Victories for amyotrophic lateral sclerosis patients (ALS), typically, are small. Compared to the relief patients with other neurologic dieases might see from, say, levodopa therapy in Parkinson's disease therapy, success might be measured in treating spasticity, muscle cramps, or excessive saliva. This rule of thumb, however, would exclude a small group of patients receiving human fetal neural stem cells in a Phase I study.

In the piece, six experienced a stable, very slowly progressing or improved disease course at more than approximately 700-to- 850 days post-surgery. The trial’s most impressive responder couldn’t walk without a cane before his treatment of one million cells—500,000 on either side of his lower spine; after several months he walked unaided in a 2.5 mile walk-a-thon.1

The company behind the study, Neuralstem, Inc., says their stem cell technology enables the production of neural stem cells of the human brain and spinal cord in commercial quantities, and the ability to control the differentiation of these cells constitutively into mature, physiologically relevant human neurons and glia. They received FDA approval to commence a NSI-566/ALS Phase II trial in April 2013, following conclusion of the Phase I trial to test the safety of its stem cells and transplantation surgery in patients with ALS in February 2013.

The Phase I safety trial enrolled 18 patients. It began with 12 late- to mid-stage ALS patients who received a series of injections in the L2-L4 lumbar region. The first six patients were all non-ambulatory with permanent paralysis. Of these, the first three patients were treated with five unilateral cell injections, while the next three patients received 10 bilateral injections in the same region. The trial then progressed to patients who were ambulatory. The first three of these received five unilateral injections. The next three patients received 10 bilateral injections in the same lumbar region.

The aforementioned six study patients who experienced positive results shared two common clinical characteristics. They had no bulbar features of ALS, a form of the disease that destroys motor neurons in the corticobulbar area of the brainstem in the early stages and typically progresses faster than the limb-onset ALS. Additionally, these patients all received stem cell transplantation early in the course of their disease (at an average of two years, one month after symptom-onset). Two of the patients showing stabilization or improvement were among the three to receive transplants in both the lumbar and cervical regions.

Of the nine remaining patients in the trial, three subjects had a long disease course (5.6, 11.6 and 12.7 years of known disease), at the time of their transplantation, likely representing atypical ALS, and have had little change in the trajectory of their disease. Finally, six of the trial patients died of their disease, seven-to-30 months after surgery. Two of these patients had features of bulbar ALS at the time of their transplantation.

Now, the NSI-566/ALS Phase II dose escalation and safety trial will expand to two centers. The trial is designed to treat up to 15 patients, in five different dosing cohorts, increasing to a maximum of 40 injections, and 400,000 cells per injection based on safety. (Phase I topped out at 15 injections of 100,000 cells each.) The first 12 patients will receive injections in the cervical region of the spinal cord only, where the stem cells could help preserve breathing function. The final three patients will receive both cervical and lumbar injections.

Neuralstem originally received approval from the FDA to move into the cervical (upper back) stage of the trial in the fall of 2011. The first of six patients in the cervical cohorts to receive stem cells was treated on November 18, 2011, which marked the first FDA-approved intraspinal surgical transplantation of stem cells into the cervical region. 

For more on the team’s work, Practical Neurology talked to Eva Feldman, MD, Russell N. DeJong Professor of Neurology, Director of the A. Alfred Taubman Medical Research Institute, and Director of the Program for Neurology Research and Discovery at the University of Michigan, and Karl Johe, PhD, Neuralstem Chief Scientific Officer and developer of the cells used in the trial.

Can you talk about your Phase I findings and the data you presented at the Canadian Neurological Sciences Federation Congress?

Dr. Feldman: As we continue to analyze data from Phase I of our trial, we continue to be pleased with the results. While the trial was designed to test the safety of direct intraspinal injections of stem cells in patients with ALS, we have found that a subset of patients have shown little progression of their disease, in some cases more than two years since surgery.

As we have reported, these individuals had no bulbar features of ALS and surgical transplantation occurred early within the course of their disease (average of two years and one month after symptom onset at the time of surgery). These very preliminary results suggest that intraspinal stem cell transplantation of ALS subjects with no bulbar symptoms early in the course of their disease could slow disease progression.

The FDA recently approved your Phase II trial. What are your objectives and what do you hope to learn?

Dr. Feldman: Our goal for the second phase of the trial is to continue to demonstrate the safety of the cells and of our methodology. We have designed this phase of the trial to further measure efficacy of the treatment and to deliver more stem cells with each operation. Our ultimate goal is to accumulate sufficient safety data and positive exploratory endpoints to progress to a widespread Phase III trial to test the efficacy of this new therapy in a larger cohort of patients.

What are the challenges facing stem cell therapy in ALS?

Dr. Feldman: We have taken great care to design the trial so that the surgery is unlikely to compromise the remaining function of ALS patients who enter the trial. The challenge is three fold. First, can we continue to safely deliver these stem cells to the spinal cord? Second, because this is a different type of transplant compared to larger whole organ transplants (like for example a heart or kidney), can we discontinue transplant rejection drugs after a period of initial administration? And, finally, the third and key question: Can we measure efficacy of our treatment, i.e. in the simplest of terms, does stem cell therapy work in ALS patients?

Can you talk about cultivating human fetal neural stem cells? How are they different than embryonic stem cells?

Dr. Johe, Chairman of Neuralstem: Neuralstem’s FDA approved cGMP cell banks are cultured in serum free medium. The cells have a mitotic capacity of roughly 60 doublings, so unlike ES cells, they are not “immortal.” The cells constituitively differentiate into regionally specific and relevant phenotypes; they do not have to be “driven” to their desired fate unlike ES cells. This makes for a more robust and efficient and predictable manufacturing process. ES cells for instance need to be “driven” to a specific neural precursor fate, as opposed to their many other potential fates, then culled for purity/safety purposes. Our culture methods start with the right neural stem cell for a particular purpose.

  1. Fox, C. FDA-approved Stem Cell Trial Dramatically Slows ALS.; 2013-05-30.