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    • 3. 发明申请
    • COMPOSITIONS AND METHODS OF TREATMENT USING MODULATORS OF MOTONEURON DISEASES
    • 使用MOTONEURON疾病调节剂的组合物和治疗方法
    • US20110076236A1
    • 2011-03-31
    • US12994098
    • 2009-05-21
    • Marc K. HellersteinPatrizia Fanara
    • Marc K. HellersteinPatrizia Fanara
    • A61K49/00G01N33/53A61K31/4439A61K9/127A61P25/00A61P21/00
    • G01N33/6896G01N33/5058G01N2500/10G01N2800/2835
    • The invention disclosed herein describes a novel therapeutic target for motoneuron diseases (altered dynamics of microtubules in neurons); methods for measuring the state of activity of this therapeutic target in subjects with established, incipient, or potential motoneuron disease; the discovery of drug agents that modulate neuronal microtubule dynamics in living subjects with motoneuron diseases; the discovery that administration of such agents, alone or in combinations, can improve MT-mediated transport of “synaptic vesicle cargo” molecules along and through axons; the discovery that such modulation of altered microtubule dynamics and improvement in MT-transport of molecules along axons can provide marked neuroprotective therapy for living subjects with motoneuron diseases, including delay in symptoms and prolongation of survival; and the discovery that monitoring of neuronal microtubule dynamics in response to therapeutic interventions in subjects with motoneuron diseases, allows diagnostic monitoring, to optimize therapeutic regimens and treatment strategies in individual subjects or in drug trials. The monitoring involves measuring isotope enrichment in secreted synaptic vesicle cargo molecules.
    • 本文公开的发明描述了运动神经元疾病(神经元中微管的动力学改变)的新型治疗靶标; 用于测量具有确定的,初期的或潜在的运动神经元疾病的受试者中该治疗靶标的活性状态的方法; 发现在运动神经元疾病的活体中调节神经元微管动力学的药剂; 发现这种药物单独或组合地可以改善MT介导的“突触小泡载体”分子沿轴突和轴突的转运; 发现改变的微管动力学的这种调节和沿着轴突的分子的MT转运的改善可以为具有运动神经元疾病的活动受试者提供显着的神经保护疗法,包括延迟症状和延长生存期; 并且发现通过对具有运动神经元疾病的受试者的治疗干预来监测神经元微管动力学,允许诊断监测,优化个体受试者或药物试验中的治疗方案和治疗策略。 监测涉及测量分泌的突触囊泡货物分子中的同位素富集。
    • 5. 发明授权
    • Monitoring two dimensions of diabetes pathogenesis
    • 监测糖尿病发病机制的两个维度
    • US08741589B2
    • 2014-06-03
    • US11451735
    • 2006-06-12
    • Marc K. Hellerstein
    • Marc K. Hellerstein
    • C12Q1/54
    • A61K49/0008A61K49/0004G01N33/60G01N33/6893G01N2800/042
    • Provided are methods for determining concurrently with a simple, minimally invasive test, the adequacy of pancreatic beta-cell compensation and/or the presence of tissue insulin resistance in a subject human or an experimental animal. The methods allow for the determination of a subject's or experimental animal's susceptibility to developing type 2 diabetes mellitus (DM2) or to progression to more advanced forms of DM2. Among other uses, the methods allow for diagnostic classification of subjects for decisions regarding therapeutic interventions, clinical differentiation between type 1 DM and DM2, clinical monitoring of treatments intended to reduce risk of developing DM2 in non-diabetic subjects, clinical monitoring of agents intended to improve existing DM2 and to prevent progression of DM2, clinical development and testing of new compounds, candidate agents, or candidate therapies for preventing progression to DM2 or disease progression in existing DM2, and preclinical screening of candidate agents or candidate therapies in experimental animals to identify and characterize agents having insulin-sensitizing properties, pancreatic stimulatory or regenerative properties or other desirable actions.
