Trial of Prasinezumab in Early-Stage Parkinson’s Disease

Pagano, Gennaro; Taylor, Kirsten I.; Anzures-Cabrera, Judith; Marchesi, Maddalena; Simuni, Tanya; Marek, Kenneth; Postuma, Ronald B.; Pavese, Nicola; Stocchi, Fabrizio; Azulay, Jean‐Philippe; Mollenhauer, Brit; López-Manzanares, Lydia; Russell, David; Boyd, James T.; Nicholas, Anthony P.; Luquín, María Rosario; Hauser, Robert A.; Gasser, Thomas; Poewe, Werner; Ricci, Benedicte; Boulay, Anne; Vogt, Annamarie; Boess, Frank; Dukart, Juergen; D’Urso, Giulia; Finch, Rebecca; Zanigni, Stefano; Monnet, Annabelle; Pross, Nathalie; Hahn, Andrea; Svoboda, Hanno; Britschgi, Markus; Lipsmeier, Florian; Volkova-Volkmar, Ekaterina; Lindemann, Michael; Dziadek, Sebastian; Holiga, Štefan; Rukina, Daria; Kustermann, Thomas; Kerchner, Geoffrey A.; Fontoura, Paulo; Umbricht, Daniel; Doody, Rachelle S.; Nikolcheva, Tania; Bonni, Azad

doi:10.1056/nejmoa2202867

Cited by 216 publications

(178 citation statements)

References 16 publications

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“…Monoclonal antibodies are also tested in the field of PD treatment research. A novel monoclonal antibody that binds aggregated α-synuclein, called prasinezumab, was assessed in the phase 2 clinical trial for its effect on PD, however its result was negative [ 108 ]. Despite this, we have not found any papers describing the use of aducanumab, zagotenemab or prasinezumab in the LPS neuroinflammatory model.…”

Section: Therapeutic Strategies Targeting Neuroinflammation and Cogni...mentioning

confidence: 99%

Lipopolysaccharide-Induced Model of Neuroinflammation: Mechanisms of Action, Research Application and Future Directions for Its Use

2022

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Despite advances in antimicrobial and anti-inflammatory therapies, inflammation and its consequences still remain a significant problem in medicine. Acute inflammatory responses are responsible for directly life-threating conditions such as septic shock; on the other hand, chronic inflammation can cause degeneration of body tissues leading to severe impairment of their function. Neuroinflammation is defined as an inflammatory response in the central nervous system involving microglia, astrocytes, and cytokines including chemokines. It is considered an important cause of neurodegerative diseases, such as Alzheimer’s disease, Parkinson’s disease and amyotrophic lateral sclerosis. Lipopolysaccharide (LPS) is a strong immunogenic particle present in the outer membrane of Gram-negative bacteria. It is a major triggering factor for the inflammatory cascade in response to a Gram-negative bacteria infection. The use of LPS as a strong pro-inflammatory agent is a well-known model of inflammation applied in both in vivo and in vitro studies. This review offers a summary of the pathogenesis associated with LPS exposure, especially in the field of neuroinflammation. Moreover, we analyzed different in vivo LPS models utilized in the area of neuroscience. This paper presents recent knowledge and is focused on new insights in the LPS experimental model.

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Section: Therapeutic Strategies Targeting Neuroinflammation and Cogni...mentioning

confidence: 99%

Lipopolysaccharide-Induced Model of Neuroinflammation: Mechanisms of Action, Research Application and Future Directions for Its Use

2022

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“…Cinpanemab binds to the N terminus of aggregated α-Syn species, while prasinezumab binds to the C terminus of monomeric protein. Both trials found that treatments had no meaningful effect when compared to the placebo [ 173 , 174 ]. The lack of effect suggests that targeting the extracellular protein may be ineffective.…”

Section: Questioning α-Syn: Are We On the Right Track?mentioning

confidence: 99%

Multiple system atrophy: α-Synuclein strains at the neuron-oligodendrocyte crossroad

