Research ALS Today, Spring 2015

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RESEARCH ALS TODAY

THE ALS ASSOCIATION

VOLUME 16

Using Motor Neurons Sheila Essey Award Drosophilia About CReATe Tirasemtic Clinical Research Recipient Journal News

1-3 3 4-5 6 6-7 7 8

SPRING 2015

Using Motor Neurons Derived from Induced Pluripotent Stem Cells to Understand ALS

Dhruv Sareen1, Robert Baloh1,2 and Clive N. Svendsen1 1 Board of Governors, Regenerative Medicine Institute and

Department of Biomedical Sciences, Cedars-Sinai Medical Center 2 Department of Neurology, Cedars-Sinai Medical Center

We need better models to understand amyotrophic lateral sclerosis (ALS) Our present understanding of the underlying biological basis for ALS-associated neurodegeneration in humans is primarily derived from rodent and other cellular models of familial ALS or from post-mortem patient tissue. However, mice have a fundamentally different biology than humans, and patient tissue limits the study to only after death. Furthermore, because we do not know the cause of sporadic ALS, which accounts for 90 percent of the ALS population, it is impossible to model this in animals. But new cutting-edge stem cell technology circumvents this problem. Cells drawn from a patient’s blood can be sent back in time to a very early stage using a few specific chemicals. These cells, termed induced pluripotent stem cells (iPSCs), can be grown indefinitely. When given specific signals, they can then be made into the motor neurons that die in ALS. iPSCs capture the patient’s exact genetic material and provide an unlimited supply of cells that can be studied in the dish, i.e., the ALS patient’s “avatar.” Our focus is to use this unique source of motor neurons to try to understand why they do not function normally in ALS. We will also generate “clinical grade” iPSC lines that will provide a new source of replacement tissue for autologous or allogeneic cell therapies currently under development at Cedars-Sinai Medical Center (CSMC).

Quality The quality of motor neurons generated from the iPSCs will affect the value of the derived information. As such, we are developing optimized techniques that can turn patient iPSCs into specifically the spinal lower motor neurons that are affected in ALS (see figure). Most published motor neuron differentiation methods focus on the generation of spinal motor neurons; however, the cortical upper motor neurons also play a crucial role in ALS. By using principles from human nervous system development, we will also establish ways to produce upper motor neurons to examine this specific population. The limitless quantity of iPSCs

A rapid and directed motor neuron differentiation protocol with high-efficiency differentiation of iPSCs into spinal lower motor neurons.

permits their use in multiple experiments. The iPSC technology will allow us to create a patient’s avatar-in-a-dish, which can be used to correlate patient clinical parameters such as site of onset and severity with any phenotypic changes in the same patient’s motor neurons. Selected patient iPSC lines will also be genetically modified to develop a toolbox of “reporter” cell lines. When motor neurons are generated from iPSCs, they will produce markers that can be seen under the microscope to allow other members of the Neuro Collaborative to identify the motor neurons and track their health over time, and see how they respond to new drug treatments.

Collaboration is key for success The Neuro Collaborative (three leading California labs headed by Drs. Cleveland, Finkbeiner and Svendsen and funded by The ALS Association) is not working in isolation. We are also working closely with companies, such as Emulate, which are developing more physiological Continued on page 2


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