A Phase 1 Randomized Trial of Specific Active <scp>α‐Synuclein</scp> Immunotherapies <scp>PD01A</scp> and <scp>PD03A</scp> in Multiple System Atrophy

Meissner, Wassilios G.; Traon, Anne Pavy‐Le; Foubert‐Samier, Alexandra; Galabova, Gergana; Galitzky, Monique; Kutzelnigg, Alexandra; Laurens, Brice; Lührs, Petra; Medori, Rossella; Péran, Patrice; Sabatini, Umberto; Vergnet, Sylvain; Volc, Dieter; Poewe, Werner; Schneeberger, Achim; Staffler, Günther; Rascol, Olivier

doi:10.1002/mds.28218

Cited by 61 publications

(43 citation statements)

References 20 publications

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“…Clinical scores did not differ between treatment groups during the course of this study. The PD trial was conducted in Austria where 36 PD patients received 4 s.c. injections of either 15 or 75 μg vaccine every 4 weeks with a booster 24 weeks after the last injection ( Affiris, 2018 ; Meissner et al, 2020 ). Patients were assessed for levels of dopamine receptors using DAT-SPECT and brain volume by MRI over a 12 month period.…”

Section: Alpha Synuclein Targeted Immunotherapymentioning

confidence: 99%

Amyloid-β and α-Synuclein Immunotherapy: From Experimental Studies to Clinical Trials

Nimmo¹,

Kelly²,

Verma³

et al. 2021

Front. Neurosci.

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Alzheimer’s disease and Lewy body diseases are the most common causes of neurodegeneration and dementia. Amyloid-beta (Aβ) and alpha-synuclein (αSyn) are two key proteins involved in the pathogenesis of these neurodegenerative diseases. Immunotherapy aims to reduce the harmful effects of protein accumulation by neutralising toxic species and facilitating their removal. The results of the first immunisation trial against Aβ led to a small percentage of meningoencephalitis cases which revolutionised vaccine design, causing a shift in the field of immunotherapy from active to passive immunisation. While the vast majority of immunotherapies have been developed for Aβ and tested in Alzheimer’s disease, the field has progressed to targeting other proteins including αSyn. Despite showing some remarkable results in animal models, immunotherapies have largely failed final stages of clinical trials to date, with the exception of Aducanumab recently licenced in the US by the FDA. Neuropathological findings translate quite effectively from animal models to human trials, however, cognitive and functional outcome measures do not. The apparent lack of translation of experimental studies to clinical trials suggests that we are not obtaining a full representation of the effects of immunotherapies from animal studies. Here we provide a background understanding to the key concepts and challenges involved in therapeutic design. This review further provides a comprehensive comparison between experimental and clinical studies in Aβ and αSyn immunotherapy and aims to determine the possible reasons for the disconnection in their outcomes.

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Section: Alpha Synuclein Targeted Immunotherapymentioning

confidence: 99%

Amyloid-β and α-Synuclein Immunotherapy: From Experimental Studies to Clinical Trials

Nimmo¹,

Kelly²,

Verma³

et al. 2021

Front. Neurosci.

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“…Recently, a phase 1 randomized placebo-controlled clinical trial has been completed to assess the safety, tolerance, and immunogenicity of subcutaneous injections of PD01 and PD03 in patients with early MSA. The results of the trial showed the vaccines to be safe and well-tolerated, as well as highly immunogenic, since the treatment with either peptide resulted in considerable IgG antibody production against PD01 and PD03 (US National Library of Medicine, 2014Medicine, -2017bMeissner et al, 2020). Although the outcomes appear promising, further studies in this area are needed.…”

Section: Immunizationmentioning

confidence: 99%

Novel Therapies for Parkinsonian Syndromes–Recent Progress and Future Perspectives

Przewodowska

Marzec

Madetko

2021

Front. Mol. Neurosci.

