公开(公告)号：US20250049953A1

公开(公告)日：2025-02-13

申请号：US18801053

申请日：2024-08-12

Applicant: THE TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK

Inventor： Nourdine CHAKOURI ,  Manu BEN JOHNY ,  Steven O. MARX

IPC: A61K48/00 ,  A61K38/18 ,  A61P9/06 ,  C12N15/86

Abstract: Treatments and methods for inhibiting late Na current use fibroblast growth factor homologous factor (FHF), an endogenous channel modulator, to inhibit late Na current with high potency. A minimal effector domain is engineered within FHF (the “FHF-inhibiting-X-region” (FixR)) as a peptide inhibitor of late Na current that may be delivered intracellularly, for example as a cell-penetrating peptide, or via viral or plasmid delivery. As a non-limiting example, human adenovirus type 5 may be genetically modified with the sequence 5′-ATGGCTGCGGCGATAGCCAGCTCCTTGATCCGGCAGAAGCGGCAGGCGAGGGAG TCCAACAGCGACCGAGTGTCGGCCTCCAAGCGCCGCTCCAGCCCCAGCAAAGAC GGGCGCTCC-3′ (SEQ ID NO: 1). As pathophysiological impact of late Na current extends beyond cardiac myocytes to other physiological settings, including neurons of the central and peripheral nervous system and skeletal muscle, these treatments and methods provide potential therapeutic avenues for a range of human ailments, including cardiac conditions, neurological/neuropsychiatric disorders, and skeletal muscle conditions. Neurological/neuropsychiatric disorders include, for example, epilepsy and autism spectrum disorders, pain-related diseases, and myotonia.

公开(公告)号：US20220397567A1

公开(公告)日：2022-12-15

申请号：US17624497

申请日：2020-07-02

Applicant: THE TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK ,  THE NEW YORK AND PRESBYTERIAN HOSPITAL ,  HARVARD UNIVERSITY

Inventor： Steven O. MARX ,  Alexander KUSHNIR ,  Sergey ZAKHAROV ,  Alexander KATCHMAN ,  Steven P. GYGI ,  Marian KALOCSAY ,  Manu BEN-JOHNY ,  Henry M. COLECRAFT ,  Guoxia LIU

IPC: G01N33/50

Abstract: The method for increasing contractility in patients with systolic heart failure involves screening for candidate small molecules which block the interaction between Rad and the plasma membrane and/or block the interaction between Rad and the CaV1.2/CaVβ2 complex, or between Rad and CaVβ2, in order to increase cardiac contractility. A method for preventing calcium overload and arrhythmias in heart disease involves preventing the dissociation of Rad and the CaV1.2/CaVβ2 complex, or between Rad and CaVβ2, during beta-adrenergic system activation. Additionally, a method of screening for drugs that block interaction between an RGK GTPase protein and a β-subunit of the calcium channel is provided. A suitable technique, such as fluorescence resonance energy transfer (FRET), may be used to assess blocking of the interaction between the RGK GTPase protein and the β-subunit of the calcium channel for the treatment of heart disease, pain, diabetes, skeletal muscle disorders and/or central nervous system (CNS) disorders.