    • 提供了用于通过简单的微创测试同时测定胰腺β细胞补偿的充分性和/或受试者或实验动物中组织胰岛素抵抗的存在的方法。 该方法允许确定受试者或实验动物对发展为2型糖尿病(DM2)的敏感性或进展至更高级的DM2形式。 除了其他用途之外,这些方法允许受试者的诊断分类用于治疗干预,1型DM和DM2之间的临床分化,旨在降低在非糖尿病受试者中发展DM2的风险的治疗的临床监测,旨在 改善现有的DM2,并防止DM2的进展,新化合物,候选药物或候选药物的临床开发和检测,以防止DM2进展或现有DM2中的疾病进展,以及临床前筛选实验动物中的候选药物或候选治疗,以鉴定 并表征具有胰岛素敏感性,胰刺激或再生性质或其它期望作用的药剂。
    • 6. 发明授权
    • Method for high-throughput screening of compounds and combinations of compounds for discovery and quantification of actions, particularly unanticipated therapeutic or toxic actions, in biological systems
    • 高通量筛选化合物和化合物组合的方法,用于发现和定量生物系统中的作用,特别是意料之外的治疗或毒性作用
    • US08663602B2
    • 2014-03-04
    • US13031084
    • 2011-02-18
    • Marc K. Hellerstein
    • Marc K. Hellerstein
    • A61K49/00
    • G01N33/5067A61K49/0008G01N33/5088G01N33/60G01N33/6848Y02A90/22
    • The invention enables high-throughput screening of compounds in living systems to detect unanticipated or unintended biological actions. The invention also allows for screening, detection, and confirmation of new indications for approved drugs. Screening and detection of toxic effects of compounds also can be achieved by using the methods of the invention. The methods comprise administering isotope-labeled substrates to a living system so that the label is incorporated into molecules in a manner that reveals flux rates through metabolic pathways thought to be involved in a disease. Comparisons between living systems exposed to compounds and living systems not so exposed reveals the effects of the compounds on the flux rates through the metabolic pathways. Combinations or mixtures of compounds can be systematically screened to detect unanticipated or unintended biological actions, including synergistic actions, in the same manner.
    • 本发明使得生物系统中化合物的高通量筛选能够发现未预期的或非预期的生物作用。 本发明还允许筛选,检测和确认经批准的药物的新适应症。 化合物的毒性作用的筛选和检测也可以通过使用本发明的方法来实现。 所述方法包括向活体系统施用同位素标记的底物,使得将标记以通过被认为参与疾病的代谢途径揭示通量速率的方式并入分子中。 暴露于化合物的活体系与未暴露的生物体系之间的比较揭示了化合物对通过代谢途径的通量速率的影响。 可以以相同的方式系统地筛选化合物的组合或混合物以检测意外的或非预期的生物作用,包括协同作用。
    • 7. 发明授权
    • Methods for determining the metabolism of sugars and fats in an individual
    • 确定个体中糖和脂肪代谢的方法
    • US07504233B2
    • 2009-03-17
    • US10701990
    • 2003-11-04
    • Marc K. Hellerstein
    • Marc K. Hellerstein
    • C12Q1/54
    • G01N33/58A61K49/0004
    • Provided herein are methods for determining the metabolism of one or more sugars and/or fatty acids, and applications thereof. Such applications include determining the rate of glycogen synthesis and glycolysis, which are believed to be early markers for predicting elevated risk of diabetes and cardiovascular disease. Other applications include methods for screening drugs that effect sugar and/or fatty acid metabolism. The methods are useful for at least partially characterizing drugs for desirable or undesirable (toxic) characteristics. Drugs that are at least partially characterized using the methods of the invention can then be further developed in pre-clinical testing and clinical trials. Such drugs may be found to be useful in treating obesity, diabetes, cardiovascular disease, and other disorders of metabolism.
