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US-12616667-B2 - Compositions and methods for improving neurological diseases and disorders

US12616667B2US 12616667 B2US12616667 B2US 12616667B2US-12616667-B2

Abstract

In various aspects and embodiments provided are compositions and methods for identifying patients in need of improving cognition and/or treating a neurodegenerative disease in a patient and treating such patient. More specifically, the disclosure in some embodiments includes administration of a β-AR agonist (such as a β-agent) and a peripherally acting β-blocker (PABRA) to a patient in need thereof.

Inventors

  • Anthony P. Ford
  • Gabriel Vargas
  • Wei Chen
  • Renee S. Martin

Assignees

  • CURASEN THERAPEUTICS, INC.

Dates

Publication Date
20260505
Application Date
20221114

Claims (9)

  1. 1 . A method comprising: administering to a subject desiring improvement in cognitive function a β-agent and a peripherally acting β-blocker (PABRA), wherein the β-agent is Compound 03-5 administered at a 3 or 6 mg daily dose and the peripherally acting β-blocker (PABRA) is nadolol administered at a 3 mg daily dose.
  2. 2 . The method of claim 1 , wherein the Compound 03-5 is administered at a 6 mg daily dose and the peripherally acting β-blocker (PABRA) is nadolol administered at a 3 mg daily dose.
  3. 3 . A method comprising: administering to a subject identified as having mild dementia and desiring improvement in cognitive function, a β-agent and a peripherally acting β-blocker (PABRA), wherein the PABRA is administered in a subtherapeutic dose, wherein the β-agent is Compound 03-5 administered at a 3 or 6 mg daily dose and the peripherally acting β-blocker (PABRA) is nadolol administered at a 3 mg daily dose.
  4. 4 . A method comprising: administering to a subject having Parkinson's disease associated with REM sleep behavior disorder (RBD+PD) and/or positive response to RBD Single-Question Screen (RBD1Q) and desiring improvement in cognitive function, a β-agent and a peripherally acting β-blocker (PABRA), wherein the β-agent is Compound 03-5 administered at a 3 or 6 mg daily dose and the peripherally acting β-blocker (PABRA) is nadolol administered at a 3 mg daily dose.
  5. 5 . The method of claim 4 , wherein the patient does not have hallucinations.
  6. 6 . A method comprising: administering to a subject having mild cognitive impairment (MCI) or mild dementia due to Parkinson's disease associated with REM sleep behavior disorder (RBD+PD) and/or positive response to RBD Single-Question Screen (RBD1Q) and desiring improvement in cognitive function, a β-agent and a peripherally acting β-blocker (PABRA), wherein the β-agent is Compound 03-5 administered at a 3 or 6 mg daily dose and the peripherally acting β-blocker (PABRA) is nadolol administered at a 3 mg daily dose.
  7. 7 . The method of claims 1, 3, 4, or 6 , wherein the β-agent is Compound 03-5 administered at a 3 mg daily dose and the peripherally acting β-blocker (PABRA) is nadolol administered at a 3 mg daily dose.
  8. 8 . The method of claims 3, 4, or 6 , wherein the β-agent is Compound 03-5 administered at a 6 mg daily dose and the peripherally acting β-blocker (PABRA) is nadolol administered at a 3 mg daily dose.
  9. 9 . A method comprising: administering to a subject desiring improvement in cognitive function a β-agent and a peripherally acting β-blocker (PABRA), wherein: i) the β-agent is Compound 03-5 administered at a 0.3, 1, 3 or 6 mg daily dose and the peripherally acting β-blocker (PABRA) is nadolol administered at a 1 or 2 mg daily dose, or ii) the β-agent is Compound 03-5 administered at a 0.3 or 1 mg daily dose and the peripherally acting β-blocker (PABRA) is nadolol administered at a 3 mg daily dose.