Reddy

Dieriks

2022

Mol Neurodegeneration

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The aberrant accumulation of α-Synuclein within oligodendrocytes is an enigmatic, pathological feature specific to Multiple system atrophy (MSA). Since the characterization of the disease in 1969, decades of research have focused on unravelling the pathogenic processes that lead to the formation of oligodendroglial cytoplasmic inclusions. The discovery of aggregated α-Synuclein (α-Syn) being the primary constituent of glial cytoplasmic inclusions has spurred several lines of research investigating the relationship between the pathogenic accumulation of the protein and oligodendrocytes. Recent developments have identified the ability of α-Syn to form conformationally distinct “strains” with varying behavioral characteristics and toxicities. Such “strains” are potentially disease-specific, providing insight into the enigmatic nature of MSA. This review discusses the evidence for MSA-specific α-Syn strains, highlighting the current methods for detecting and characterizing MSA patient-derived α-Syn. Given the differing behaviors of α-Syn strains, we explore the seeding and spreading capabilities of MSA-specific strains, postulating their influence on the aggressive nature of the disease. These ideas culminate into one key question: What causes MSA–specific strain formation? To answer this, we discuss the interplay between oligodendrocytes, neurons and α-Syn, exploring the ability of each cell type to contribute to the aggregate formation while postulating the effect of additional variables such as protein interactions, host characteristics and environmental factors. Thus, we propose the idea that MSA strain formation results from the intricate interrelation between neurons and oligodendrocytes, with deficits in each cell type required to initiate α-Syn aggregation and MSA pathogenesis. Graphical Abstract

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“…The anti-α-syn-directed monoclonal antibody Cinpanemab has shown highly promising preclinical efficacy and selectivity for potential pathologically relevant α-syn species [15]; however, development was halted due to lacking overall effects on clinical measures of disease progression and changes in DaT-SPECT imaging (Dopamine transporter single-photon emission computed tomography) [19]. Prasinezumab, a monoclonal antibody targeting aggregated α-syn, had no meaningful effect on global or imaging measures of Parkinson's disease progression in a recent phase II study but generated positive signals on multiple secondary and exploratory end points [23]. Although disappointing, the negative data have not deterred Roche/Prothena from commencing a Phase 2b trial in early PD patients.…”

Section: Introductionmentioning

confidence: 99%

A Novel C-Type Lectin Receptor-Targeted α-Synuclein-Based Parkinson Vaccine Induces Potent Immune Responses and Therapeutic Efficacy in Mice

et al. 2022

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The progressive accumulation of misfolded α-synuclein (α-syn) in the brain is widely considered to be causal for the debilitating clinical manifestations of synucleinopathies including, most notably, Parkinson’s disease (PD). Immunotherapies, both active and passive, against α-syn have been developed and are promising novel treatment strategies for such disorders. To increase the potency and specificity of PD vaccination, we created the ‘Win the Skin Immune System Trick’ (WISIT) vaccine platform designed to target skin-resident dendritic cells, inducing superior B and T cell responses. Of the six tested WISIT candidates, all elicited higher immune responses compared to conventional, aluminum adjuvanted peptide-carrier conjugate PD vaccines, in BALB/c mice. WISIT-induced antibodies displayed higher selectivity for α-syn aggregates than those induced by conventional vaccines. Additionally, antibodies induced by two selected candidates were shown to inhibit α-syn aggregation in a dose-dependent manner in vitro. To determine if α-syn fibril formation could also be inhibited in vivo, WISIT candidate type 1 (CW-type 1) was tested in an established synucleinopathy seeding model and demonstrated reduced propagation of synucleinopathy in vivo. Our studies provide proof-of-concept for the efficacy of the WISIT vaccine technology platform and support further preclinical and clinical development of this vaccine candidate.

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Trial of Prasinezumab in Early-Stage Parkinson’s Disease

Cited by 216 publications

References 16 publications

Lipopolysaccharide-Induced Model of Neuroinflammation: Mechanisms of Action, Research Application and Future Directions for Its Use

Lipopolysaccharide-Induced Model of Neuroinflammation: Mechanisms of Action, Research Application and Future Directions for Its Use

Multiple system atrophy: α-Synuclein strains at the neuron-oligodendrocyte crossroad

A Novel C-Type Lectin Receptor-Targeted α-Synuclein-Based Parkinson Vaccine Induces Potent Immune Responses and Therapeutic Efficacy in Mice

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