Clinical Trials outside U.S.: Amyotrophic Lateral Sclerosis

Strategies

ALS is a fatal neurodegenerative disease causing the progressive loss of brain and spinal cord motor neurons. The most prominent pathology of the disease involves the death of large motor neurons in the spinal cord and brainstem. Patients eventually become paralyzed, and approximately 50 percent die within three years after onset of symptoms, usually as the result of respiratory failure.

The disease is rare before age 40, and incidence rises with advancing age, peaking at around age 70. Approximately 10 percent of cases are familial, displaying an autosomal dominant pattern of inheritance. However, familial patients cannot be distinguished clinically or pathologically from sporadic ALS patients. About 20 percent of familial ALS cases have been linked to mutations in the gene encoding the cytosolic Cu27Zn2+ Superoxide dismutase 1, suggesting that an abnormal function of this enzyme may play a pivotal role in the pathogenesis and progression of familial ALS. The mechanism of motor neuron death in ALS remains unclear. However, the most prevalent hypothesis for motor neuron death has been that mutant SOD1 protein within motor neurons elicits oxidative stress, causing multiple cellular changes and eventually triggering cell death. Motor neuron death in ALS is complex and may involve multiple pathways including formation of protein aggregates, axonal transport defects, oxidative damage, mitochondrial defects, and alterations in calcium homeostasis, triggering cell death.

There are at least two major strategies for using stem cells to treat ALS. The first, and most obvious, is to produce new motor neurons to replace those lost in the disease. The second is to produce support cells to protect existing motor neurons from ongoing degeneration, either with or without genetic modification to express enzymes, transporters, or spécifie growth factors. This idea has gained much momentum recently as a result of inroads made regarding the contribution of different cellular subtypes to disease initiation and progression. In more and more studies, glial cells are being shown to modulate many neuronal functions including glutamate uptake, synaptic plasticity, trophic factor support, and even neural transmission. Astrocytes and microglia surrounding motor neurons have now also been shown to play a crucial role in motor neuron health and survival in ALS.

Stem Cell Treatments in China

Although a number of centers outside the United States advertise stem cell therapies for ALS, very [Page 109]few of these have been subject to serious preclinical and postoperative follow—up. A Chinese neurosur—geon, Huang Hongyun, provided stem cell treatments in Beijing, China, although there is not sufficient information about his work to indicate with scientific certainty that the treatment is safe and effective. He reported that he has treated patients with ALS with spinal cord and forebrain injections, each including 1 million olfactory ensheathing cells, which are the part of the brain involved in the sense of smell (olfaction), taken from fetuses. All treatments were performed in a Beijing hospital. Doctors inserted these olfactory ensheathing cells directly into the brains of the patients after drilling holes in their skulls under local anesthesia. Dr. Hongyun said he began his work in this area by transplanting olfactory ensheathing cells into patients with spinal cord injury. He added that he had operated on about 500 spinal cord patients and 200 others with ALS by June 2005.

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