The molecular tweezer CLR01 reduces aggregated, pathologic, and seeding-competent α-synuclein in experimental multiple system atrophy

Herrera‐Vaquero, Marcos; Bouquio, Danielle; Kallab, Martin; Biggs, Karl; Nair, Gayatri; Ochoa, Jessica M; Heras‐Garvin, Antonio; Heid, Christian; Hadrović, Inesa; Poewe, Werner; Wenning, Gregor K.; Klärner, Frank‐Gerrit; Schräder, Thomas; Bitan, Gal; Stefanova, Nadia

doi:10.1016/j.bbadis.2019.07.007

Cited by 28 publications

(42 citation statements)

References 38 publications

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“…The cells then were incubated with the transduction complexes for 48 h and subsequently visualized using uorescence microscopy. The integrated FRET density was analyzed by ow cytometry as described previously (26,32).…”

Section: Biosensor-cell Seeding Assaymentioning

confidence: 99%

The molecular tweezer CLR01 improves behavioral deficits and reduces tau pathology in P301S-tau transgenic mice

Siddique

et al. 2020

Preprint

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Background: Molecular tweezers (MTs) are broad-spectrum inhibitors of abnormal protein aggregation. A lead MT, called CLR01, has been demonstrated to inhibit the aggregation and toxicity of multiple amyloidogenic proteins in vitro and in vivo. Previously, we evaluated the effect of CLR01 in the 3×Tg mouse model of Alzheimer’s disease, which overexpresses mutant human presenilin 1, amyloid β-protein precursor, and tau and found that subcutaneous administration of the compound for one month led to a robust reduction of amyloid plaques, neurofibrillary tangles, and microgliosis. CLR01 also has been demonstrated to inhibit tau aggregation in vitro and tau seeding in cell culture, yet because in Alzheimer’s disease (AD) and in the 3×Tg model, tau hyperphosphorylation and aggregation are thought to be downstream of Aβ insults, the study in this model left the question whether CLR01 affected tau in vivo directly or indirectly open.Methods: To determine if CLR01 could ameliorate tau pathology directly in vivo, we tested the compound similarly using the P301S-tau (line PS19) mouse model. Mice were administered 0.3- or 1.0-mg/Kg per day CLR01 and tested for muscle strength and behavioral deficits, including anxiety- and disinhibition-like behavior. Their brains then were analyzed by immunohistochemical and biochemical assays for pathological forms of tau, neurodegeneration, and glial pathology.Results: CLR01 treatment ameliorated muscle-strength deterioration, anxiety-, and disinhibition-like behavior. Improved phenotype was associated with decreased levels of pathologic tau forms, suggesting that CLR01 exerts a direct effect on tau in vivo. Limitations of the study included a relatively short treatment period of the mice at an age in which full pathology is not yet developed. In addition, high variability in this model lowered the statistical significance of the findings of some outcome measures.Conclusions: The findings suggest that CLR01 is a particularly attractive candidate for the treatment of AD because it targets simultaneously the two major pathogenic proteins instigating and propagating the disease, amyloid β-protein (Aβ) and tau, respectively. In addition, our study suggests that CLR01 can be used for the treatment of other tauopathies in the absence of amyloid pathology.

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Section: Biosensor-cell Seeding Assaymentioning

confidence: 99%

The molecular tweezer CLR01 improves behavioral deficits and reduces tau pathology in P301S-tau transgenic mice

Siddique

et al. 2020

Preprint

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“…↓ α-syn oligomers ↓ GCIs ↓ Microglial activation ↑ Neuroprotection ↑ Motor function [123]. CLR01 α-syn aggregation In PLP-hα-syn mice: ↓ α-syn oligomers ↓ GCIs ↓ Anxiety-like behaviour ↑ Neuroprotection [124]. PBT434…”

