Columbia University

The State University of New York

Washington University

University of Missouri

Ira S Cohen

Richard B Robinson

Michael R Rosen

Peter R Brink

Han-Gang Yu

Peter Danilo

Glenn R Gaudette

Arthur P Grollman

Xiaoqin Zou

Jianmin Cui

Irina Potapova

Lev Protas

Amy B Rosen

The present disclosure relates to methods and compositions for modulating the activity of KCNQ channels as a means for reducing the effects of aberrant KCNQ channel function associated with epilepsy, deafness and arrhythmias including but not limited to, Long-QT syndrome ('LQTS'), and atrial fibrillation. The present disclosure also relates to the discovery of certain regions of KCNQ channels that interact with various channel stimulating molecules such as, ATP, and PIP, as well as KCNQ channel domains that effect voltage dependant channel activation. The disclosure is also directed to the use of small molecules to modulate KCNQ channel activity in a cell. Moreover, the present disclosure relates to the therapeutic effects of treating a subject with modulators of KCNQ channel activity.

KCNQ channels as therapeutic targets

A device and method for analyzing cells includes a housing with a chamber, a barrier supported by a frame disposed within the chamber, and a plate arranged at a bottom surface of the housing interior of the chamber. The plate is adapted to receive and sustain cells and the barrier separates the plate into at least two contiguous separate areas. In some embodiments, a thin rubber strip is arranged at the bottom edge of the barrier, which facilitates control of the area in which each cell type is grown, the size of the gap between the cells, and helps prevents over growth of the two cell types on to each other.

Device and method for growing and analyzing cells

The invention provides a method of creating an atrioventricular bypass tract for a heart comprising growing mesenchymal stem cells into a strip with two ends, and attaching one end of the strip onto the atrium of the heart, and attaching the other end of the strip to the ventricle of the heart. By this attachment, a tract is created that connects the atrium to the ventricle to provide a path for electrical signals generated by the sinus node to propagate across the tract and excite the ventricle.

Creation of a biological atrioventricular bypass to compensate for atrioventricular block

A method for treating a subject afflicted with a cardiac disorder, in vivo, comprises (i) inducing differentiation of a progenitor cell, in vitro, to a cardiogenic cell; and (ii) administering a therapeutically effective amount of the cardiogenic cell of step (i) to the subject, thereby treating the cardiac disorder in the subject. This invention further provides related articles of manufacture and methods.

Differentiation of human mesenchymal stem cells to cardiac progenitor cells that promote cardiac repair

This invention provides a bypass bridge comprising a tract of gap junction-coupled cells having a first end and a second end, both ends capable of being attached to two selected sites in a heart so as to allow the conduction of a pacemaker and/or electrical signal/current across the tract between the two sites, wherein the cells functionally express a sodium channel. The invention also provides related methods of making the bypass bridge, methods of implanting same in a heart, and methods of treating a disorder associated with an impaired conduction in a subject's heart.

Biological bypass bridge with sodium channels, calcium channels and/or potassium channels to compensate for conduction block in the heart

This invention provides methods for determining the ability of a gene construct to alter the rhythm and contractility of a syncytial cell. Furthermore, this invention provides methods for constructing a gene construct capable of altering the rhythm or contractility of a syncytial cell. Finally, this invention provides a method for constructing a gene construct capable of coupling to a syncytial cell.

Assay system for monitoring the effects of genetically engineered cells to alter function of a synctium

A method of delivering an oligonucleotide or a plasmid expressing an oligonucleotide into a target cell comprises introducing an oligonucleotide into a donor cell, particularly a stem cell, and contacting the target cell with the donor cell under conditions permitting the donor cell to form a gap junction with the target cell, whereby the oligonucleotide or a product of the oligonucleotide is delivered into the target cell from the donor cell.