    • 本文提供了确定一种或多种糖和/或脂肪酸的代谢的方法及其应用。 这些应用包括确定糖原合成和糖酵解的速率,这被认为是预测糖尿病和心血管疾病风险升高的早期标志物。 其他应用包括用于筛选影响糖和/或脂肪酸代谢的药物的方法。 所述方法可用于至少部分表征药物以获得期望的或不期望的(有毒的)特征。 可以在临床前临床试验和临床试验中进一步开发使用本发明方法至少部分表征的药物。 可以发现这些药物可用于治疗肥胖,糖尿病,心血管疾病和其他代谢紊乱。
    • 8. 发明授权
    • Methods for comparing relative flux rates of two or more biological molecules in vivo through a single protocol
    • 通过单一方案比较体内两种或多种生物分子的相对通量率的方法
    • US07262020B2
    • 2007-08-28
    • US10872280
    • 2004-06-17
    • Marc K. Hellerstein
    • Marc K. Hellerstein
    • C12Q1/02
    • G01N33/502G01N33/5088G01N2800/52
    • The invention relates to techniques for measuring and comparing relative molecular flux rates of different biological molecules by administering isotope-labeled water to one or more tissues or individuals and comparing the molecular flux rates of two or more biological molecules, including biological molecules in different chemical classes. The methods find use in several applications including diagnosing, prognosing, or monitoring a disease, disorder, or condition, the in vivo high-throughput screening of chemical entities and biological factors for therapeutic effects in various disease models, and the in vivo high-throughput screening of chemical entities and biological factors for toxic effects.
    • 本发明涉及通过向一个或多个组织或个体施用同位素标记的水并比较两种或多种生物分子(包括不同化学类别中的生物分子)的分子通量速率来测量和比较不同生物分子的相对分子通量速率的技术 。 该方法可用于多种应用,包括诊断,预后或监测疾病,病症或状况,化学实体的体内高通量筛选和各种疾病模型中治疗效果的生物因子,以及体内高通量 筛选化学实体和生物因素的毒性作用。
    • 10. 发明授权
    • Methods for screening cellular proliferation using isotope labels
    • 使用同位素标记物筛选细胞增殖的方法
    • US06808875B2
    • 2004-10-26
    • US10155536
    • 2002-05-24
    • Marc K. Hellerstein
    • Marc K. Hellerstein
    • C12Q100
    • A61K31/665C12Q1/48C12Q1/68C12Q1/6809C12Q1/70G01N33/5005G01N33/5088G01N33/60
    • The present invention relates to methods for measuring the proliferation and destruction rates of cells by measuring deoxyribonucleic acid (DNA) synthesis and/or destruction. In particular, the methods utilize non-radioactive stable isotope labels to endogenously label DNA synthesized through the de novo nucleotide synthesis pathway in a cell. The amount of label incorporated in the DNA is measured as an indication of cellular proliferation. The decay of labeled DNA over time is measured as an indication of cellular destruction. Such methods do not involve radioactivity or potentially toxic metabolites, and are suitable for use both in vitro and in vivo. Therefore, the invention is useful for measuring cellular proliferation or cellular destruction rates in humans for the diagnosis, prevention, or management of a variety of disease conditions in which cellular proliferation or cellular destruction is involved. The invention also provides methods for measuring proliferation or destruction of T cells in a subject infected with human immunodeficiency virus (HIV) and methods of screening an agent for a capacity to induce or inhibit cellular proliferation or destruction. In addition, the invention provides methods for measuring cellular proliferation in a proliferating population which utilize both radioactive isotope labels and stable isotopes to endogenously label DNA through the de novo nucleotide synthesis pathway.
    • 本发明涉及通过测量脱氧核糖核酸(DNA)合成和/或破坏来测量细胞的增殖和破坏率的方法。 特别地,该方法利用非放射性稳定同位素标记来内生标记通过细胞中从头核苷酸合成途径合成的DNA。 测量结合在DNA中的标记量作为细胞增殖的指示。 随着时间的推移,标记的DNA的衰变被测量为细胞破坏的指示。 这些方法不涉及放射性或潜在的毒性代谢物,并且适用于体外和体内。 因此,本发明可用于测量人类的细胞增殖或细胞破坏率,用于诊断,预防或管理涉及细胞增殖或细胞破坏的各种疾病状况。 本发明还提供了测量感染人类免疫缺陷病毒(HIV)的受试者的T细胞增殖或破坏的方法以及筛选诱导或抑制细胞增殖或破坏能力的试剂的方法。 此外,本发明提供了用于测量增殖群体中的细胞增殖的方法,其利用放射性同位素标记和稳定同位素来通过从头核苷酸合成途径内源性标记DNA。