Columbia University

Hynek Wichterle

Thomas M Jessell

Arie Zask

Brent R Stockwell

Sara Wilson

Mirza Peljto

Makiko Nagai

Ivo Lieberam

Pieter Bos

Christopher E Henderson

Sebastian Thams

Emily Rhodes Lowry

Serge Przedborski

The present invention provides, inter alia, a compound having the structure: Also provided are compositions containing a pharmaceutically acceptable carrier and one or more compounds according to the present invention. Further provided are methods for treating or ameliorating the effects of a disorder in a subject, methods of suppressing the toxicity of endoplasmic reticulum (ER) stress in a subject, methods of treating or ameliorating the effects of a disease involving axon degeneration in a subject, and methods for treating or ameliorating the effects of a neurodegenerative disease.

Substituted pyrrolo[2,3-b]pyridines for suppressing toxic endoplasmic reticulum stress

The present invention relates to culture systems comprising differentiated stem cells, that may be used for identifying agents useful in treating degenerative nervous system disorders and are suitable for high-throughput screening applications. It is based, at least in part, on the discovery that co-cultures of (i) astrocytes expressing a mutated SODI gene and (ii) stem-cell derived motor neurons manifested cell death via a Bax-dependent mechanism, and modeled motor neuron death in amyotrophic lateral sclerosis.

Stem cell-based culture system for drug development

The present invention provides, inter alia, methods for identifying a candidate agent that may be effective to treat or ameliorate an effect of a neurodegenerative disease in a subject. These methods include: (a) contacting a wildtype neuron and a mutant neuron with a stressor which is effective to accelerate the degeneration of the mutant neuron; (b) further contacting the wildtype neuron and the mutant neuron from step (a) with a candidate agent; and (c) determining whether the candidate agent lowers a wildtype to mutant survival ratio or increases both wildtype and mutant neuron survival.

Methods for identifying candidates for the treatment of neurodegenerative diseases

Disclosed are methods for generating a neuron expressing Hoxc8 transcription factor or a caudal motor neuron comprising culturing an embryonic stem cell in a composition which is essentially free of retinoids and comprises an isotonic salt solution, so as to generate the neuron which expresses Hoxc8 transcription factor or the caudal motor neuron. Disclosed are also methods for generating a caudal brachial motor neuron, a thoracic motor neuron, or a lumbar motor neuron from an embryonic stem cell in a composition essentially free of retinoids and comprising ADFNK medium, an amount of FGF-2, or Gdf11 respectively. Disclosed are also methods of transplanting a motor neuron into a subject comprising generating the motor neuron and transplanting the motor neuron into the subject. Disclosed is also a population of motor neuron cells enriched for motor neuron cells expressing Foxp1 and expressing a gene associated with Spinal Muscular Atrophy (SMA) or Amyotrophic Lateral Sclerosis (ALS).

Caudal motor neuron derived from embryonic stem cells under conditions essentially free of any retinoid

The present invention provides in vitro systems for use in identifying modulators of neural differentiation. Also provided are modulators identified by these systems. The present invention further provides methods for identifying a modulator of neural differentiation, a modulator of a Wnt signalling pathway, a modulator of Wnt-dependent neural differentiation, a modulator of a BMP signalling pathway, a modulator of BMP-dependent neural differentiation, a modulator of a Hh signalling pathway, and a modulator of Hh-dependent neural differentiation. Also provided are modulators identified by these methods.

Systems and methods for screening for modulators of neural differentiation

The present invention provides a method for inducing differentiation of an embryonic stem cell into a differentiated neural cell. The present invention further provides a method for producing differentiated neural cells, and a population of cells comprising the differentiated neural cells. Additionally, the present invention provides a method for repopulating a spinal cord in a subject, and a method for treating nervous tissue degeneration in a subject in need of treatment. The present invention further provides neural progenitor cells, differentiated neural cells, and uses of same. Also provided is a transgenic non-human animal containing the differentiated neural cells. The present invention is further directed to a method for isolating a population of differentiated neural cells. Finally, the present invention provides a method for identifying an agent for use in treating a condition associated with neuron degeneration.

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New York, NY, United States of America

Hynek Wichterle