At the Bench

In Nick Maragakis’ lab, Angelo Lepore, Ph.D, a postdoctoral fellow, is in the midst of surgery, using neural precursor cells designed by Hongjun Song’s lab:

Angelo Lepore,
Ph.D, postdoctoral
fellow at Johns
Hopkins Medicine.

Can you explain what you are doing and why?

I am transplanting these cells into the cervical spinal cord of adult rats. Specifically, these neural precursor cells are glial progenitor cells derived from human induced pluripotent stem cells, or iPS cells. In collaboration with Hongjun Song’s lab, iPS cells were derived from skin fibroblasts of normal healthy patients and patients with ALS. (Amyotrophic lateral sclerosis, often referred to as Lou Gehrig's Disease, progressively affects nerve cells in the brain and the spinal cord.) The iPS cells are pluripotent and can form tumors if injected into animals; therefore, the cells were first pre-differentiated in culture towards a glial lineage prior to transplantation. We are trying specifically to replace astrocytes, one of the major glial cell types of the central nervous system.

We are interested in astrocytes because dysfunction of these cells occurs in ALS, and this dysfunction plays an important role in the ultimate death of motor neurons. Therefore, we want to replace these dysfunctional cells with healthy astrocytes via glial progenitor transplantation in order to better protect vulnerable motor neurons. 

I choose to target cervical spinal cord because this is where the motor neurons that control the important respiratory muscle, the diaphragm, are located. Respiratory dysfunction is the ultimate cause of death of ALS patients, so the diaphragm is a key therapeutic target.

Can you say a bit about this current project in the context of previous research?

In 2008, we published results in Nature Neuroscience showing that transplantation of glial progenitors into the cervical spinal cord of rats modeled to have ALS is a feasible method for astrocyte replacement. This strategy resulted in extension of life, partial rescue of motor neurons, and slowing of respiratory function loss. These initial proof-of-principle studies were conducted with glial progenitors derived from the rodent nervous system.  We are now testing this same therapeutic paradigm with more clinically-relevant sources of glial progenitors derived from the human nervous system.

Any particular challenges you’re encountering?

Neural precursor cells derived from the rodent nervous system survive and integrate well for extremely long periods of time following transplantation into the adult rat spinal cord—basically the entire life of the animal. However, cells derived from the human do not survive as well using the same immune suppression regimen that we use for rodent-derived cells. We are, therefore, testing other immune suppression strategies to allow for optimal transplant survival. This is crucial because if we want to replace dysfunctional astrocytes, the new transplant-derived cells need to survive and integrate in the spinal cord potentially for the life of the recipient.

Any surprising findings?

I think that the original findings were extremely exciting because they showed that this strategy of multi-segmental delivery of glial progenitors to the cervical spinal cord of ALS rats is a realistic way to provide a healthy astrocytic environment in the ALS spinal cord and can produce significant benefit.

Could you comment a bit about the hopes riding on this research?

There is hope that this or some derivation of this strategy can be useful. With ALS, patients basically live only three to five years following initial diagnosis. This strategy allows for targeting therapy to respiratory function, and will therefore hopefully allow these patients to live longer. Any extension of life, especially quality of life, that is associated with enhanced respiratory function would be great. Targeting respiratory function is a good strategy, as is targeting astrocytes because of their important role in maintaining the health of motor neurons, the cells that are ultimately lost in this disease. I think that we first need to examine the potential of human-derived cells following transplantation before we can say whether this strategy will work in human patients. Regardless, the initial results are promising, but it’s a long way off before this will be translated to the clinic.

--Interviewed by Maryalice Yakutchik