**8. References**

446 Amyotrophic Lateral Sclerosis

From the two sets of experiments described in this section, we can conclude that stem cell delivery of growth factors is an effective strategy for ALS treatment. We also know that different sets of delivery tools are needed for the motor neuron cell bodies in the spinal cord and their synaptic connections to the skeletal muscles. Our current knowledge leads us to an initial thought for future development of the field of ALS growth factor/stem cell therapy. Motor neuron cell body protection will be provided by stem cell derived wild type astrocytes and microglia (from hNPC for example); while synaptic/axonal protection will be provided by stem cell derived myoblasts (from hMSC for example). Those cells will be genetically modified to enhance delivery of neurotrophic factors. Lastly, GDNF is only one of the many neurotrophic factors that showed to have beneficial effect on ALS rodent models as mentioned in Section 2 of this chapter. We expect there will soon be tests on the

Despite the exciting breakthroughs in stem cell research aiming to treat ALS, there is still a long way to go to translate those successes to the clinic and help patients. Since we are still uncertain about the fate of stem cells after transplantation, thorough safety tests are needed. Then, optimal cell dose, source of cells, stage of cells, route of delivery, injection sites, and immunosuppressive regimen (to ensure grafted cell survival in host) will need to be

Clinical trials that involve stem cells on ALS patients are in the initial stage. In 2010 the phrase I clinical trial of hMSC transplantation performed in Italy was reported. (Mazzini et. al., 2010) Autologous MSC isolated from bone marrow derived cells were transplanted to the thoracic region of 9 ALS patients. Neither adverse effect nor significant improvement was found. However, it provides initial evidence that MSC injection is safe. Large volume (1 mL) of cells can be infused to the spinal cord without causing observable

Neuralstem and Emory ALS center have begun the phase I trial of spinal cord derived stem cells for patients with ALS. The advantages of using neural stem cells derived from human fetal spinal cord are no tumor formation and minimal HLA (human leukocyte antigen) expression, thus, resulting in a low overall antigenicity of the cells. The first surgery of the trial took place a year ago, and the 9th surgery was performed earlier in 2011, without the need for patients to be on ventilators or to be taken to intensive care post-operation. The trial was staged, first enrolling non-ambulatory patients, and the first ambulatory patient

In this chapter, we introduced the current application of stem cells in ALS (summarized in Figure 1). There are three points we should keep in mind about this topic. First, stem cell therapy design should be aimed at neuroprotection rather than motor neuron replacement. Motor neuron replacement is technically difficult to achieve. Also, in theory it will not bring much improvement to the patients because the evidence shows that glial cells are the actual determinant of ALS disease progression. Secondly, combining stem cell transplantation and growth factor delivery provides the best result in slowing disease progression and

**4.3 Future research directions** 

other neurotrophic factors.

**5. Clinical translation** 

defects.

was enrolled early 2011.

**6. Conclusion** 

determined as well (Papadeas and Margaskis, 2009).


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**20** 

*USA* 

**Glial Cells as Therapeutic Targets for ALS** 

*Department of Neurology, Johns Hopkins University, Baltimore, Maryland,* 

Although Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease characterized by motor neuron death, recent studies now implicate the non-neuronal environment as a major contributor to motor neuron loss. This body of evidence has been amassed over the past 10-15 years and highlights glial cells as new therapeutic targets for ALS. Glial cells, once thought to be simply the "glue" of the central nervous system (CNS), are now realized to actively participate in neural transmission and serve complex roles in regulation of the

Several glial cell types including astrocytes, microglia, and oligodendrocytes exist in the CNS; each serves a distinct function. Astrocytes comprise the majority of the CNS cellular space and act to regulate neurotransmitter concentrations at synapses, provide trophic support for neurons, and maintain metabolic and ionic homeostasis. Astrocytes can participate in the immune response, however, microglia serve as the resident immune cell of the CNS. Microglia are mobile, phagocytic, and constantly screening the CNS for possible infection or injury. Upon activation, microglia can secrete pro-inflammatory cytokines and chemokines to promote the clearance of any infectious agents and recruit other immune cells to the site of injury. Depending on the stimuli, microglia also are known to release neurotrophic growth factors and anti-inflammatory molecules to aid in repair and resolution of neural damage. Oligodendrocytes are the myelinating glia of the CNS which intimately interact with, and provide metabolic support to neurons. Oligodendrocytes are capable of producing myelin sheaths which insulate axons and aid in the conduction of

Ongoing research strives to define exactly how glial cells affect motor neuron survival in ALS. Furthermore, translation of these studies to the clinical setting begs for novel

The bulk of work on glial cells in ALS is derived from studies in rodent ALS models. The most widely used ALS models are rodents that ubiquitously express the human mutant superoxide dismutase 1 (SOD1) protein associated with dominantly-inherited familial ALS (fALS) (Gurney et al., 1994). Currently, 12 different SOD1 mutations have been expressed in lines of transgenic mice leading to development of motor neuron disease. By far, the most commonly used model is the SOD1 G93A mutant mouse which contains 25 copies of the

**2. Non-neuronal cells contribute to motor neuron death in ALS** 

**1. Introduction** 

CNS environment.

action potentials.

approaches to treat this new target for ALS.

Amanda M. Haidet-Phillips and Nicholas J. Maragakis

