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Publication Number
US-11338015-B2
Publication Date
2022-05-24
Expiration Date
Abstract
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.
Core Innovation
The invention concerns a method of inhibiting development of a neurologic or neurocognitive deficit of subarachnoid hemorrhage in a subject. The method comprises administering an agent that inhibits binding of PSD-95 to an NMDAR2 subunit to a subject having a subarachnoid hemorrhage, wherein the agent is an inhibitor peptide comprising an amino acid sequence of SEQ ID NO:38 or SEQ ID NO:7 at the C-terminus linked to an internalization peptide, or the inhibitor peptide in lipidated form.
The described clinical context relates to subjects undergoing endovascular aneurysm repair, where administration of a PSD-95 inhibitor (TAT-NR2B9C) is associated with reduced post-procedure embolic ischemic lesions detected by MRI (DWI/FLAIR). The study further reports improved neurological and neurocognitive outcomes following treatment, with the greatest benefit in patients whose aneurysm ruptured before surgery, causing subarachnoid hemorrhage (SAH).
The partial content also reports minimal drug-related serious adverse events and a significant reduction in procedure-associated pain. In addition to imaging measures, the study outcomes include infarct lesion number and infarct volume, along with clinical measures such as NIHSS and modified Rankin Scale (mRS), as well as neurocognitive outcomes.
Claims Coverage
The partial content provides one independent claim describing the core method, with multiple dependent refinements. Three inventive features are identified: inhibition of PSD-95 binding to an NMDAR2 subunit in a subarachnoid hemorrhage subject, a specifically defined inhibitor peptide format, and a limitation that administering is not in the course of a clinical trial.
Inhibiting PSD-95 binding to an NMDAR2 subunit in SAH subjects
A method of inhibiting development of a neurologic or neurocognitive deficit of subarachnoid hemorrhage by administering an agent that inhibits binding of PSD-95 to an NMDAR2 subunit to a subject having a subarachnoid hemorrhage.
Inhibitor peptide at the C-terminus linked to an internalization peptide or lipidated inhibitor peptide
The agent is an inhibitor peptide comprising the amino acid sequence of SEQ ID NO:38 or SEQ ID NO:7 at the C-terminus linked to an internalization peptide, or the agent is the inhibitor peptide in lipidated form.
Administration not in the course of a clinical trial
The administering to the subject is not in the course of a clinical trial.
Overall, the independent claim is directed to preventing neurologic or neurocognitive deficits of subarachnoid hemorrhage by administering a PSD-95/NMDAR2 binding inhibitor in a specified inhibitor-peptide format, with the additional limitation that the administration is not in the course of a clinical trial.
Stated Advantages
Reduced post-procedure embolic ischemic lesions detected by MRI (DWI/FLAIR).
Improved neurological and neurocognitive outcomes, with greatest benefit in patients whose aneurysm ruptured before surgery causing SAH.
Minimal drug-related serious adverse events.
Significant reduction in procedure-associated pain.
Documented Applications
Treatment context in subjects undergoing endovascular aneurysm repair, including cases where aneurysm rupture before surgery causes subarachnoid hemorrhage (SAH).
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