Section: Discussionmentioning

confidence: 99%

“…In addition, despite transgenic animal models have contributed to identify important aspects of the disease, they artificially overexpress α-syn in oligodendrocytes, thus concealing the mechanism which triggers MSA and the accumulation of α-syn [83,204,205]. Novel strategies targeting α-syn aggregation, such as α-syn immunotherapy and small molecules, hold, however, promising therapeutic potential that still have to be evaluated in human trials [123][124][125]145,148]. In order to do that, it will be necessary to improve the design of clinical studies by selecting patient cohorts as homogeneous as possible and at early stages of the disease, before the neurodegenerative process is too advanced and neuronal rescue is still feasible.…”

Section: Discussionmentioning

confidence: 99%

“…The use of small molecules to target α-syn oligomerization and aggregation has shown promising results in the PLP-hα-syn mouse model of MSA [123][124][125]. Anle138b, a small compound with high bioavailability and low toxicity, which can be delivered orally [124], reduced α-syn accumulation leading to neuroprotection, reduction of microglial activation and preservation of the motor function in MSA mice [123]. Based on this data, a phase I trial in MSA patients is currently in preparation [126].…”

Section: α-Syn Aggregation Inhibitorsmentioning

confidence: 99%

“…Based on this data, a phase I trial in MSA patients is currently in preparation [126]. The molecular tweezer CLR01 reduced the formation of putative high-molecular-weight α-syn oligomers and promoted dopaminergic neuron survival in the substantia nigra (SN) of PLP-hα-syn mice, supporting the view that these species are key to the neurodegenerative process in MSA [124]. Thus, CLR01 constitutes an attractive therapeutic candidate for disease modification.…”

Section: α-Syn Aggregation Inhibitorsmentioning

confidence: 99%

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MSA: From basic mechanisms to experimental therapeutics

Heras‐Garvin

Stefanova

2020

Parkinsonism & Related Disorders

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Multiple system atrophy (MSA) is a rare and fatal neurodegenerative disorder characterized by rapidly progressive autonomic and motor dysfunction. Pathologically, MSA is mainly characterized by the abnormal accumulation of misfolded α-synuclein in the cytoplasm of oligodendrocytes, which plays a major role in the pathogenesis of the disease. Striatonigral degeneration and olivopontecerebellar atrophy underlie the motor syndrome, while degeneration of autonomic centers defines the autonomic failure in MSA. At present, there is no treatment that can halt or reverse its progression. However, over the last decade several studies in preclinical models and patients have helped to better understand the pathophysiological events underlying MSA. The etiology of this fatal disorder remains unclear and may be multifactorial, caused by a combination of factors which may serve as targets for novel therapeutic approaches. In this review, we summarize the current knowledge about the etiopathogenesis and neuropathology of MSA, its different preclinical models, and the main disease modifying therapies that have been used so far or that are planned for future clinical trials.

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Multiple System Atrophy: Recent Developments and Future Perspectives

et al. 2019

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Multiple system atrophy (MSA) is a rare and fatal neurodegenerative disorder characterized by a variable combination of parkinsonism, cerebellar impairment, and autonomic dysfunction. The pathologic hallmark is the accumulation of aggregated α‐synuclein in oligodendrocytes, forming glial cytoplasmic inclusions, which qualifies MSA as a synucleinopathy together with Parkinson's disease and dementia with Lewy bodies. The underlying pathogenesis is still not well understood. Some symptomatic treatments are available, whereas neuroprotection remains an urgent unmet treatment need. In this review, we critically appraise significant developments of the past decade with emphasis on pathogenesis, diagnosis, prognosis, and treatment development. We further discuss unsolved questions and highlight some perspectives. © 2019 International Parkinson and Movement Disorder Society

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The molecular tweezer CLR01 reduces aggregated, pathologic, and seeding-competent α-synuclein in experimental multiple system atrophy

Cited by 28 publications

References 38 publications

The molecular tweezer CLR01 improves behavioral deficits and reduces tau pathology in P301S-tau transgenic mice

The molecular tweezer CLR01 improves behavioral deficits and reduces tau pathology in P301S-tau transgenic mice

MSA: From basic mechanisms to experimental therapeutics

Multiple System Atrophy: Recent Developments and Future Perspectives

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