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Publication Number
US-10064910-B2
Publication Date
2018-09-04
Expiration Date
Abstract
The invention provides a combination treatment for ischemia conditions in or otherwise affecting the CNS, such as stroke. The treatment invoices administration of a PSD-95 inhibitor and performing reperfusion therapy (e.g. by administration of tPA). Administration 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.
Core Innovation
The disclosed invention relates to methods of treating a damaging effect of ischemia on the central nervous system. The method comprises administering a PSD-95 inhibitor to a gyrencephalic primate having or at risk of ischemia, and performing reperfusion therapy, where the PSD-95 inhibitor and reperfusion treat the damaging effect of the ischemia on the central nervous system of the primate. The reperfusion therapy is performed more than 4.5 hours after onset of ischemia.
The invention addresses ischemia-induced damage in the central nervous system and the difficulty of extending the effective reperfusion window beyond a delay after ischemia onset. The disclosed combination therapy uses PSD-95 inhibition together with reperfusion after ischemia onset to treat ischemic damage, and is stated to preserve a time window for reperfusion beyond an earlier effective period.
The disclosed content includes PSD-95 inhibitor designs and reperfusion modalities. The PSD-95 inhibitor includes PSD-95 inhibitor peptides such as Tat-NR2B9c (NA-1) and related variants, including internalization-lipidated or dimerized variants and PL-motif peptides. Reperfusion therapy includes thrombolytic therapy such as tPA/alteplase and plasminogen activators, and mechanical reperfusion, with imaging and/or biomarker-based eligibility checks to avoid hemorrhage.
Claims Coverage
The partial claim set includes one independent claim directed to treating ischemic damage in a gyrencephalic primate by combining PSD-95 inhibition with reperfusion at a late time after onset. The dependent claims refine this core with specific time windows, specific PSD-95 inhibitors, specific thrombolytic agents, interval relationships between PSD-95 inhibition and reperfusion, and imaging-based eligibility criteria.
Late reperfusion combined with PSD-95 inhibitor for ischemic CNS damage in gyrencephalic primates
A method of treating a damaging effect of ischemia on the central nervous system by administering a PSD-95 inhibitor to a gyrencephalic primate having or at risk of ischemia and performing reperfusion therapy, wherein the PSD-95 inhibitor and reperfusion treat a damaging effect of the ischemia on the central nervous system of the primate, and wherein the reperfusion therapy is performed more than 4.5 hours after onset of ischemia.
PSD-95 inhibitor used with reperfusion within an expanded time window beyond 4.5 hours
The method wherein the reperfusion therapy is performed between more than 4.5 hours and less than 24 hours after the onset of ischemia.
Tat-NR2B9c as the PSD-95 inhibitor
The method wherein the PSD-95 inhibitor is tat-NR2B9c.
Thrombolytic reperfusion using tPA
The method wherein the reperfusion therapy is performed using a thrombolytic agent tPA.
Interval between PSD-95 administration and reperfusion of 30 minutes to 6 hours
The method wherein an interval between administering PSD-95 and reperfusion therapy is 30 minutes to 6 hours.
Imaging- and eligibility-based reperfusion decision to avoid hemorrhage
The method further specifying that reperfusion therapy is carried out after determining that a primate is eligible for reperfusion based on absence of a completed infarction, presence of an ischemic penumbra, and absence of hemorrhage as assessed by CT, MRI, or PET.
The inventive coverage centers on combining PSD-95 inhibition with reperfusion in gyrencephalic primates, including reperfusion performed more than 4.5 hours after ischemia onset. The refinements cover expanded reperfusion time windows, Tat-NR2B9c, thrombolytic reperfusion with tPA, the interval between PSD-95 administration and reperfusion, and imaging-based eligibility criteria indicating absence of hemorrhage and presence of ischemic penumbra.
Stated Advantages
Extends the effective reperfusion window beyond more than 4.5 hours after onset of ischemia.
Supports compatibility of PSD-95 inhibition with reperfusion, including Tat-NR2B9c with tPA and dissociation of the NR2B:PSD-95 complex.
Uses imaging and assessment criteria to avoid hemorrhage during reperfusion.
Documented Applications
Treating a damaging effect of ischemia on the central nervous system in a gyrencephalic primate, including ischemia having or at risk of stroke, by administering a PSD-95 inhibitor and performing reperfusion therapy after onset of ischemia.
Thrombolytic reperfusion therapy as part of the combination, including reperfusion using tPA (alteplase/plasminogen activators).
Mechanical reperfusion as part of the combination therapy.
Imaging and biomarker-based eligibility determination using CT, MRI, or PET to assess absence of hemorrhage, presence of ischemic penumbra, and absence of a completed infarction prior to reperfusion.
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