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Publication Number
US-11878044-B2
Publication Date
2024-01-23
Expiration Date
Abstract
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.
Core Innovation
The invention relates to treating stroke in a human subject by administering a PSD-95 inhibitor comprising a peptide that has SEQ ID NO:38 or SEQ ID NO:68 at its C-terminus, linked to an internalization peptide, together with reperfusion therapy. The PSD-95 inhibitor and reperfusion therapy synergistically treat the stroke.
A problem addressed is that reperfusion therapy, including tPA, has a limited effective window of approximately 3–4.5 hr. The invention aims to increase reperfusion efficacy and/or reduce loss of efficacy over time, such that the usable reperfusion window can be extended beyond the tPA limitation described.
The invention also includes patient/subgroup selection for reperfusion therapy based on unacceptable risk of side effects, using diagnostic criteria described in the partial content such as CT, MRI, or PET, together with criteria involving completed infarction, ischemic penumbra, and lack of hemorrhage. In subjects without unacceptable risk, reperfusion therapy is administered together with the PSD-95 inhibitor for synergistic treatment, while subjects with unacceptable risk do not receive reperfusion therapy.
Claims Coverage
The independent claims cover two treatment methods: a general stroke treatment method combining a PSD-95 inhibitor peptide linked to an internalization peptide with reperfusion therapy such that the combination synergistically treats stroke; and a subject-population treatment method that adds an analysis step for unacceptable risk of reperfusion side effects and uses that analysis to decide whether to administer reperfusion therapy, while still requiring synergistic treatment for those receiving reperfusion.
PSD-95 inhibitor peptide linked to an internalization peptide for synergistic reperfusion treatment
Administering a PSD-95 inhibitor comprising a peptide comprising SEQ ID NO:38 or SEQ ID NO:68 at its C-terminus, the peptide being linked to an internalization peptide to a human subject having or at risk of stroke, and performing reperfusion therapy on the subject, wherein the PSD-95 inhibitor and reperfusion therapy synergistically treat the stroke.
Risk-based reperfusion therapy decision using unacceptable risk of side effects with synergistic treatment
Analyzing human subjects presenting sign(s) and/or symptom(s) of stroke for unacceptable risk of side effects of reperfusion therapy; administering the PSD-95 inhibitor comprising a peptide comprising SEQ ID NO:38 or SEQ ID NO:68 at its C-terminus linked to an internalization peptide; providing reperfusion therapy to human subjects without unacceptable risk and not providing reperfusion therapy to human subjects with unacceptable risk, wherein in the human subjects without unacceptable risk receiving reperfusion therapy, the reperfusion therapy and the PSD-95 inhibitor synergistically treat the stroke.
Across the independent claims, the core inventive coverage is the synergy between a PSD-95 inhibitor peptide (SEQ ID NO:38 or SEQ ID NO:68 at its C-terminus) linked to an internalization peptide and reperfusion therapy, with the second independent claim further requiring a decision rule based on unacceptable risk of side effects of reperfusion therapy.
Stated Advantages
Increased reperfusion efficacy and/or reduced loss of efficacy over time.
Potential extension of the usable reperfusion window beyond the described ~3–4.5 hr limitation for tPA.
Documented Applications
Treating stroke in a human subject having or at risk of stroke by administering a PSD-95 inhibitor peptide linked to an internalization peptide together with reperfusion therapy such that the combination synergistically treats the stroke.
Treating a subject population of humans presenting signs and/or symptoms of stroke by administering the PSD-95 inhibitor and using an analysis of unacceptable risk of side effects of reperfusion therapy to decide who receives reperfusion therapy, while ensuring synergistic treatment for those without unacceptable risk.
Patient/subgroup selection for whether to administer reperfusion therapy using diagnostic criteria described in the partial content (CT, MRI, or PET) including absence of completed infarction, presence of an ischemic penumbra, and lack of hemorrhage.
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