Immunotherapy against tauopathy in a transgenic mouse model

转基因小鼠模型中针对 tau 蛋白病的免疫疗法

基本信息

批准号：
8822935
负责人：
David Morgan
金额：
$ 35.88万
依托单位：
UNIVERSITY OF SOUTH FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-05-15 至 2017-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8822935
关键词：
Acute Address Adverse event Age Alzheimer&apos s Disease Amyloid Amyloid beta-Protein Antibodies Antibody Response Avastin Axonal Transport Behavioral Binding Binding Sites Brain Brain Diseases Brain region Categories Cause of Death Cessation of life Clinic Clinical Trials Cognitive Data Dementia Deposition Disease Dose Doxycycline Drug Industry Epitopes Etanercept FDA approved Frontotemporal Dementia Genes Health Histologic Human Humira IgG1 Immunotherapeutic agent Immunotherapy Individual Injection of therapeutic agent Lead Lobe Measures Mediating Memory impairment Methods Modeling Modification Monoclonal Antibodies Mus Mutation Nerve Degeneration Neurodegenerative Disorders Neurons Organism Pathology Patients Peptides Peripheral Pharmaceutical Preparations Pharmacologic Substance Phase Phenotype Phosphorylation Pick Disease of the Brain Prevention strategy Prosencephalon Protein Isoforms Proteins Regulation Research Research Design Route Safety Silver Staining Structure Tauopathies Temporal Lobe Testing Therapeutic Therapeutic antibodies Time Transgenic Mice Transgenic Model Vaccination Vaccines age related aged amyloid pathology base behavior measurement cost effective experience middle age mouse model neurochemistry neuron loss nitration pre-clinical prevent research study response tau Proteins tau aggregation transgene expression

项目摘要

DESCRIPTION (provided by applicant): Tau pathology is implicated as a pathogenic factor in a number of neurodegenerative disorders. Mutations in the tau gene cause some familial cases of frontotemporal lobe dementia, which occurs without concomitant amyloid pathology. The Tg4510 mouse is a transgenic model based on one of these mutations in tau. It is an aggressive model of tauopathy and results in age-dependent tau deposition, behavioral disturbance and neurodegeneration in multiple forebrain structures. Immunotherapy is rapidly advancing with almost 30 FDA approved medications. Immunotherapy is also one of the most advanced anti-amyloid approaches. Multiple clinical trials are testing anti-Aβ immunotherapy as a treatment for dementia. Our group supplied the bulk of the preclinical mouse data supporting the use of one of these agents being pursued in the clinic by Pfizer. Although less extensively examined, presently there are only a few therapeutic strategies targeting tau as a treatment for dementia. Given the broader involvement of tau in neurodegenerative disorders than amyloid, approaches targeting this peptide may have even greater impact than anti-amyloid strategies. This application will investigate the use of anti-tau antibodies as an approach to removing tau deposits in the Tg4510 mouse model. Preliminary data shows that a single intracranial injection of an antibody directed against all forms of tau (tau-5, mid domain epitope IgG1, not phosphorylation specific) can reduce histologically identified tau and reduce silver stained deposits identified by Gallyas. We wish to pursue this initial observation to address 4 specific aims. The first aim will examine the efficacy of 9 different antibodies from 3 different categories using intracranial injections. The first category is antibodies binding all isoforms of tau, like the tau-5 antibody which was successful in the preliminary data. The second category is antibodies targeting specific phosphorylated residues on tau. In a different tau model, Sigurdsson's group has shown vaccines targeting phospho-forms of tau can reduce tau deposition (ref in application). The third category of antibodies targets specific modifications of tau, including conformational changes, nitration and truncation. These latter antibodies might have a greater safety profile, if effective, as they should not target tau isoforms involved with regulation of axonal transport. The second aim will test whether some of these antibodies can prevent further tau deposition using young mice and systemic administration. Aim 3 will test if the systemic route of administration can remove pre-existing tau deposits using systemic administration in older mice. Aim 4 will test the hypothesis that combining intracranial injections to clear pre-existing deposits and following up with systemic administration to prevent formation of new deposits is a superior strategy than either alone.

