KR-20260062940-A - How to treat brain damage after a stroke

Abstract

A method for treating brain damage in subjects includes the step of administering a therapeutically effective dose of a PKM2 (pyruvate kinase M2) protein variant. The protein variant is delivered systemically and can reduce tissue damage following reperfusion of ischemic brain tissue. This method specifically involves the use of the G415R variant among PKM2 protein variants. Treatment is applicable to both brain damage caused by hemorrhagic stroke and ischemic stroke. To maximize therapeutic efficacy, the PKM2 protein variant is administered intravenously ideally within one hour after reperfusion.

Inventors

• 리우, 즈-런

Assignees

• 프로다 바이오테크, 엘엘씨

Dates

Publication Date

20260507

Application Date

20240805

Priority Date

20230803

Claims (20)

1. A method for treating ischemic-reperfusion brain injury (IRI) in a subject, comprising the step of administering a therapeutically effective amount of a PKM2 (pyruvate kinase M2) protein variant, wherein the PKM2 protein variant is delivered systemically and can reduce tissue damage after reperfusion of ischemic brain tissue.
2. In claim 1, the method wherein the PKM2 protein variant is a G415R mutant.
3. In claim 1, the method wherein the brain damage is caused by a hemorrhagic stroke.
4. In claim 1, the method wherein the brain damage is caused by an ischemic stroke.
5. A method according to claim 1, wherein the PKM2 protein variant is administered systemically.
6. A method according to claim 1, wherein the PKM2 protein variant is administered at any point within 2 hours after reperfusion.
7. A method for improving recovery and tissue repair after ischemic stroke and reperfusion, and hemorrhagic stroke, comprising the step of administering a therapeutically effective amount of a PKM2 (pyruvate kinase M2) protein variant having a mutation in G415R to damaged tissues to a patient in need thereof, wherein the PKM2 protein variant is capable of preventing neuronal cell death and promoting regeneration.
8. In claim 7, the above PKM2 protein variant is not constitutive PKM2.
9. In claim 7, the above ischemic stroke is an acute ischemic stroke.
10. A method for treating brain damage caused by hemorrhagic stroke in a subject, comprising the step of administering a therapeutically effective amount of a PKM2 (pyruvate kinase M2) protein variant, wherein the PKM2 protein variant is delivered systemically and can reduce brain tissue damage.
11. A method for improving recovery and tissue repair after ischemic stroke and reperfusion, and hemorrhagic stroke, comprising the step of administering a therapeutically effective amount of a mutant of pyruvate kinase M2 (PKM2) having a mutation in G415R to tissue damaged by ischemic stroke to a patient in need thereof, wherein the composition prevents neuronal cell death and promotes regeneration.
12. In paragraph 11, the above PKM2 variant is not a constitutive PKM2, method.
13. In paragraph 11, the above method is a method for preserving nerve tissue.
14. In paragraph 11, the above ischemic stroke is an acute ischemic stroke.
15. In claim 11, the method comprises a therapeutic agent comprising PKM2 derived from a human or non-human animal.
16. In paragraph 11, the method wherein the therapeutic agent is disposed within a pharmaceutically acceptable carrier.
17. In paragraph 11, the above composition is administered systemically.
18. In claim 11, the above composition is a method for reducing neuronal cell death induced by ischemic injury.
19. In claim 11, the above composition is a method for improving brain function recovery after a stroke.
20. In claim 11, the method wherein the pyruvate kinase M2 or variant is a dimer.

Description

How to treat brain damage after a stroke The present application relates to a system and method for improving recovery and tissue repair by preventing neuronal cell death and promoting regeneration following stroke and reperfusion injury, and hemorrhagic stroke. Ischemia and stroke are interconnected medical conditions characterized by restricted blood flow to the brain, which can lead to potential brain damage and neurological deficits. Ischemia refers to a decrease in the supply of oxygen and nutrients due to insufficient blood supply to tissues or organs. While this condition can occur in various parts of the body, when it affects the brain, it is known as cerebral ischemia. Cerebral ischemia can occur when blood vessels supplying blood to the brain become blocked or narrowed, thereby blocking the necessary blood flow. Furthermore, a stroke is a medical emergency that occurs when blood flow to a part of the brain is suddenly interrupted, resulting in brain cell damage and neurological dysfunction. Stroke is the fifth most common cause of death in the United States and a major cause of long-term disability. Ischemic stroke and ischemia-reperfusion injury are related concepts involving the restriction of blood flow to tissues or organs, particularly the brain, during a stroke, and the subsequent restoration of blood flow. Ischemia-reperfusion injury refers to damage that occurs when blood flow is restored to a tissue or organ after ischemia has persisted for a certain period. While restoring blood flow is essential to prevent further damage, paradoxically, a series of complex biochemical processes can exacerbate initial damage. This damage worsens the prognosis of the stroke, potentially increasing brain damage and neurological deficits. Treatment for ischemic stroke involves rapidly restoring blood flow to the affected brain region to preserve as much viable tissue as possible. Therefore, there is a continuous demand for improved methods to treat or alleviate ischemia, stroke, and ischemia-reperfusion injury. Novel therapeutic strategies and interventions to address these conditions have a significant impact on patients' health and quality of life. This application addresses these requirements in particular. The present patent discloses embodiments related to the treatment of brain injury using a PKM2 protein variant. One embodiment comprises a method for treating ischemia-reperfusion brain injury (IRI) in a subject by administering a therapeutically effective amount of a PKM2 protein variant, wherein the PKM2 protein variant is delivered systemically and can reduce tissue damage following reperfusion of ischemic brain tissue. In one embodiment, the PKM2 protein variant of the method is a G415R mutant. In another embodiment, the method is intended to treat brain injury caused particularly by hemorrhagic stroke or ischemic stroke. In an additional embodiment, the PKM2 protein variant is administered intravenously within one hour after reperfusion. Another aspect includes a method for improving recovery and tissue repair after ischemic or hemorrhagic stroke by administering a PKM2 protein variant having a G415R mutation. In one aspect, the PKM2 protein variant of the method is not constitutive PKM2. In another aspect, the ischemic stroke being treated is an acute ischemic stroke. One embodiment includes a method for treating brain damage caused by hemorrhagic stroke using a PKM2 protein variant delivered systemically. In one embodiment, the method preserves neural tissue. In another embodiment, PKM2 is derived from a human or non-human animal. Another aspect involves how PKM2 (G415R) provides survival benefits. For example, G415R significantly reduced mortality in both MCAO and ICH models compared to other groups (Figs. 2 and 7). Additionally, in the ICH model, G415R reduced brain water content, which indicates a reduction in edema (Fig. 3). Furthermore, G415R significantly reduced infarct size in the MCAO model (Fig. 5). Additionally, one embodiment comprises the therapeutic agent being placed within a pharmaceutically acceptable carrier and administered systemically. In one embodiment, the composition reduces neuronal death induced by ischemic injury or reduces fibrosis of damaged tissue. In another embodiment, the composition improves brain function recovery after stroke, and pyruvate kinase M2 is a dimer. Figure 1 shows that the results of the modified neurological severity score (mNSS) test were significantly improved after G415R treatment in mice that had undergone induced intracerebral hemorrhage (ICH). Figure 2 illustrates the increase in survival rate of intracerebral hemorrhage (ICH) mice after G415R treatment. Figure 3 shows that brain water content measurements were significantly improved after G415R treatment in mice that had undergone induced intracerebral hemorrhage (ICH). Figures 4a and 4b show that neurological function was significantly improved in mice treated with G415R through the Corne