Stem Cells and Hope in ALS: Part 2

by Clive N. Svendsen, Ph.D., and Geneviève Gowing, Ph.D. on Wed, 2013-05-29 05:00

Clive N. Svendsen, Ph.D.
Geneviève Gowing, Ph.D.

Replacing lost motor neurons would be the ultimate goal for ALS. Unfortunately, major obstacles — including survival of transplanted motor neurons, the generation of functional connections and long-distance projection (from the brain to the spinal cord, or the spinal cord to muscle) — need to be overcome before this approach can become feasible.

Thus, at this point in time, transplanting cells that have the ability to support and promote the survival of existing motor neurons is more realistic and has been a focus point for some of the work that is being performed in many laboratories. Induced pluripotent stem cell, or iPS cell, technology is new and therefore not yet suitable for cell therapy in humans. However, there are many other types of stem cells, such as multipotent, neural stem cells (NSCs) and glial restricted precursors (GRPs), that have the potential to be used for transplantation therapy.

NSCs and GRPs have the ability to become the most abundant cell type in the brain: astrocytes. These star-shaped cells have many important roles in the central nervous system and are key players in regulating and supporting proper neuronal function. Of interest, many studies have now shown that not only motor neurons but other cells — including astrocytes — are often sick and dysfunctional in ALS. Dysfunctional astrocytes can no longer properly support the function of motor neurons and can even do the opposite — accelerate motor neuron death!

In 2003, ALS researchers published an article indicating that the presence of cells not carrying disease-causing mutations (i.e., healthy cells) could prevent the degeneration of sick motor neurons and extend life span in ALS animal models. This suggests that transplanting healthy cells into the diseased nervous system could have therapeutic potential.

Since these initial studies, the ability of the scientific community to perform stem cell transplantation using NSCs and GRPs has been demonstrated and, in some cases, has shown therapeutic benefits. However, in the Svendsen lab, we saw no functional benefit and no motor neuron protection when healthy cells were transplanted into the lumbar spinal cord.

To date, well-controlled studies involving the transplantation of human stem cells into the spinal cord in animal models of ALS have not resulted in any obvious amelioration of disrupted motor neuron function. There could be several reasons for this lack of effect:

  1. The animal models used to date present an extremely severe set of disease characteristics.
  2. The amount of cells (dose) or number of transplant sites were insufficient to protect an adequate number of diseased motor neurons and result in an observable functional effect.
  3. Human cells transplanted into the animals do not have time to fully develop and mature (when they would have the most therapeutic effect) prior to the animal reaching terminal stages of the disease.

Currently, our laboratory is being funded by the California Institute for Regenerative Medicine (CIRM) to perform preclinical safety studies for the transplantation of neural stem cells genetically engineered to produce a powerful growth factor called glial cell line-derived neurotrophic factor (GDNF). GDNF is a well-known molecule that promotes motor neuron survival.

In this approach, we combine stem cells and gene therapy, two very strong therapeutic approaches. We have several publications showing that these cells survive following transplantation into the nervous system of an ALS rat model (see image below) and protect motor neurons in the spinal cord in a rat model of ALS.

Picured above: The images depict transplantation of human neural stem cells (NSCs) into the spinal cord of an ALS animal model. (A) Following transplantation NSCs (red) surround motor neurons (green). (B and C) NSCs are shown in green; nestin, a marker for neural progenitor cells, is shown in red. (D) The cells can be engineered to express the growth factor GDNF (shown in purple). (E) GDNF can be seen following transplantation of NSCs producing the growth factor.

Thus, we are supplying motor neurons with a source of healthy cells that can both support their function and produce GDNF simultaneously. However, although motor neuron survival was increased, the cells' connections to muscle was lost, so paralysis was not ameliorated by our treatment in these studies.

In a different approach, we have shown that the transplantation of mesenchymal stem cells (MSCs) into the muscles of ALS rats resulted in a mild amelioration of disrupted motor neuron function. This effect was enhanced following the transplantation of MSCs engineered to produce GDNF and also resulted in an increased life span of the treated ALS rats.