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Background: Atypical parkinsonian syndromes are rare, fatal neurodegenerative diseases associated with abnormal protein accumulation in the brain. Examples of these syndromes include progressive supranuclear palsy, multiple system atrophy, and corticobasal degeneration. A common clinical feature in parkinsonism is a limited improvement with levodopa. So far, there are no disease-modifying treatments to address these conditions, and therapy is only limited to the alleviation of symptoms. Diagnosis is devastating for patients, as prognosis is extremely poor, and the disease tends to progress rapidly. Currently, potential causes and neuropathological mechanisms involved in these diseases are being widely investigated.Objectives: The goal of this review is to summarize recent advances and gather emerging disease-modifying therapies that could slow the progression of atypical parkinsonian syndromes.Methods: PubMed and Google Scholar databases were searched regarding novel perspectives for atypical parkinsonism treatment. The following medical subject headings were used: “atypical parkinsonian syndromes—therapy,” “treatment of atypical parkinsonian syndromes,” “atypical parkinsonian syndromes—clinical trial,” “therapy of tauopathy,” “alpha-synucleinopathy treatment,” “PSP therapy/treatment,” “CBD therapy/treatment,” “MSA therapy/treatment,” and “atypical parkinsonian syndromes—disease modifying.” All search results were manually reviewed prior to inclusion in this review.Results: Neuroinflammation, mitochondrial dysfunction, microglia activation, proteasomal impairment, and oxidative stress play a role in the neurodegenerative process. Ongoing studies and clinical trials target these components in order to suppress toxic protein accumulation. Various approaches such as stem cell therapy, anti-aggregation/anti-phosphorylation agent administration, or usage of active and passive immunization appear to have promising results.Conclusion: Presently, disease-modifying strategies for atypical parkinsonian syndromes are being actively explored, with encouraging preliminary results. This leads to an assumption that developing accurate, safe, and progression-halting treatment is not far off. Nevertheless, the further investigation remains necessary.

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“…In 2020, a clinical trial with PD01 and PD03 in MSA patients showed that both AFFITOPEs® presented immunogenicity and good tolerability. However, the authors noticed that the antibody levels in the plasma were higher in individuals receiving PD01 than in patients receiving PD03 (Meissner et al 2020 ). In contrast, substantial levels of PD03-induced antibodies were reported in PD patients (Poewe et al 2021 ).…”

Section: Msa Pathogenesis: Identifying Putative Targets For Disease Modificationmentioning

confidence: 99%

Current experimental disease-modifying therapeutics for multiple system atrophy

2021

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Multiple system atrophy (MSA) is a challenging neurodegenerative disorder with a difficult and often inaccurate early diagnosis, still lacking effective treatment. It is characterized by a highly variable clinical presentation with parkinsonism, cerebellar ataxia, autonomic dysfunction, and pyramidal signs, with a rapid progression and an aggressive clinical course. The definite MSA diagnosis is only possible post-mortem, when the presence of distinctive oligodendroglial cytoplasmic inclusions (GCIs), mainly composed of misfolded and aggregated α-Synuclein (α-Syn) is demonstrated. The process of α-Syn accumulation and aggregation within oligodendrocytes is accepted one of the main pathological events underlying MSA. However, MSA is considered a multifactorial disorder with multiple pathogenic events acting together including neuroinflammation, oxidative stress, and disrupted neurotrophic support, among others. The discussed here treatment approaches are based on our current understanding of the pathogenesis of MSA and the results of preclinical and clinical therapeutic studies conducted over the last 2 decades. We summarize leading disease-modifying approaches for MSA including targeting α-Syn pathology, modulation of neuroinflammation, and enhancement of neuroprotection. In conclusion, we outline some challenges related to the need to overcome the gap in translation between preclinical and clinical studies towards a successful disease modification in MSA.

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A Phase 1 Randomized Trial of Specific Active α‐Synuclein Immunotherapies PD01A and PD03A in Multiple System Atrophy

Abstract: This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

Cited by 61 publications

References 20 publications

Amyloid-β and α-Synuclein Immunotherapy: From Experimental Studies to Clinical Trials

Amyloid-β and α-Synuclein Immunotherapy: From Experimental Studies to Clinical Trials

Novel Therapies for Parkinsonian Syndromes–Recent Progress and Future Perspectives

Current experimental disease-modifying therapeutics for multiple system atrophy

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