The α-Synuclein Seeding Amplification Assay for Parkinson’s Disease

International Journal of Molecular Sciences, Год журнала: 2025, Номер 26(1), С. 389 - 389

Опубликована: Янв. 4, 2025

Parkinson’s disease (PD) is the second most common neurodegenerative in world. Currently, PD incurable, and diagnosis of mainly relies on clinical manifestations. The central pathological event abnormal aggregation deposition misfolded α-synuclein (α-Syn) protein aggregates Lewy body (LB) affected brain areas. Behaving as a prion-like seeding, α-syn can induce facilitate native unfolded α-Syn to aggravate aggregation, leading progression. Recently, blood-based seeding amplification assay (SAA), Kluge et al. identified activity patients with Parkin (PRKN) gene variants. Additionally, was also sporadic Leucine-rich repeat kinase 2 (LRRK2) or glucocerebrosidase (GBA) Principally, SAA be used detect activity, which will significantly enhance diagnosis, progression monitoring, prognosis prediction, anti-PD therapy. significance future strategies protocol are highlighted proposed, whereas challenges limitations discussed.

Язык: Английский

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Small molecule modulators of Alpha-Synuclein Aggregation and Toxicity: Pioneering an Emerging Arsenal Against Parkinson’s Disease

Ageing Research Reviews, Год журнала: 2024, Номер 101, С. 102538 - 102538

Опубликована: Окт. 9, 2024

Язык: Английский

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Factors responsible for alpha-Synuclein aggregation

Progress in molecular biology and translational science, Год журнала: 2025, Номер unknown

Опубликована: Янв. 1, 2025

Язык: Английский

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A Triosmium Carbonyl Cluster that Inhibits α-Synuclein Aggregation and Disassembles Preformed Aggregates

Chemical Communications, Год журнала: 2025, Номер unknown

Опубликована: Янв. 1, 2025

Osmium carbonyl clusters inhibit fibril formation and disassemble them too!

Язык: Английский

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Immunotherapy for Parkinson’s Disease and Alzheimer’s Disease: A Promising Disease-Modifying Therapy

Cells, Год журнала: 2024, Номер 13(18), С. 1527 - 1527

Опубликована: Сен. 12, 2024

Alzheimer's disease (AD) and Parkinson's (PD) are two neurodegenerative diseases posing a significant burden due to their increasing prevalence socio-economic cost. Traditional therapeutic approaches for these exist but provide limited symptomatic relief without addressing the underlying pathologies. This review examines potential of immunotherapy, specifically monoclonal antibodies (mAbs), as disease-modifying treatments AD PD. We analyze pathological mechanisms PD, focusing on roles amyloid-beta (Aβ), tau (τ), alpha-synuclein (α-syn) proteins. discuss latest advancements in mAb therapies targeting proteins, evaluating efficacy clinical trials preclinical studies. also explore challenges faced translating from bench bedside, including issues related safety, specificity, trial design. Additionally, we highlight future directions research, emphasizing need combination therapies, improved biomarkers, personalized treatment strategies. aims insights into current state antibody-based immunotherapy modifying course ultimately improving patient outcomes quality life.

Язык: Английский

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QuantificationofCinpanemab (BIIB054) Binding toα-Synuclein in Cerebrospinal Fluid of Phase 1 Single Ascending Dose Samples

Journal of Pharmacology and Experimental Therapeutics, Год журнала: 2024, Номер 392(1), С. 100003 - 100003

Опубликована: Июнь 27, 2024

Through its pathological and genetic association to Parkinson9s Disease (PD), α-synuclein (α-syn) remains a favorable therapeutic target that is being investigated using various modalities, including many passive immunotherapy approaches clinically targeting different forms of α-syn epitopes. Whereas published studies from some trials have demonstrated engagement in plasma, none shown direct drug-antigen interactions the disease-relevant compartment, central nervous system (CNS). Cinpanemab (BIIB054) selectively targets aggregated with low affinity binding monomeric forms. The avidity-driven binding, drug concentration, very levels plus heterogeneous nature cerebrospinal fluid (CSF) made it not possible measure drug-target by conventional assays. Here we overcame these challenges zero-length crosslinking stabilize BIIB054-α-syn complexes then quantified crosslinked Meso Scale Discovery (MSD) electrochemiluminescence assay. CSF samples healthy volunteers (HV, n=46) individuals PD (PD, n=18) study 228HV101 (Phase I clinical trial BIIB054), dose- time- dependent cinpanemab measurable detected at doses {greater than or equal to}15 mg/kg. Complex formation displayed positive correlation concentration (Spearman rank = 0.8295 (HV), 0.8032 (PD) p < 0.0001 PD)). observed consistent intrinsic for monomer provides evidence behaving expected dynamics compartment. Significance Statement A cross-linking method MSD detection was developed enable quantification cinpanemab–α-syn Phase 1 preventing signal loss caused their rapid dissociation. Observed time-dependent were cinpanemab's provided confidence had engaged desired site action. This first demonstration an antibody CNS.

