COMMENTARY

Guest Editorial: January 2005: Stem Cell Research and Amyotrophic Lateral Sclerosis

Carmel Armon, MD

Disclosures

January 11, 2005

Introduction

The pathophysiology of amyotrophic lateral sclerosis (ALS) is complex and poorly understood despite many years of study, and because of this, no treatments have proved effective in slowing disease progression to any significant degree. Some scientists have suggested that stem cells, with their ability to differentiate into a variety of cell lines, could play an important role in restoring damaged motor neurons and even generating new ones. Are stem cells a dream come true for those with ALS? Or are they something less? The answer to both questions may be "yes."

ALS, also known as Lou Gehrig's disease, is a progressive disease that manifests as a gradual evolution and spread of weakness and wasting of the affected patient's muscles. It leads to dysfunction, disability, and ultimately death or chronic ventilator dependency, which occur an average of 3 years after weakness is first detected.

Approximately 5% to 10% of individuals with ALS have relatives with the disease. The majority of ALS cases (90% to 95%) are sporadic, apparently occurring "out of the blue," but a rare form of ALS is seen in 3 western Pacific locations: Guam, the Kii peninsula in Japan, and western New Guinea.

Many of the etiologic factors associated with this devastating condition remain misunderstood or unexplained. The factors that initiate the chain of events leading to motor neuron death are unknown, but the autosomal dominant hereditary pattern in most affected families suggests that the altered gene responsible for the disease in those families results in a "gain of function," or production of a toxic product, that ultimately initiates the disease process. Even in 15% to 20% of families in whom the abnormal gene (the zinc-copper superoxide dismutase 1 [SOD1]) has been identified, the mechanism of action that precipitates disease onset is unknown. We also do not know the reasons for differing ages of onset and rates of progression associated with specific mutations in the gene, nor do we know why penetrance is incomplete (most, but not all, carriers are affected). Even less is known about the etiology of the disease in sporadic or western Pacific cases.

The direct underlying cause of muscle weakness and wasting, however, is the progressive loss of the muscles' motor neurons. The affected motor nerve cells reside in the spinal cord or brainstem connecting to muscles directly (lower motor neurons), and in the motor cortex of the brain (upper motor neurons), connecting to the lower motor neurons. Nerve cells and circuits involved in higher-order planning and sequencing that reside in the anterior portion of the brain (prefrontal motor neurons) also may be affected.

No treatment halts or reverses the course of ALS. There is 1 US Food and Drug Administration (FDA)-approved treatment (riluzole) that may add 2-3 months to patients' mean survival. Meticulous attention to nutrition and timely institution of noninvasive ventilatory support may extend life by 6-12 months.

Stem cells, also known as progenitor cells, are cells that have not undergone differentiation to acquire a specific structure or role; they have the potential to self-renew, divide, and differentiate into specialized cell types.[1,2] They are also sometimes termed "pluripotential" or "undifferentiated" cells because they can differentiate and develop into various cell lines. The differentiation of stem cells into mature cells is tightly regulated; otherwise, intricate plants and animals, with their many interrelated tissues, organs, and systems, could not exist.

By contrast, mature or differentiated cells have acquired specific structures and roles, and in many cases have lost the ability to divide and replicate. Also in contrast to stem cells, malignant cells or "dedifferentiated" cells divide in an uncontrolled fashion, and rather than resulting in useful, differentiated, or specialized cells, these types of cells threaten to kill the organism.

Stem cell differentiation must be turned on, given direction, and turned off as needed in order to properly supply the basic building blocks of tissues in different organ systems. This requirement for precise regulation applies to an even greater degree to the differentiation of neuronal progenitor cells, because effective neural function depends on establishing precise linkages and interactions between different individual neurons and classes of neurons.

By definition, stem cells, including neuronal progenitor cells, are present in embryos. Stem cells may be found in umbilical cord blood. In adults, these cells are present in bone marrow and in other organs in which controlled self-renewal is needed.[1] Neuronal progenitor cells have also been shown to persist into adulthood in specific brain locations near the ventricles where they support ongoing learning and the establishment of new memories through their division, differentiation, migration, and insertion into new circuitry.

Stem cells could help patients with ALS in several ways. Ideally, they could be induced to differentiate into lower motor neurons in order to replace those neurons that die because of ALS. Perhaps stem cells could rescue dying motor neurons by reconnecting these neurons to partly denervated muscle before it has died completely. Better yet, they could be induced to differentiate into upper motor neurons in the cortex and connect to the lower motor neurons.

Unfortunately, the expectation that stem cells will play such a regenerative role in patients with ALS is unrealistic because of the complexity of the task, which presents obstacles that currently are insurmountable. A more realistic expectation for stem cells is that they play a supportive role in maintaining the viability of or extending the function of surviving motor neurons.[3] The stem cells could be induced to differentiate into supporting cells, glia, or interneurons that might produce factors that would support motor neurons, or perhaps the stem cells themselves might produce such factors.