Delivery of DNA or RNA via gap junctions from host cells to target cells and a cell-based delivery system for antisense or siRNA

The present invention provides methods and compositions relating to the labeling of target cells with nanometer scale fluorescent semiconductors referred to as quantum dots (QDs). Specifically, a delivery system is disclosed based on the use of negatively charged QDs for delivery of a tracking fluorescent signal into the cytosol of target cells via a passive endocytosis-mediated delivery process. In a specific embodiment of the invention the target cell is a stem cell, preferably a mesenchymal stem cell (MSC). Such labeled MSCs provide a means for tracking the distribution and fate of MSCs that have been genetically engineered to express, for example, a hyperpolarization-activated cyclic nucleotide-gated ('HCN') channel and administered to a subject to create a biological pacemaker. The invention is based on the discovery that MSCs can be tracked in vitro for up to at least 6 weeks. Additionally, QDs delivered in vivo can be tracked for up to at least 8 weeks, thereby permitting for the first time, the complete 3-D reconstruction of the locations of all MSCs following administration into a host.

Quantum dot labeled stem cells for use in providing pacemaker function

A method of creating an atrioventricular bypass tract for a heart comprises growing mesenchymal stem cells into a strip with two ends, attaching one end of the strip onto the atrium of the heart, and attaching the other end of the strip to the ventricle of the heart, to create a tract connecting the atrium to the ventricle to provide a path for electrical signals generated by the sinus node to propagate across the tract and excite the ventricle.

This invention provides a composition for delivery of a gene to a syncytial structure comprising stem cells incorporated with the gene. This invention also provides a composition for ion channel transfer which comprises stem cells incorporated with a compound in an amount sufficient to create ion channels. This invention also provides for a method of expressing a functional gene product in a syncytial structure comprising administering a composition, comprising stem cells that have been incorporated with a gene, to the syncytial structure. This invention further provides a method of expressing a functional ion channel in a syncytial structure comprising administering a composition, comprising stem cells that have been incorporated with a compound in an amount sufficient to create ion channels, to the syncytial structure. This invention also provides a composition for delivery of small molecules comprising stem cells incorporated with the small molecules or genes encoding the small molecules.

Mesenchymal stem cells as a vehicle for ion channel transfer in syncytial structures

This invention provides for a chamber and system designed for use in assaying drug effects on heart rate. The chamber consists of a series of wells. Cardiac myocytes disaggregated from neonatal animals are plated onto the bottom of each well and grown under standard tissue culture conditions. When drugs are to be assayed, the cells in each well are loaded with a calcium sensitive dye and the beating rate in each is monitored with a photodiode. A drug is added in graded concentrations to each well, and equilibrated and effects on rate are observed. This construct permits use of a cell based bioassay for the study of drugs or agents that may alter cardiac rate. This invention can be used in high throughput screening of drugs to evaluate/predict their effects on cardiac rate and rhythm.

High throughput biological heart rate monitor that is molecularly determined

This invention provides for a method of inducing a current in the heart in a subject which comprises contacting a cell of the heart of a subject with a compound in a sufficient amount to induce a current in the cell of the heart of a subject. This invention also provides a method of treating a cardiac condition in a subject which comprises contacting a cell of the heart of the subject with a compound in an amount sufficient to increase the current expression of the cell, thereby treating the cardiac condition in the subject.

Implantation of biological pacemaker that is molecularly determined

This invention provides for a chamber and system designed for use in assaying drug effects on heart rate. The chamber consists of a series of wells, each 3 mm by 3 mm in inner diameter. Cardiac myocytes disaggregated from neonatal animals are plated onto the bottom of each well and grown under standard tissue culture conditions. The chamber holds from 24-96 such wells. When drugs are to be assayed, the cells in each well are loaded with a calcium sensitive dye and the beating rate in each is monitored with a photodiode. Drug is added in graded concentrations to each well, and equilibrated and effects on rate are observed. This construct permits use of a cell based bioassay for the study of drugs or agents that may alter cardiac rate. This invention can be used in high throughput screening of drugs to evaluate/predict their effects on cardiac rate and rhythm. Further provided for by this invention is a vector which comprises a compound which encodes an ion channel.

Growing community of inventors

Stony Brook, NY, United States of America

Ira S Cohen