公募シンポジウム

公募シンポジウム11【ヒトと社会に役立つタウバイオロジー】

2021/10/1　10:00～12:00　ZOOM C会場 S11-1 タウ凝集細胞モデルによるタウ凝集抑制剤の開発 Development of fibrillar tau cell line and tau aggregation suppressor compounds ^○松本弦長崎大学大学院医歯薬学総合研究科 ^○Gen Matsumoto Nagasaki University Graduate School of Biomedical Sciences Neurofibrillary tangles (NFT) composed by hyperphosphorylated tau protein are a major pathological hallmark of a number of neurodegenerative diseases called tauopathy, including Alzheimer’s diseases, front-temporal lobe degeneration (FTLD), progressive supra nucleus palsy (PSP) and cortico-basal degeneration (CBD). As Tau protein has prion-like propagation properties, it is predicted that the transmission of fibrillar Tau relates to disease progression. We previously developed a cell line which constitutively maintained intracellular Tau fibrils and demonstrated that the filamentous tau aggregates were transmissible among cells. Super-resolution microscopic imaging revealed that intracellular large tau inclusions were composed by tiny tau microfilaments that were less AT8 reactive than large inclusions, suggesting that the phosphorylation at S202/T205 occurred after tau fibril formation and may not be necessary to initiate aggregation. To investigate whether the pre-formed intracellular tau aggregates are degraded by an intrinsic cellular system, we developed a screening system to evaluate cellular tau aggregation and found several compounds that reduced numbers of cells with tau inclusions without growth inhibition. In this symposium, we show that our compounds promote the aggrephagy through the enhancement of p62 S403-phosphorylation and reduce the intracellular tau aggregate formation. Although the non-S403-phosphorylated p62 infrequently co-localized with the intracellular tau fibrils in the normal conditions, the treatment of aggrephagy enhancer enables the efficient co-localization with p62 and tau fibrils, resulted in the reduction of intracellular tau filaments.		2021/10/1　10:00～12:00　ZOOM C会場 S11-2 抗タウオパチー薬開発とタウオリゴマー Development of anti-tauopathy drugs and tau oligomer. ^○添田義行学習院大学理学部生命科学科高島研究室 ^○Yoshiyuki Soeda Laboratory for Alzheimer's Disease, Department of Life Science, Faculty of Science, Gakushuin University In Alzheimer's disease (AD), the microtubule-associated protein tau is abnormally hyperphosphorylated and aggregated. The abnormal tau is eventually converted into intracellular neurofibrillary tangles (NFTs). Further, tau inclusions have been observed in several neurodegenerative diseases, referred to as tauopathies. The spreading of NFTs across the brain is positively correlated with dementia severity. Facts indicate that tau aggregation is a useful therapeutic target in dementia patients. Many studies have revealed that secreted extracellular tau is involved in tau pathology spreads. Thus, not only intracellular tau but also extracellular tau can be a target for dementia. Tau-targeted drugs with different mechanisms are being tested in clinical trials, and are (1) post-translational modification inhibitors, (2) tau aggregation inhibitors, (3) immunotherapeutics, (4) oligonucleotides that reduce tau expression, and (5) microtubule stabilizers. Clinical trials are ongoing; however, we also need to explore treatments using unconventional mechanisms. The postmortem analyses of the brain in AD, and animal studies have repeatedly shown that before NFTs formation, tau oligomer is toxic. We focused on tau oligomers and found that a granular tau oligomer is an intermediate form of tau fibrils. The amounts were elevated in the prefrontal cortex of Braak stage I. Further, pharmacological approaches have shown the importance of granular tau oligomer on tau-related toxicity. Early intervention may be necessary for achieving the full effect of tau-targeting drugs; therefore, a test that can detect the early stages of AD is needed. We will introduce the tau-targeted drugs in the clinical trials and our studies, and discuss future tauopathies therapy.