描述（由申请人提供）：tau 病理学是许多神经退行性疾病的致病因素。tau 基因突变会导致一些家族性额颞叶痴呆病例，而这种情况的发生并不伴有淀粉样蛋白病理学。Tg4510 小鼠是转基因模型。基于 tau 蛋白的这些突变之一，它是一种侵袭性的 tau 蛋白病模型，会导致年龄依赖性 tau 蛋白沉积、行为障碍。免疫疗法正在迅速发展，有近 30 种 FDA 批准的药物也是最先进的抗淀粉样蛋白方法之一，我们的研究小组正在测试抗 Aβ 免疫疗法。大量临床前小鼠数据支持辉瑞在临床上使用其中一种药物，尽管研究较少，但鉴于更广泛的范围，目前只有少数针对 tau 的治疗策略。由于 tau 蛋白比淀粉样蛋白更参与神经退行性疾病，因此针对该肽的方法可能比抗淀粉样蛋白策略具有更大的影响，该应用将研究使用抗 tau 抗体作为去除 Tg4510 小鼠模型中 tau 沉积物的方法。表明单次颅内注射针对所有形式 tau 的抗体（tau-5，中域表位 IgG1，非磷酸化特异性）可以减少组织学鉴定的 tau 蛋白并减少 Gallyas 鉴定的银染色沉积物，我们希望进行这一初步观察以解决 4 个具体目标，第一个目标是使用颅内注射检查 3 个不同类别的 9 种不同抗体的功效。 tau 的所有亚型，例如在初步数据中取得成功的 tau-5 抗体，第二类是针对 tau 上特定磷酸化残基的抗体。 Sigurdsson 的研究小组已经证明，针对 tau 磷酸化形式的疫苗可以减少 tau 沉积（参考文献中的应用）。如果有效，因为它们不应该针对参与轴突运输调节的 tau 异构体，第二个目标是使用年轻小鼠和全身给药来测试其中一些抗体是否可以阻止进一步的 tau 沉积。目标 3 将测试全身给药途径是否可以在老年小鼠中使用全身给药来清除预先存在的 tau 沉积物，目标 4 将测试结合颅内注射以清除预先存在的沉积物并随后进行全身给药以防止形成的假设。新存款是比单独使用任何一种策略都要优越的策略。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Pseudocatalytic Antiaggregation Activity of Antibodies: Immunoglobulins can Influence α-Synuclein Aggregation at Substoichiometric Concentrations.

抗体的假催化抗聚集活性：免疫球蛋白可以影响亚化学计量浓度下的 α-突触核蛋白聚集。

DOI：
发表时间：
2016-04
期刊：
影响因子：
5.1
作者：
Breydo, Leonid;Morgan, Dave;Uversky, Vladimir N
通讯作者：
Uversky, Vladimir N

Fractalkine overexpression suppresses tau pathology in a mouse model of tauopathy.

Fractalkine 过度表达可抑制 tau 蛋白病小鼠模型中的 tau 蛋白病理。

DOI：
发表时间：
2013-06
期刊：
影响因子：
4.2
作者：
Nash, Kevin R;Lee, Daniel C;Hunt Jr, Jerry B;Morganti, Josh M;Selenica, Maj;Moran, Peter;Reid, Patrick;Brownlow, Milene;Guang;Savalia, Miloni;Gemma, Carmelina;Bickford, Paula C;Gordon, Marcia N;Morgan, David
通讯作者：
Morgan, David

Tau-Directed Immunotherapy: A Promising Strategy for Treating Alzheimer's Disease and Other Tauopathies.

Tau 定向免疫疗法：治疗阿尔茨海默病和其他 Tau 病的有前途的策略。

DOI：
发表时间：
2016-03
期刊：
影响因子：
0
作者：
Schroeder SK;Joly-Amado A;Gordon MN;Morgan D
通讯作者：
Morgan D

Partial rescue of memory deficits induced by calorie restriction in a mouse model of tau deposition.

部分挽救 tau 蛋白沉积小鼠模型中热量限制引起的记忆缺陷。

DOI：
发表时间：
2014-09-01
期刊：
影响因子：
2.7
作者：
Brownlow, Milene L;Joly;Azam, Sana;Elza, Mike;Selenica, Maj;Pappas, Colleen;Small, Brent;Engelman, Robert;Gordon, Marcia N;Morgan, Dave
通讯作者：
Morgan, Dave

Metabolic changes over the course of aging in a mouse model of tau deposition.

tau 沉积小鼠模型在衰老过程中的代谢变化。

DOI：
发表时间：
2016-08
期刊：
影响因子：
4.2
作者：
Joly;Serraneau, Karisa S;Brownlow, Milene;Marín de Evsikova, Caralina;Speakman, John R;Gordon, Marcia N;Morgan, Dave
通讯作者：
Morgan, Dave