonate has already been tested for the treatment of ALS patients, showing no clinical benefit. However, a genetic subgroup analysis indicated that lithium carbonate was beneficial in patients homozygous for the C allele of rs12608932 in UNC13A 76,77 , with a follow-up clinical trial recently announced 76 . Given the apparent heterogeneity in patient response to lithium, further research into its mode of action, and preclinical testing of other GSK3 inhibitors like tideglusib is warranted.…”

Section: Discussionmentioning

confidence: 99%

PP2A and GSK3 act as modifiers of FUS-ALS by modulating mitochondrial transport

Tziortzouda,

Steyaert,

Scheveneels

et al. 2023

Preprint

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ALS is a fatal neurodegenerative disease which currently lacks effective treatments. Mutations in the RNA-binding protein FUS are a common cause of familial ALS, accounting for around 4% of fALS cases. Studying the mechanisms by which mutant FUS is toxic to neurons may provide insight into the pathogenesis of both familial and sporadic forms of ALS. Here we identify Protein Phosphatase 2A (PP2A) and Glycogen Synthase Kinase 3 (GSK3) as novel modifiers of FUS-ALSin vivo, looking from fly to human. PP2A-C and GSK3β inhibition rescued FUS-induced toxicity inDrosophilaand disease-relevant phenotypes in human iPSC-derived spinal motor neurons (sMNs). In bothDrosophilaand human iPSC-sMNs, we observed reduced GSK3β inhibitory phosphorylation, suggesting that FUS dysfunction results in GSK3β hyperactivity. We found that PP2A acts upstream of GSK3, affecting its inhibitory phosphorylation, and in synergy they modulate mitochondrial transport through the motor protein kinesin. Our data providein vivoevidence that PP2A and GSK3 are disease modifiers, and reveal an unexplored mechanistic link between PP2A, GSK3 and kinesin in FUS-associated ALS.

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Section: Discussionmentioning

confidence: 99%

PP2A and GSK3 act as modifiers of FUS-ALS by modulating mitochondrial transport

Tziortzouda,

Steyaert,

Scheveneels

et al. 2023

Preprint

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“…A protocol for this study has recently been published. 91 While the mechanism by which lithium carbonate could influence disease progression in UNC13A-ALS remains unclear, preclinical studies show that lithium induces sprouting of pyramidal neurons and induces synaptogenesis, which might counter-effect the previously described loss in synaptic transmission resulting from UNC13A depletion. 92 93 Other proposed mechanisms relate to regulation of intracellular calcium homeostasis and an increase in autophagy, a process through which cells are able to degrade intracellular components, which was shown to be activated by lithium.…”

Section: Potential Treatments Targeting Unc13a Lithium Carbonatementioning

confidence: 99%

“…A total of 171 patients homozygous for the C-allele at rs12608932 will be included. A protocol for this study has recently been published 91…”

Section: Potential Treatments Targeting Unc13amentioning

confidence: 99%

UNC13Ain amyotrophic lateral sclerosis: from genetic association to therapeutic target

Willemse

Harley

Eijk

et al. 2023

J Neurol Neurosurg Psychiatry

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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with limited treatment options and an incompletely understood pathophysiology. Although genomewide association studies (GWAS) have advanced our understanding of the disease, the precise manner in which risk polymorphisms contribute to disease pathogenesis remains unclear. Of relevance, GWAS have shown that a polymorphism (rs12608932) in theUNC13Agene is associated with risk for both ALS and frontotemporal dementia (FTD). Homozygosity for the C-allele at rs12608932 modifies the ALS phenotype, as these patients are more likely to have bulbar-onset disease, cognitive impairment and FTD at baseline as well as shorter survival. UNC13A is expressed in neuronal tissue and is involved in maintaining synaptic active zones, by enabling the priming and docking of synaptic vesicles. In the absence of functional TDP-43, risk variants inUNC13Alead to the inclusion of a cryptic exon inUNC13Amessenger RNA, subsequently leading to nonsense mediated decay, with loss of functional protein. Depletion ofUNC13Aleads to impaired neurotransmission. Recent discoveries have identifiedUNC13Aas a potential target for therapy development in ALS, with a confirmatory trial with lithium carbonate inUNC13Acases now underway and future approaches with antisense oligonucleotides currently under consideration. ConsideringUNC13Ais a potent phenotypic modifier, it may also impact clinical trial outcomes. This present review describes the path from the initial discovery ofUNC13Aas a risk gene in ALS to the current therapeutic options being explored and how knowledge of its distinct phenotype needs to be taken into account in future trials.

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“…These analyses showed a different effect of lithium in homozygous carriers of the C allele at SNP rs12608932 in UNC13A , leading to a 40.1% improvement in the probability of survival at 12 months. Currently, a multicenter clinical trial with lithium is being conducted in patients homozygous for this allele in UNC13A [ 114 ], thus constituting UNC13A genotyping as a true predictive biomarker.…”

Section: New Horizons In Als Biomarker Research: An Insight Into the ...mentioning

confidence: 99%

Biofluid Biomarkers in the Prognosis of Amyotrophic Lateral Sclerosis: Recent Developments and Therapeutic Applications

Sánchez-Tejerina

Llauradó

Sotoca

et al. 2023

Cells

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Amyotrophic lateral sclerosis is a neurodegenerative disease characterized by the degeneration of motor neurons for which effective therapies are lacking. One of the most explored areas of research in ALS is the discovery and validation of biomarkers that can be applied to clinical practice and incorporated into the development of innovative therapies. The study of biomarkers requires an adequate theoretical and operational framework, highlighting the “fit-for-purpose” concept and distinguishing different types of biomarkers based on common terminology. In this review, we aim to discuss the current status of fluid-based prognostic and predictive biomarkers in ALS, with particular emphasis on those that are the most promising ones for clinical trial design and routine clinical practice. Neurofilaments in cerebrospinal fluid and blood are the main prognostic and pharmacodynamic biomarkers. Furthermore, several candidates exist covering various pathological aspects of the disease, such as immune, metabolic and muscle damage markers. Urine has been studied less often and should be explored for its possible advantages. New advances in the knowledge of cryptic exons introduce the possibility of discovering new biomarkers. Collaborative efforts, prospective studies and standardized procedures are needed to validate candidate biomarkers. A combined biomarkers panel can provide a more detailed disease status.

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Lithium carbonate in amyotrophic lateral sclerosis patients homozygous for the C-allele at SNP rs12608932 in UNC13A: protocol for a confirmatory, randomized, group-sequential, event-driven, double-blind, placebo-controlled trial

Cited by 16 publications

References 62 publications

PP2A and GSK3 act as modifiers of FUS-ALS by modulating mitochondrial transport

PP2A and GSK3 act as modifiers of FUS-ALS by modulating mitochondrial transport

UNC13Ain amyotrophic lateral sclerosis: from genetic association to therapeutic target

Biofluid Biomarkers in the Prognosis of Amyotrophic Lateral Sclerosis: Recent Developments and Therapeutic Applications

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