Despite the shortage of evidence that human stem cells transplanted into animal models can significantly ameliorate ALS symptoms, we and many others believe that stem cell therapy has great potential to delay motor neuron degeneration and enhance motor neuron function in ALS patients. However, this hypothesis can only be fully tested in humans affected by the disease. Therefore, based on the demonstrated safety of the approach, stem-cell-centered therapies have slowly but surely moved toward the clinic.

The first phase 1 clinical trial using direct spinal transplantation of human neural stem cells in the lumbar spinal cord was initiated in 2010 by the company Neuralstem and is now complete. This trial showed that the procedure used to transplant neural stem cells into people with ALS was safe and tolerable. Interestingly, one patient out of 15 appeared to show remarkable recovery. However, the neurologists involved with this trial remain cautious as large doses of immunosuppression that were given to patients to prevent rejection of the cells may have had a secondary effect on the course of disease — it's also possible that this patient could have been misdiagnosed. Effects need to be seen in a number of patients within any stem cell trial to be considered positive.

Other companies, such as Q Therapeutics Inc., are also forging ahead with the goal of taking human GRPs to the clinic for patients affected by ALS and other disorders of the nervous system.

In other work, investigators have studied the possibility of using hematopoietic-derived stem cells as well as mesenchymal stem cells for the treatment of ALS (the Mazzini trial in Italy is one example; other mesenchymal trials in the USA can be found on

A somewhat controversial phase 1-2 clinical trial led by the company BrainStorm Cell Therapeutics Inc. is putting mesenchymal stem cells into the cerebrospinal fluid of patients with ALS. The rationale behind this approach is not clear as the cells have not been shown to migrate from the cerebrospinal fluid into the spinal tissue to reach dying motor neurons. The company also promoted very early positive results before a full analysis had been completed — somewhat based on the experience of a single patient. This is a very dangerous approach for the stem cell field and raises false hope and expectations based on incomplete evidence. However, early data has demonstrated this approach to at least be safe, and further work is planned to pursue an FDA-approved phase 2 clinical trial for patients affected by ALS.

With many clinical trials using stem cells as a therapeutic tool for ALS on the horizon, we will soon be able to determine if the large investments and enormous hope that we have poured into this approach equals the excitement felt by many in the field.

Science and technology is moving forward at an astonishing pace toward better disease modeling and groundbreaking stem cell therapy trials, it is without a doubt that the continuous, relentless and dedicated efforts of researchers and clinicians around the world will result in innovative therapeutic approaches and efficient treatment for ALS patients. Thus, the future of ALS therapy is an optimistic one. It is a very exciting time for stem-cell-based research!

For the first part of this blog, see Stem Cells and Hope in ALS: Part 1, which was published May 22, 2013.

About the Authors

Clive N. Svendsen, Ph.D.
Director, Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, Calif.
Department of Biomedical Sciences, Cedars-Sinai Medical Center
Professor in Residence, Department of Medicine
, University of California, Los Angeles
Consultant Professor,
Department of Neurosurgery, Stanford University, Palo Alto, Calif.

Svendsen did his pre-doctoral research at both the University of Cambridge and Harvard University. After receiving his Ph.D. in neuroscience from the University of Cambridge, he continued to develop a research program in neural stem cells and neurodegeneration before moving to become Professor of Anatomy and Neurology at the University of Wisconsin. There he co-founded the Stem Cell and Regenerative Medicine Center.

He now directs the Cedars-Sinai Regenerative Medicine Institute in Los Angeles, where 20 faculty members and almost 100 staff members are using induced pluripotent stem cells to model and treat diseases such as diabetes, hepatitis C, macular degeneration, osteoporosis and neurodegenerative disorders. His own lab is performing the world’s first combined growth factor and stem cell transplant trial for ALS, and striving to learn more about the origins and new treatments for diseases of the nervous system.

Geneviève Gowing, Ph.D.
Gowing is a project scientist in the laboratory of Dr. Clive Svendsen at the Regenerative Medicine Institute of Cedars-Sinai Medical Center in Los Angeles. She was trained in the laboratory of Dr. Jean-Pierre Julien at Université Laval, Québec City, Québec, Canada, where she studied the role of microglia in mouse models of ALS. Her work in Svendsen’s lab is focused on assessing the potential of stem-cell-based and other therapies in animal models of ALS.

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