Recent data from Clement and colleagues[4] show that in chimeric, genetically engineered mouse models, motor neurons carry mutated SOD1 genes and glial cells carry healthy genes. Survival is extended in these chimeric mice, as compared with nonchimeric mice in which all motor neurons and all glial cells carry mutated SOD1 genes.[4] This finding suggests that if healthy stem cells could get to the spinal cords of patients with ALS, their survival might also be extended. It remains to be determined whether a mechanism that compensates for a particular genetic error would apply to sporadic patients without that error. Nevertheless, even if this form of therapy were effective only for patients with familial disease, it would be a great leap forward.

In previous experiments, intraspinal transplantation of neurons derived from a human teratoma cell line was shown to ameliorate dysfunction and extend survival in G93A SOD1 transgenic mice.[5] Furthermore, the life span of G93A SOD1 mice was extended by intravenous administration of human umbilical cord blood. The cells were shown to have migrated into the spinal cord and brain parenchyma and survived 10-12 weeks after infusion. They exerted their beneficial effect even though only a low number of transplanted cells expressed neural antigens.[6] In another study, Sertoli cells, which are not neuronal stem cells, were implanted in the spinal cords of SOD1 transgenic mice and were shown to provide temporary protection to motor neurons in their proximity. However, viable Sertoli cells were not present at the time when the animals died.[7]

Preliminary trials with autologous hematopoietic stem cells have been reported in humans. In one, peripheral blood-purified CD34+ cells were injected intrathecally into 3 patients with ALS.[8] None reported side effects after 6-12 months, but no clinical efficacy was reported. In another, 7 patients received intraspinal transplantation of autologous bone marrow-derived stem cells.[9] Minor postoperative adverse events were transient, but muscle strength continued to decline. After 3 months, however, the investigators reported a trend toward slowing of the decline in the proximal muscle groups of the lower limb in 4 patients and a mild increase in strength in 2 patients. Lack of placebo controls and longer follow-up preclude any inferences of efficacy from this study and none were made by the investigators.

The ethics of performing human studies at this early stage of stem cell research have been questioned,[10] emphasizing the risks of premature human trials. [11] Reports of stem cell transplantation performed in China without peer review of objective data on each patient before, immediately after, and at specific long-term points following the transplantation do not provide sufficient scientific evidence to demonstrate that the treatment is safe and effective.[12]

"It is critical that scientists and clinicians are cautious, plan rigorous studies, and most importantly focus on key laboratory experiments that will provide answers to the many challenges that still face this therapeutic approach," wrote Lucie Bruijn, PhD, the Science Director and Vice President of the ALS Association. "For this therapy to be safe and have potential in the clinic, it is critical that the appropriate studies are conducted to learn more about the properties and complexities of the various stem cells.[13]"

In response to limitations on the type of stem cell research that may be performed with federal funds, the American Academy of Neurology and the American Neurological Association -- the 2 leading professional neurology organizations in the United States -- have both gone on record expressing the belief that both embryonic and adult stem cell research should be pursued rigorously and under close scrutiny, while respecting the concerns of their members and the public, regarding important ethical principles and values pertaining to research with human embryonic stem cells.[14]

The scientific concerns are 2-fold. First, because the realistic likelihood for success of any individual research effort is low, parallel research in multiple directions is imperative for the field to advance rapidly. The essence of research is trial and error, which operates by identifying ineffective directions and thereby focusing on those that hold promise. It is usually a long time between initiating research and realizing a successful treatment with clinical applications. Therefore, any delay in identification of a potentially effective therapeutic intervention translates into delaying treatments for patients with the diseases in question. Second, excluding particular types of research from federal funding may translate into an exclusion of this research from federal oversight and protections, which might lead to its migration overseas. This may be detrimental to individual patients and to the broader community of patients, clinicians, and scientists.

In November 2004, California citizens approved a referendum measure to issue bonds to fund stem cell research, including embryonic stem cell research at $300 million a year for 10 years. Since then, several other states (Illinois, New Jersey, Maryland, New York, Delaware, and Wisconsin) are considering, or being asked to consider, initiatives for state-funded stem cell research to fill the federal funding gap. This is motivated, in part, by the desire to remain on the forefront of medical research and avert a brain drain toward states that provide an economic environment more conducive to cutting-edge research.[15] The ripple effect of the California initiative is expected to result in acceleration of stem cell research nationwide.

Stem cell research carries promise for patients with ALS and may result in the development of new treatments to slow the progression of the disease. This hope needs to be tempered with caution because of the early stages of stem cell research in general, and in ALS in particular, and because of the track record of the limited efficacy of all pharmacologic interventions in transgenic murine and sporadic human ALS. Meticulous attention to the ethics and scientific rigor of future stem cell research should be supported by clinicians, scientists, and participating patients alike.

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