Summary of  the Utility of Stem Cell Therapy 

Spinal Muscular Atrophy (SMA) is one of the most common genetic diseases leading to death in childhood. SMA destroys the motor neurons controlling voluntary muscle movement, rendering muscles flaccid and weakened. SMA Type 1, or Werding-Hoffman disease, is the most severe form of SMA. Infants with SMA Type I typically show symptoms by the age of six months: they have trouble breathing, swallowing and sucking, and never achieve the ability to sit without help.

Although treatment can ease complications of SMA, no cure exists. Still, the NIH has deemed SMA one of the neurological genetic conditions closest to an effective treatment or cure in the near future. To date, the primary approaches to treating or curing SMA have focused on two strategies. First, genetic therapy - manipulating the genetic material responsible for producing SMA. Second, cellular replacement therapy - replacing dead or dying motor neurons with new ones.

Human embryonic stem cells (hESCs) offer great promise for cellular replacement strategies due to their ability to generate every cell in the body (every human is made from their hESCs), and their seemingly unlimited ability to replicate themselves (allowing for huge numbers of cells to be generated). The ability to amplify hESCs to enormous numbers already exists. Generating medically useful cell populations from hESCs has been one of the largest obstacles facing hESC researchers. How do we coax hESCs to become the one cell type that we desire for treatment of a human disease? For the first time, the Keirstead Research Group at University of California at Irvine has produced high purity cells from hESCs. In these studies, researchers coaxed hESCs to become a particular brain cell type called oligodendrocytes with greater than 95% purity, for the treatment of spinal cord injury.

This is a meaningful accomplishment as most derivations of cell populations from hESCs have been less than 20% pure, including a very diverse population of cell types. High purity cell populations are crucial because we don’t want to inject unnecessary material into the disease site that wouldn’t behave well. For example, injecting toenail cells into a spinal cord injury site will likely do little to treat the disease. As a result of our successful ability to generated purified cell populations of oligodendrocytesfrom hESCs, a clinical trial on spinal cord injured patients is anticipated to begin in 2008.

The Keirstead Research Group has been able developed human motor neurons from hESCs. With the intellectual support of Dr. Douglas Kerr and the financial support of Families of Spinal Muscular Atrophy, we have been developed means to direct hESCs to become high purity human motor neurons.  We are now testing the cells in animal models to determine whether they can work in a living system, and whether the treatment is safe.

The youngest SMA Type 1 patients would be particularly amenable to this type of therapy because patients are usually infants and the disease itself has a relatively simple pathology. First, the target has been identified, motor neurons, so we know what to replace. SMA stands in contrast to other diseases such as stroke and spinal cord injury where a complex pathology involves many targets, often difficult to define. Second, newly diagnosed patients with SMA Type I are tiny babies whose spinal environments would support and provide nutrients to a graft. A newborn infant is still growing rapidly and the grafting environment is not as hostile as it would be with stroke or spinal cord injury, where injury sites often do not have the blood supply or growth factors to keep the cells alive. Also, there is very little trauma around cells within patients with SMA Type 1. These ‘calm’ conditions make survival of transplanted motor neurons more likely. Finally, what we are asking the transplanted motor neurons to do in newborns is not as difficult as it would be with older patients. In newborns, the motor neurons will very likely have the ability to grow connections out to the muscles because the distance is short. With older patients this would prove more difficult, as they are significantly larger. In addition, the pathways along which the connections grow contain active growth inhibitors in older patients; these active growth inhibitors are absent or very much decreased in newborns, so the likelihood of growth is much greater. These facts mean that the successful application of this approach to older patients would require additional interventions to encourage more robust growth, and overcome active growth inhibitors. This research is ongoing. The absence of these additional challenges in newborns suggests that we may be able to treat them sooner.

Federal authorities mandate that clinical trials can only be considered if the research was conducted with proper accountability and record-keeping, and with evidence that the treatment is safe. These tasks are performed by Regulatory Quality Assurance Officers, who provide oversight for research investigations such that they comply with federal mandates. Without such oversight, research must be repeated under the watchful eye and record keeping of a Regulatory Quality Assurance Officer. Having to repeat the research means a significant delay and financial burden. Regulatory Quality Assurance Officers are in place in our group, overseeing the motor neuron research. This type of oversight significantly hastens the translation of bench research on rats to clinical testing on humans.

Our research and regulatory team is excited to be at a stage where we have a treatment to test, and we are working as diligently and rapidly as possible to this end.  During 2008 for the first time in the U.S., human subjects will be given spinal cord injury treatments using a human stem cell strategy developed by our team. Our goal is to ensure that SMA Type 1 is the subject of the second human stem cell clinical trial.

Hans S. Keirstead is an Associate Professor of Anatomy and Neurobiology at the Reeve-Irvine Research Center, University of California at Irvine; Michelle AuCoin is a Regulatory Quality Assurance Officer in the Keirstead Research Group.