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS This application claims benefit of priority under 35 U.S.C. § 119(e) of U.S. Ser. No. 63/279,585, filed Nov. 15, 2021, the entire contents of which is incorporated herein by reference in its entirety. FIELD OF THE INVENTION The present disclosure relates generally to compositions and methods for improving cognition and/or treating a neurodegenerative disease in a patient. BACKGROUND United States Patent Application Publication Number 20130096126 discloses “a method for enhancing learning or memory of both in a mammal having impaired learning or memory or both from a neuro-degenerative disorder, which entails the step of administering at least one compound or a salt thereof which is a β1-ARenergic receptor agonist, partial agonist or receptor ligand in an amount effective to improve the learning or memory or both of said mammal.” United States Patent Application Publication Number 20140235726 discloses “a method of improving cognition in a patient with Down syndrome, which entails administering one or more β2 adrenergic receptor agonists to the patient in an amount and with a frequency effective to improve cognition of the patient as measured by contextual learning tests.” United States Patent Application Publication Number 20160184241 discloses “a method of improving cognition in a patient with Down syndrome, which entails intranasally administering one or more β2-AR agonists or pharmaceutically-acceptable salts of either or both to the patient in an amount and with a frequency effective to improve cognition of the patient as measured contextual learning tests.” PCT Application Publication Number WO2017115873 discloses “a combination of two or more compounds selected from the group consisting of compounds represented by the Compound No. 1-130, a preventive or therapeutic agent for Alzheimer's disease (AD)” and states “In an attempt to achieve the aforementioned object, the present inventors have screened an existing drug library consisting of 1280 kinds of pharmaceutical compounds approved by the Food and Drug Administration (FDA) in America by using nerve cells induced to differentiate from iPS cells derived from AD patients, and extracted 129 kinds (including one kind of concomitant drug) of compounds that improve Aβ pathology in the nerve cells as candidate therapeutic drugs for AD.” PCT Application Publication Number WO2006108424 states “[t]he invention furthermore relates to dermatological compositions without skin sensitization properties and which contain an enantiomerically pure enantiomer of a β2 adrenoceptor agonist. PCT Application Publication Number WO2018195473 provides “methods of treating a subject who has a synucleinopathy (e.g., Parkinson's disease) that include administering to a subject in need of such treatment therapeutically effective amounts of a β2-adrenoreceptor agonist and at least one therapeutic agent.” PCT Application WO2019241736 (Ford) discloses “compositions and methods for improving cognition and/or treating a neurodegenerative disease in a patient“and that the methods may” . . . include identifying a patient in need of, or desiring improvement of, cognitive function and/or treatment of a neurodegenerative disease and administering to the patient a β agonist and optionally a peripherally acting β-blocker (PABRA).” Ford further discloses that “[e]xamples of selective peripherally acting β-blockers (PABRA) that may in certain embodiments be used in the methods disclosed herein include nadolol, atenolol, sotalol and labetalol.” PCT Application WO2018195473 (Sherzer) discloses “[a] method of treating a subject who has a synucleinopathy, the method comprising: administering to a subject in need of such treatment therapeutically effective amounts of a β2-adrenoreceptor agonist and at least one therapeutic agent selected from the group consisting of: a synucleinopathy therapeutic agent, a β2-adrenoreceptor antagonist and a health supplement, . . . to thereby treat Parkinson's disease in the subject . . . wherein the β2-adrenoreceptor antagonist is selected from the group consisting of carteolol, carvedilol, labetalol, nadolol, penbutolol, pindolol, sotalol, timolol, oxprenolol and butaxamine.” SUMMARY In one aspect, a method for improving cognitive function and/or treating a neurodegenerative disease is provided wherein the method includes administering a therapeutically effective amount of a β-AR agonist (such as a β-agent) and a sub-therapeutic dose of a peripherally acting β-blocker (PABRA) to a patient. In one embodiment, a method for improving cognitive function and/or treating a neurodegenerative disease is provided wherein the method includes administering a therapeutically effective amount of a β-AR agonist (such as a 1-agent) and a sub-therapeutic dose of a peripherally acting β-blocker (PABRA) to a patient. In one embodiment, a method for improving cognitive function and/or treating a neurodegenerative disease is provided wherein th