Trial of Cinpanemab in Early Parkinson’s Disease

Lang, Anthony E.; Siderowf, Andrew; Macklin, Eric A.; Poewe, Werner; Brooks, David J.; Fernández, Hubert H.; Rascol, Olivier; Giladi, Nir; Stocchi, Fabrizio; Tanner, Caroline M.; Postuma, Ronald B.; Simon, David K.; Tolosa, Eduardo; Mollenhauer, Brit; Cedarbaum, Jesse M.; Fraser, Kyle; Xiao, James; Evans, Karleyton C.; Graham, Danielle; Sapir, Inbal; Inra, Jennifer; Hutchison, R. Matthew; Yang, Minhua; Fox, Tara; Haeberlein, Samantha Budd; Dam, Tien

doi:10.1056/nejmoa2203395

Cited by 150 publications

(94 citation statements)

References 19 publications

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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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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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“…However, despite the huge financial costs, the results of these developments were rather discouraging. In patients with early PD, the effects of cinpanemab on clinical measures of disease progression did not differ from those of a placebo over a 52-week period [ 423 ]. Additionally, prasinezumab therapy had no meaningful effect on global or imaging measures of Parkinson’s disease progression as compared with placebo and was associated with infusion reactions [ 424 ].…”

Section: Treatment and Optimization Of The Condition Of Patients With Pdmentioning

confidence: 99%

Molecular and Cellular Interactions in Pathogenesis of Sporadic Parkinson Disease

Dolgacheva

Зинченко

Гончаров

2022

IJMS

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An increasing number of the population all around the world suffer from age-associated neurodegenerative diseases including Parkinson’s disease (PD). This disorder presents different signs of genetic, epigenetic and environmental origin, and molecular, cellular and intracellular dysfunction. At the molecular level, α-synuclein (αSyn) was identified as the principal molecule constituting the Lewy bodies (LB). The gut microbiota participates in the pathogenesis of PD and may contribute to the loss of dopaminergic neurons through mitochondrial dysfunction. The most important pathogenetic link is an imbalance of Ca2+ ions, which is associated with redox imbalance in the cells and increased generation of reactive oxygen species (ROS). In this review, genetic, epigenetic and environmental factors that cause these disorders and their cause-and-effect relationships are considered. As a constituent of environmental factors, the example of organophosphates (OPs) is also reviewed. The role of endothelial damage in the pathogenesis of PD is discussed, and a ‘triple hit hypothesis’ is proposed as a modification of Braak’s dual hit one. In the absence of effective therapies for neurodegenerative diseases, more and more evidence is emerging about the positive impact of nutritional structure and healthy lifestyle on the state of blood vessels and the risk of developing these diseases.

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“…Several passive immunotherapies for PD are now in early clinical development [18,19]. However, similar to the development of amyloid beta (Aβ) immunotherapy for Alzheimer's disease (AD), which resulted in a very low success rate in admitting such treatment modalities for clinical use [20][21][22], recent drawbacks to PD immunotherapy have also been reported.…”

Section: Introductionmentioning

confidence: 99%

“…However, similar to the development of amyloid beta (Aβ) immunotherapy for Alzheimer's disease (AD), which resulted in a very low success rate in admitting such treatment modalities for clinical use [20][21][22], recent drawbacks to PD immunotherapy have also been reported. 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].…”

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 Cinpanemab in Early Parkinson’s Disease

Cited by 150 publications

References 19 publications

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

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

Molecular and Cellular Interactions in Pathogenesis of Sporadic Parkinson Disease

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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