公开(公告)号：US11338015B2

公开(公告)日：2022-05-24

申请号：US16381757

申请日：2019-04-11

申请人： NoNO, Inc.

发明人： Michael Tymianski

IPC分类号： A61K38/16 ,  A61K38/10 ,  A61K45/06 ,  A61K49/00 ,  A61K38/08 ,  G01N33/68 ,  C07K14/705 ,  C07K14/47 ,  C12N7/00 ,  A61K38/00

摘要： The application provides data from a clinical trial of a PSD-95 inhibitor in subjects undergoing endovascular repair of an aneurysm in or otherwise affecting the CNS. The subjects were stratified by whether the aneurysm ruptured before performing the endovascular surgery. Rupture is associated with higher mortality or increased debilitation if a subject survives. The trial provided evidence of significant benefit in subjects with and without aneurysm rupture before endovascular was surgery performed. Surprisingly, the subjects benefitting most from treatment as judged both by pathology and neurocognitive outcome were those in which the aneurysm had ruptured causing a subarachnoid hemorrhage. These data constitute evidence that a PSD-95 inhibitor is beneficial not only in ischemic and hemorrhagic stroke but in forms of hemorrhage in or affecting the CNS, particularly, subarachnoid hemorrhage.

公开(公告)号：US10967041B2

公开(公告)日：2021-04-06

申请号：US16051971

申请日：2018-08-01

申请人： NONO INC.

发明人： Michael Tymianski

IPC分类号： A61K38/10 ,  A61K38/49 ,  A61K38/17

摘要： The invention provides a combination treatment for ischemia conditions in or otherwise affecting the CNS, such as stroke. The treatment involves administration of a PSD-95 inhibitor and performing reperfusion therapy (e.g., by administration of tPA). Administering a PSD-95 inhibitor in combination with reperfusion therapy increases the efficacy of the reperfusion therapy and/or slows the decline in efficacy of reperfusion therapy with time after onset of ischemia thus extending the window in which reperfusion therapy can be administered.

公开(公告)号：US10300110B2

公开(公告)日：2019-05-28

申请号：US14965694

申请日：2015-12-10

申请人： NoNO Inc.

发明人： Michael Tymianski ,  Jonathan David Garman

IPC分类号： G01N33/68 ,  A61K38/16 ,  A61K38/10 ,  A61K45/06 ,  A61K49/00 ,  A61K38/08 ,  C07K14/705 ,  C07K14/47 ,  C12N7/00 ,  A61K38/00

摘要： The application provides data from a clinical trial of a PSD-95 inhibitor in subjects undergoing endovascular repair of an aneurysm in or otherwise affecting the CNS. The subjects were stratified by whether the aneurysm ruptured before performing the endovascular surgery. Rupture is associated with higher mortality or increased debilitation if a subject survives. The trial provided evidence of significant benefit in subjects with and without aneurysm rupture before endovascular was surgery performed. Surprisingly, the subjects benefiting most from treatment as judged both by pathology and neurocognitive outcome were those in which the aneurysm had ruptured causing a subarachnoid hemorrhage. These data constitute evidence that a PSD-95 inhibitor is beneficial not only in ischemic and hemorrhagic stroke but in forms of hemorrhage in or affecting the CNS, particularly, subarachnoid hemorrhage.

公开(公告)号：US11878044B2

公开(公告)日：2024-01-23

申请号：US17177970

申请日：2021-02-17

申请人： NoNO Inc.

发明人： Michael Tymianski

IPC分类号： A61K38/10 ,  A61K38/49 ,  A61K38/17

CPC分类号： A61K38/10 ,  A61K38/1787 ,  A61K38/49 ,  A61K38/1787 ,  A61K2300/00 ,  A61K38/49 ,  A61K2300/00

摘要： The invention provides a combination treatment for ischemia conditions in or otherwise affecting the CNS, such as stroke. The treatment involves administration of a PSD-95 inhibitor and performing reperfusion therapy (e.g., by administration of tPA). Administering a PSD-95 inhibitor in combination with reperfusion therapy increases the efficacy of the reperfusion therapy and/or slows the decline in efficacy of reperfusion therapy with time after onset of ischemia thus extending the window in which reperfusion therapy can be administered.

公开(公告)号：US20180369319A1

公开(公告)日：2018-12-27

申请号：US15956563

申请日：2018-04-18

申请人： NONO, INC.

