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Induced Pluripotent Stem Cell Technology Drives ALS Research Forward

Human induced pluripotent stem cell (iPSC) technology is a revolutionary method to look at a person’s genetic makeup in a dish – like having one’s own avatar. Researchers including Drs. Clive Svendsen and Dhruv Sareen at Cedars-Sinai Medical Center (CSMC) in Los Angeles are busy generating “clinical grade” iPSC lines to use in ALS research efforts all over the globe. The ALS Association supports their project and stem cell core facility through funding the Neuro Collaborative, a large strategic initiative running in California.

Up until recently, researchers have relied on animal models to conduct ALS research. These models are valuable, however have certain limitations. For example, sporadic ALS is more difficult to emulate in animal models (although many of the disease mechanisms are similar in sporadic and familial ALS) and these models do not have the exact genetic makeup as humans. The discovery of iPSC technology fills in this important gap.

To make iPSC lines, researchers use blood or skin sample from people living with ALS and healthy people. Using standardized methods with stringent criteria, researchers begin the process of converting blood or skin samples into iPSCs, which are then converted to different types of cells when given specific signals. ALS researchers are interested in making cell types relevant to disease, including cortical upper motor neurons found in the motor cortex of the brain, spinal lower motor neurons and astrocytes, which are all affected by ALS disease.

The use of iPSCs in ALS research has many advantages. iPSCs can be grown indefinitely allowing their use in multiple experiments. In addition, these cells directly reflect a person’s specific genetic makeup, which can be used to correlate person’s clinical data, such as site of onset and severity with any observable changes in the same person’s motor neurons. iPSCs can also be genetically modified to produce “reporter” cell lines, where specific cell populations like motor neurons can be lit up with specific fluorescent colors. This allows ease of tracking individual motor neurons by an automated microscope to observe their health over time.

ALS Association funding for the Neuro Collaborative at CSMC has enabled the generation of 24 iPSCs derived from 11 healthy people, four C9orf72 mutation carriers, six SOD1 mutation carriers and three sporadic ALS cases that are available to ALS researchers worldwide. They have also enabled access to these lines for researchers globally essential for collaboration.

A recent review from Dr. Svendsen’s laboratory with leaders in the iPSC technology field outlined the advances and challenges in the ability to model ALS with these cells. They note that cooperation between ALS researchers is essential to develop and adopt methods to compare results among independent laboratories. Svendsen and colleagues also recently published a paper demonstrating that it might be beneficial to induce some aspects of aging in iPSC-derived motor neurons, thereby reflecting critical weaknesses similar to those of aged neurons that die from ALS.

Using iPSCs made at CSMC, significant progress has been made. For example, Dr. Finkbeiner, a member of the Neuro Collaborative, uses iPSCs to screen thousands of compounds at a time using the Brain Bot, an automated microscope that he developed. Biogen is currently in collaboration with Dr. Finkbeiner’s team to validate hits they discovered through their own fly genetic screen, which could serve as potential therapeutic targets. Also, Dr. Finkbeiner identified compounds that are involved in a cell degradation pathway, called autophagy, which improve the health of motor neurons. His team is in negotiations with pharmaceutical companies to take those compounds to clinical trials to test in humans.

Another important collaborative effort is between CSMC, The ALS Association and the National Institute of Neurological Disorders and Stroke (NINDS) to support a large “big data” initiative called NeuroLINCS. This program aims to use iPSCs derived from people living with ALS to make motor neurons, which will be challenged with specific compounds to better understand how they respond and how this response may change in ALS. The overall goal is to develop cell signatures through comprehensive analyses that are patient specific to use in designing more efficient clinical trials. All data will be shared with the entire ALS community.

iPSCs have emerged as an essential tool in ALS research that have the potential to identify new disease mechanisms and individual disease susceptibilities that cannot be revealed in other models. Continued donor support to ALS research is paramount in moving the ALS field closer to effective treatments and cures using this revolutionary technology.