2021/10/1　10:00～12:00　ZOOM C会場 S11-3 リン酸化タウ抗体JNJ-63733657 のプロファイルと、第I 相試験の結果と第II 相試験のデザインについて Phase 1 Single and Multiple Ascending Dose Study Results and Phase 2 Study Design of the Anti-phosphorylated-tau Antibody JNJ-63733657 ^○渡辺小百合¹,Wendy Galpern², Katrin Haeverans², Gallen Triana-Baltzer², Hartmuth Kolb², Lingjue Li², Partha Nandy², Luc Van Nueten², David Henley², Carol Davis², Pilar Lim², Masayoshi Takahashi², Hong Sun² 1.ヤンセンファーマ株式会社研究開発本部,2.Janssen Pharmaceutical K.K ^○Sayuri Watanabe¹,Wendy Galpern², Katrin Haeverans², Gallen Triana-Baltzer², Hartmuth Kolb², Lingjue Li², Partha Nandy², Luc Van Nueten², David Henley², Carol Davis², Pilar Lim², Masayoshi Takahashi², Hong Sun² 1.ヤンセンファーマ株式会社研究開発本部,2.Janssen Pharmaceutical K.K Background:JNJ-63733657 is a humanized IgG1 monoclonal antibody with high affinity for phosphorylated tau. It is under clinical investigation as a potential disease modifying treatment for Alzheimer’s disease. Methods: The two-part Ph1 study has been completed. Part 1 is a SAD study in healthy volunteers aged 55-75 years; Part 2 is a MAD study in healthy volunteers as well as subjects with prodromal or mild AD aged 55-80 years. In SAD study, five cohorts of 8 subjects received JNJ-63733657 or Placebo at increasing dose levels. In MAD study, 2 cohorts of healthy volunteers and 2 cohorts of subjects with prodromal or mild AD received placebo or JNJ-63733657 intravenously every month for 3 months. Safety, tolerability, pharmacokinetics (PK), and Pharmacodynamic (PD) effects as measured by CSF p217+ tau change was evaluated. Results: JNJ-63733657 has been generally safe and well-tolerated following single and multiple doses in healthy volunteers and subjects with prodromal or mild AD. JNJ-63733657 demonstrated linear PK in serum and CSF. CSF drug exposures were ~0.2% of serum levels. There was dose dependent reduction of CSF p217+ tau from baseline. The PK and PD profile are similar in healthy volunteers and AD patients. The Ph2 study is a multicenter, randomized, double blinded, placebo-controlled dose ranging study in subjects with early AD. Eligible subjects are defined as CDR of 0.5 with positive tau pathology as measured by tau PET. The primary objective is to evaluate slowing of cognitive decline as measured by ADAS-Cog. Key secondary endpoint includes tau PET and other cognitive and functional measures. Conclusions: JNJ-63733657 demonstrated favorable safety, tolerability, PK, and PD following single and multiple doses administration. It is currently in Ph2 development		2021/10/1　10:00～12:00　ZOOM C会場 S11-4 タウ病理の脳内進展過程を標的とした認知症診断・治療薬開発 Progression of Alzheimer's disease, tau propagation, and tau-based diagnostics and therapies. ^○武田朱公大阪大学大学院医学系研究科臨床遺伝子治療学,大阪府立病院機構大阪精神医療センターこころの科学リサーチセンター ^○Shuko Takeda 1.Clinical Gene Therapy, Graduate School of Medicine, Osaka University, Osaka, Japan,2.Osaka Psychiatric Medical Center, Osaka Psychiatric Research Center, Osaka, Japan A unique clinical course of Alzheimer's disease (AD), beginning with memory deficit as the earliest symptom, is well correlated with a progressive pattern of intracellular aggregates of tau (NFTs), which spread from the medial temporal lobe to other brain areas in a stereotypical manner. Recent findings from basic research using in vitro and in vivo models demonstrated that pathological forms of extracellular tau can be released from donor cells, taken up by recipient cells, and induce intracellular tau aggregates. On the basis of these neuropathological observations and experimental findings, the “tau propagation hypothesis” has been proposed, in which the stereotypical spreading of the tau pathology in the AD brain can be explained by the interneuron transfer of the pathological form of tau. The concept of tau propagation provides novel insight into the tau-based diagnostics and therapies for AD. Here, we will review the basic concept and recent findings on tau propagation, experimental evidence of interneuron tau transfer, and the implications of this concept for diagnostic and therapeutic targets for AD. Besides the development of effective therapies, early diagnosis during the pre-dementia phase or in the early stages of dementia are key to maximize the benefit of such therapies. We recently developed a novel rapid screening tool for cognitive impairment using an eye tracking technology. This method enables the quick and highly sensitive semi-automated assessment of patients’ cognitive function. This simple and repeatable assessment tool may be useful to measure and monitor the influence of intervention treatments.

2021/10/1　10:00～12:00　ZOOM C会場 S11-5 認知症診断・層別化バイオマーカーとしての血液中タウ分子種：実臨床への応用にむけて Tau species in human biological fluids as the diagnostic and stratification biomarkers for dementia: considerations for the clinical application ^○徳田隆彦国立研究開発法人量子科学技術研究開発機構 ^○Takahiko Tokuda National Institutes for Quantum and Radiological Science and Technology (QST) There is still a substantial unmet need for less invasive and lower-cost molecular biomarkers, namely blood-based biomarkers, for the diagnosis and stratification of patients with dementia including Alzheimer's disease (AD). We developed the world's first immunoassay to quantify plasma tau phosphorylated at threonine 181 (p-tau181) in 2017 by using an ultrasensitive digital array technology (Simoa system, Quanterix, USA). With this original assay, we reported that the plasma levels of p-tau181 were significantly higher in AD patients than those in the controls. Our study suggested that plasma p-tau181 is a promising blood biomarker for brain AD pathology. After our study, substantial evidence of the usefulness of plasma p-tau assays in the diagnosis of AD has been accumulating internationally. Now, we are developing other blood biomarkers for AD and other dementias, such as p-tau species other than p-tau181 as well as Aβ40/42, neurofilament light (NfL), TDP-43 and α-synuclein. Furthermore, for the validation and future use of those biomarkers in the clinical settings, it is essential that we should collect large-scale blood samples obtained from patients with a highly reliable diagnosis of underlying diseases. Such a "reliable diagnosis" used to mean the pathological diagnosis of the patients, but now neuroimaging techniques, such as PET imaging, of pathognomonic accumulation of abnormal protein aggregates can be used as a substitute for the pathological diagnosis. From this recognition, we have just launched the Multicenter Alliance for Brain Biomarkers (MABB) in August 2020 and have started to enroll patients with cognitive impairment and controls to collect both PET imaging data and blood samples. In my talk, I will present our results and recent studies reported from other groups regarding tau species and other dementia-related molecules in human blood as the candidates of blood-based biomarkers for AD and neurodegenerative dementias.