发明人： Michael Tymianski

IPC分类号： A61K38/08 ,  A61K38/17

摘要： A method of inhibiting the binding between N-methyl-D-aspartate receptors and neuronal proteins in a neuron is disclosed. The method comprises administering to the neuron an effective inhibiting amount of a peptide replacement agent for the NMDA receptor or neuronal protein interaction domain that effect said inhibition of the NMDA receptor-neuronal protein interaction. The method is of value in reducing the damaging effect of injury to mammalian cells. Postsynaptic density-95 protein (PSD-95) couples neuronal N-methyl-D-aspartate receptors (NMDARs) to pathways mediating excitotoxicity, ischemic and traumatic brain damage. This coupling was disrupted by transducing neurons with peptides that bind to modular domains on either side of the PSD-95/NMDAR interaction complex. This treatment attenuated downstream NMDAR signaling without blocking NMDAR activity, protected cultured cortical neurons from excitotoxic insults, dramatically reduced cerebral infarction volume in rats subjected to transient focal cerebral ischemia, and traumatic brain injury (TBI) in rats.

公开(公告)号：US20170043030A1

公开(公告)日：2017-02-16

申请号：US15245693

申请日：2016-08-24

申请人： NoNO Inc.

发明人： Michael Tymianski ,  Jonathan David Garman ,  Hong Cui

IPC分类号： A61K47/48 ,  A61K38/10 ,  A61K31/277

CPC分类号： A61K47/64 ,  A61K31/275 ,  A61K31/277 ,  A61K38/08 ,  A61K38/10 ,  A61K45/06 ,  A61K47/645 ,  C07K16/1072 ,  C07K2319/10 ,  A61K2300/00

摘要： The invention provides methods of delivering pharmacologic agents linked to an internalization peptide, in which an inflammatory response inducible by the internalization peptide is inhibited by co-administration of an anti-inflammatory or by linking the internalization peptide to biotin or similar molecule. Such methods are premised in part on the results described in the examples whereby administration of a pharmacological agent linked to tat at high dosages is closely followed by an inflammatory response, which includes mast cell degranulation, histamine release and the typical sequelae of histamine release, such as redness, heat, swelling, and hypotension.

摘要翻译： 本发明提供了递送与内化肽连接的药理学试剂的方法，其中通过共同给予抗炎剂或通过将内化肽与生物素或类似分子连接来抑制内化肽诱导的炎症反应。 这些方法部分地基于实施例中描述的结果，其中以高剂量施用与tat连接的药剂紧随其后是炎性反应，其包括肥大细胞脱粒，组胺释放和组胺释放的典型后遗症，例如 作为发红，发热，肿胀和低血压。

公开(公告)号：US20150190459A1

公开(公告)日：2015-07-09

申请号：US14279243

申请日：2014-05-15

申请人： NoNO INC.

发明人： Michael Tymianski

IPC分类号： A61K38/08

CPC分类号： A61K38/08 ,  A61K38/1709

摘要： A method of inhibiting the binding between N-methyl-D-aspartate receptors and neuronal proteins in a neuron is disclosed. The method comprises administering to the neuron an effective inhibiting amount of a peptide replacement agent for the NMDA receptor or neuronal protein interaction domain that effect said inhibition of the NMDA receptor-neuronal protein interaction. The method is of value in reducing the damaging effect of injury to mammalian cells. Postsynaptic density-95 protein (PSD-95) couples neuronal N-methyl-D-aspartate receptors (NMDARs) to pathways mediating excitotoxicity, ischemic and traumatic brain damage. This coupling was disrupted by transducing neurons with peptides that bind to modular domains on either side of the PSD-95NMDAR interaction complex. This treatment attenuated downstream NMDAR signaling without blocking NMDAR activity, protected cultured cortical neurons from excitotoxic insults, dramatically reduced cerebral infarction volume in rats subjected to transient focal cerebral ischemia, and traumatic brain injury (TBI) in rats.

