# US 9,241,970 B2 · Therapy for subarachnoid hemorrhage and ischemia

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- Number: US 9,241,970 B2
- Document ID: US9241970B2
- Status: Granted
- Kind: B2
- Application number: 13/774,053
- Filed: 2013-02-22
- Published: 2013-06-20
- Granted: 2016-01-26
- Earliest claimed: 2011-12-13
- Assignees: NoNO Inc.
- Applicants: NoNO Inc.
- Inventors: Michael Tymianski
- Web page: https://patentgrep.com/patent/US9241970B2

## CPC

- A61K 38/162: {from virus}
- A61K 38/08: Peptides having 5 to 11 amino acids {(A61K38/043 - A61K38/046 take precedence)}
- A61K 38/10: Peptides having 12 to 20 amino acids {(A61K38/043 - A61K38/046 take precedence)}
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61K 49/00: Preparations for testing in vivo
- C07K 14/47: from mammals
- C07K 14/70571: {for neuromediators, e.g. serotonin receptor, dopamine receptor}
- C12N 7/00: Viruses; Bacteriophages; Compositions thereof; Preparation or purification thereof (preparing medicinal viral antigen or antibody compositions, e.g. virus vaccines, A61K39/00)
- G01N 33/6893: {related to diseases not provided for elsewhere}
- A61K 38/00: Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00)
- C07K 2319/10: containing a tag for extracellular membrane crossing, e.g. TAT or VP22
- C12N 2740/16311: concerning HIV regulatory proteins
- C12N 2740/16322: New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes
- C12N 2740/16371: Demonstrated in vivo effect
- G01N 2800/2871: Cerebrovascular disorders, e.g. stroke, cerebral infarct, cerebral haemorrhage, transient ischemic event
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)
- G01N: INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES (measuring or testing apparatus or processes other than immunoassay, involving enzymes or microorganisms C12M, C12Q)

## 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 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.

## Claims

### Claim 1

A method of treating a subarachnoid hemorrhage in a human subject, comprising:
administering an agent that binds to PSD-95 and inhibits binding of PSD-95 to an NMDAR2B subunit to a subject having a subarachnoid hemorrhage, wherein development of neurocognitive deficits in the subject is inhibited, wherein the administering to the subject is not in the course of a clinical trial.

### Claim 2 (depends on 1)

The method of claim 1, wherein the subarachnoid hemorrhage is the result of physical trauma.

### Claim 3 (depends on 1)

The method of claim 1, wherein the subarachnoid hemorrhage occurs spontaneously.

### Claim 4 (depends on 3)

The method of claim 3, wherein the subarachnoid hemorrhage is due to a ruptured aneurysm.

### Claim 5 (depends on 3)

The method of claim 3, wherein the subarachnoid hemorrhage is due to arteriovenous malformation.

### Claim 6 (depends on 1)

The method of claim 1, wherein the agent inhibits development of infarctions detectable by MRI.

### Claim 7 (depends on 1)

The method of claim 1, wherein the agent reduces pain resulting from endovascular surgery.

### Claim 8 (depends on 7)

The method of claim 7, wherein the pain is along a path traversed by an endoscope used in performing the endoscopic surgery.

### Claim 9 (depends on 1)

The method of claim 1, wherein the agent is administered during or after a surgery to repair a blood vessel causing the hemorrhage.

### Claim 10 (depends on 1)

The method of claim 1, wherein the agent is administered before, during or after administering another agent effective to reduce damaging effects of subarachnoid hemorrhage.

### Claim 11 (depends on 1)

The method of claim 1, wherein the agent is administered by day 4 following a rupture causing the subarachnoid hemorrhage.

### Claim 12 (depends on 1)

The method of claim 1, wherein the agent is administered on multiple occasions within twelve days post rupture causing the subarachnoid hemorrhage.

### Claim 13 (depends on 1)

The method of claim 1, wherein the agent is administered twice daily for at least two days or once daily for at least three days.

### Claim 14 (depends on 1)

The method of claim 1, wherein the dose of the agent is 1-3 mg/kg.

### Claim 15 (depends on 1)

The method of claim 1, wherein the agent is a peptide having an amino acid sequence consisting or comprising of X1tSX2V (SEQ ID NO:7), wherein t and S are alternative amino acids, X1 is selected from among E, Q, and A, X2 is selected from among A, Q, D, N, (N-Methyl)-A, (N-methyl)-Q, (N-methyl)-D, and (N-methyl)-N, or the peptide is an agent according to a formula shown below

### Claim 16 (depends on 15)

The method of claim 15, wherein the peptide is linked to an internalization peptide or is lipidated thereby facilitating passage of the peptide across a cell membrane or the blood brain barrier.

### Claim 17 (depends on 1)

The method of claim 1, wherein the agent is a peptide having an amino acid sequence consisting or comprising of YGRKKRRQRRRKLSSIESDV (SEQ ID NO:6) or YGRKKRRQRRRKLSSIETDV (SEQ ID NO:37).

### Claim 18 (depends on 1)

The method of claim 1, wherein the agent is a myristoylated peptide.

### Claim 19 (depends on 18)

The method of claim 18, wherein peptide has an amino acid sequence consisting or comprising of KLSSIESDV (SEQ ID NO:5) or KLSSIETDV (SEQ ID NO:43).

### Claim 20 (depends on 18)

The method of claim 18, wherein the myristoylation is at the N-terminus of the peptide.

### Claim 21 (depends on 1)

The method of claim 1, comprising:
administering the agent that inhibits binding of PSD-95 to the NMDAR2B subunit to subjects having a subarachnoid hemorrhage, wherein the damaging effect is reduced in the administered population compared to control subjects not receiving the agent.

### Claim 22 (depends on 1)

The method of claim 1, wherein the subject receives endovascular surgery to repair a blood vessel causing the subarachnoid hemorrhage ruptured before the surgery.

### Claim 23 (depends on 1)

The method of claim 1, wherein the agent is administered within a period starting 30 minutes before and ending 60 minutes after a surgery.