Язык: Английский

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Safety, Tolerability, and Pharmacokinetics of Single Doses of Exidavnemab (BAN0805), an Anti‐α‐Synuclein Antibody, in Healthy Western, Caucasian, Japanese, and Han Chinese Adults

The Journal of Clinical Pharmacology, Год журнала: 2024, Номер 64(11), С. 1432 - 1442

Опубликована: Авг. 6, 2024

Exidavnemab is a monoclonal antibody (mAb) with high affinity and selectivity for pathological aggregated forms of α-synuclein low physiological monomers, which in clinical development as disease-modifying treatment patients synucleinopathies such Parkinson's disease. Safety, tolerability, pharmacokinetics, immunogenicity, exploratory biomarkers were assessed two separate Phase 1 single ascending dose studies, including intravenous (IV) (100 to 6000 mg) or subcutaneous (SC) (300 administration exidavnemab healthy volunteers (HVs). Across the total 98 Western, Caucasian, Japanese, Han Chinese HVs enrolled, 95 completed study. was generally well tolerated. There no serious adverse events safety issues identified laboratory analyses. Headache, asymptomatic COVID-19, back pain, post lumbar puncture syndrome most frequently reported treatment-emergent events. Following IV infusion, pharmacokinetics approximately linear range 100-6000 mg. The terminal half-life 30 days, exposure comparable across volunteers. absolute SC bioavailability ∼71%. Cerebrospinal fluid relative serum after within expected mAbs (approximately 0.2%). anti-drug rates there effect immunogenicity on safety. Dose-dependent reduction free plasma observed. In summary, found have an excellent pharmacokinetic profile tolerated HVs, supporting continued development.

Язык: Английский

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Imunoterapia no tratamento das doenças neurodegenerativas

Brazilian Journal of Health Review, Год журнала: 2024, Номер 7(3), С. e70933 - e70933

Опубликована: Июнь 28, 2024

As doenças neurodegenerativas são condições caracterizadas pela perda gradual de neurônios no sistema nervoso central, o que gera sintomas demenciais, cognitivos e somáticos. Essas estão relacionadas a fatores genéticos ambientais, sendo envelhecimento populacional é considerado principal fator risco. Estudos indicam como diabetes, uso crônico álcool, poluição ambiental, entre outros, também podem contribuir para desenvolvimento dessas enfermidades, porém cada doença neurodegenerativa possui sua própria etiologia fisiopatologia. Na Doença Alzheimer, por exemplo, há acúmulo proteína beta-amilóide hiperfosforilação da tau, causa funcional neuronal, enquanto na Parkinson, ocorre formação agregados proteicos alfa-sinucleína nos neurônios, afeta diversos sistemas neurotransmissores. Já Esclerose Múltipla, resposta auto imune leva à destruição bainha mielina dos comprometendo suas funções. Objetivo: O propósito deste artigo discorrer sobre imunoterapia contexto do tratamento certas enfermidades neurodegenerativas. Métodos: os empenhos investidos nesse estudo foram destinados uma análise integrativa literatura, utilizando artigos científicos últimos cinco anos. Discussão: diagnóstico geralmente clínico, através anamnese, histórico médico, exame neurológico testes cognitivos, alguns exames complementares utilizados ressonância magnética, eletroencefalograma, outros. busca, principalmente, controlar retardar progressão inclui medicamentos, terapias físicas ocupacionais, além medidas melhorar qualidade vida paciente seus cuidadores.O prognóstico das ruim, devido natureza progressiva incurável. curso varia acordo com tipo gravidade condição, levando frequentemente incapacidade redução paciente. A tem surgido opção promissora doenças, visando neutralização proteínas neurotóxicas modulação proteger preservar as funções cognitivas. Conclusão: terapia imunológica estratégia neurodegenerativas, Parkinson combatendo acumuladas respostas inflamatórias. Apesar desafios, oferece esperança abordagem mais eficaz personalizada

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Zero-length crosslinking: A breakthrough approach for evaluating target engagement in α-synuclein immunotherapy

Journal of Pharmacology and Experimental Therapeutics, Год журнала: 2024, Номер 392(1), С. 100036 - 100036

Опубликована: Дек. 27, 2024

Язык: Английский

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