摘要翻译： 公开了抑制神经元中N-甲基-D-天冬氨酸受体和神经元蛋白之间结合的方法。 该方法包括向神经元施用有效抑制量的NMDA受体或神经元蛋白相互作用区域的肽置换剂，其影响NMDA受体 - 神经元蛋白相互作用的所述抑制。 该方法在降低对哺乳动物细胞损伤的破坏作用方面是有价值的。 突触后密度-95蛋白（PSD-95）将神经元N-甲基-D-天冬氨酸受体（NMDAR）与介导兴奋性毒性，缺血性和创伤性脑损伤的途径相结合。 通过用PSD-95NMDAR相互作用复合物的任一侧结合模块结构域的肽转导神经元来破坏该偶联。 这种治疗减弱下游NMDAR信号，而不阻断NMDAR活性，保护培养的皮层神经元免受兴奋性毒性损伤，大大减少了大鼠局部脑缺血大鼠脑损伤的体积，大鼠外伤性脑损伤（TBI）。

公开(公告)号：US08748387B2

公开(公告)日：2014-06-10

申请号：US13675893

申请日：2012-11-13

申请人： NoNO Inc.

发明人： Michael P. Belmares ,  Jonathan David Garman ,  Peter S. Lu ,  Michael W. Salter ,  Michael Tymianski

IPC分类号： C07K14/435 ,  A61K38/16 ,  A61K38/10 ,  A61K38/08

CPC分类号： C07K7/08 ,  A61K38/08 ,  A61K38/10 ,  C07K7/06

摘要： The invention provides agents useful for treating pain. An exemplary agent comprises or consists of the a portion of a retroviral Tat protein. One such agent is the peptide Tat-NR2B9c. This peptide has previously been described as an agent for inhibiting damaging effects of stroke and similar conditions via inhibition of PSD95 interactions with NMDA receptors and/or NOS. The present application provides data showing that the Tat-NR2B9c peptides is effective in alleviation of pain. The alleviation of pain can be obtained at a dose of the peptide below the dose required to inhibit PSD-95 interactions with NMDAR or NOS.

摘要翻译： 本发明提供可用于治疗疼痛的药剂。 一个示例性药剂包含一部分逆转录病毒Tat蛋白或由其组成。 一种这样的药剂是Tat-NR2B9c肽。 此肽以前已经被描述为通过抑制与NMDA受体和/或NOS的PSD95相互作用来抑制中风和类似条件的损伤作用的药剂。 本申请提供了显示Tat-NR2B9c肽有效缓解疼痛的数据。 疼痛缓解可以在低于抑制PSD-95与NMDAR或NOS相互作用所需剂量的肽剂量下获得。

公开(公告)号：US20220175879A1

公开(公告)日：2022-06-09

申请号：US17524673

申请日：2021-11-11

申请人： NoNO Inc.

发明人： Michael Tymianski

IPC分类号： A61K38/16 ,  A61K38/10 ,  A61K45/06 ,  A61K49/00 ,  C07K14/47 ,  C07K14/705 ,  C12N7/00 ,  G01N33/68 ,  A61K38/08

摘要： The application provides data from a clinical trial of a PSD-95 inhibitor in subjects undergoing endovascular repair of an aneurysm in or otherwise affecting the CNS. The subjects were stratified by whether the aneurysm ruptured before performing the endovascular surgery. Rupture is associated with higher mortality or increased debilitation if a subject survives. The trial provided evidence of significant benefit in subjects with and without aneurysm rupture before endovascular was surgery performed. Surprisingly, the subjects benefitting most from treatment as judged both by pathology and neurocognitive outcome were those in which the aneurysm had ruptured causing a subarachnoid hemorrhage. These data constitute evidence that a PSD-95 inhibitor is beneficial not only in ischemic and hemorrhagic stroke but in forms of hemorrhage in or affecting the CNS, particularly, subarachnoid hemorrhage.

公开(公告)号：US20210308209A1

公开(公告)日：2021-10-07

申请号：US17177970

申请日：2021-02-17

申请人： NoNO Inc.

发明人： Michael Tymianski

IPC分类号： A61K38/10 ,  A61K38/49 ,  A61K38/17

摘要： The invention provides a combination treatment for ischemia conditions in or otherwise affecting the CNS, such as stroke. The treatment involves administration of a PSD-95 inhibitor and performing reperfusion therapy (e.g., by administration of tPA). Administering a PSD-95 inhibitor in combination with reperfusion therapy increases the efficacy of the reperfusion therapy and/or slows the decline in efficacy of reperfusion therapy with time after onset of ischemia thus extending the window in which reperfusion therapy can be administered.