Caroline Helwick

October 16, 2013

NEW ORLEANS — Neural stem cell transplant shows early promise as a treatment for amyotrophic lateral sclerosis (ALS), according to preliminary results in a small patient population.

"Our approach is simple: to graft stem cells into the diseased area," said Eva Feldman, MD, PhD, principal investigator of the phase 2 trial testing a proprietary line of human spinal cord–derived neural stem cells developed by Neuralstem of Rockville, Maryland.

"Overall, the results demonstrate that lumbar, cervical, and dual-targeted intraspinal transplantation of stem cells in ALS patients is feasible and well tolerated, supporting future trial phases examining therapeutic dosing and efficacy. But whether or not there is a benefit, we simply don't know yet," she said.

Dr. Feldman is director of the A. Alfred Taubman Medical Research Institute and Director of Research of the ALS Clinic at the University of Michigan Health System, Ann Arbor. Her co-investigators are from Emory University, Atlanta, Georgia.

She is also president of the American Neurological Association (ANA), and she presented the first results of a phase 1 trial here at the ANA's 2013 Annual Meeting.

Risk-Escalation Design

With stem cell therapy, the goal is to prevent further degeneration of neurons and progression of disability. Neural stem cells can self-renew and differentiate into both glial and neuronal progenitor cells, ultimately yielding astrocytes, oligodendrocytes, and functional neurons, she explained.

The results of the phase 1 study, presented for the first time at the ANA meeting, suggest that early intervention, before patients develop bulbar symptoms, works best.

Dr. Feldman told Medscape Medical News, "Based on the survival data we have, we have seen that the efficacy appears to occur in patients with disease duration less than 2 years, with no bulbar symptoms that are affecting their ability to speak, swallow, and breathe. We want to target treatment to patients it will most help, and we also want to target therapy to the cervical part of the spinal cord because that supplies strength to the diaphragm, which allows patients to continue to breathe."

On the basis of results in rodents and pigs, the researchers established that intraspinal injections of stem cells could preserve spinal cord function after mechanical or chemical injury. The mechanism is not completely clear, but in animal models the cells seemed to preserve endangered synapses — not replace destroyed synapses, she said.

The first-in-human trial was a phase 1 open-label, feasibility and safety study of stem cell transplantation in 15 patients with ALS. The study's overall objective was to assess safety and feasibility of stem cell transplantation into lumbar and cervical spinal cord regions.

Altogether, the 15 patients underwent a total of 18 surgeries. The population included patients in all stages of the disease — some ambulatory, some nonambulatory, some with bulbar disease, and some with disease duration over 10 years. Most patients were diagnosed with ALS about 2 years earlier.

Patient cohorts consisting of 3 patients with ALS each followed a "risk-escalation" paradigm. The earliest cohorts were nonambulatory patients who received unilateral lumbar or bilateral lumbar injections. The final 3-patient cohort received bilateral lumber injections followed 18 months later by unilateral cervical injections.

All injections delivered 100,000 cells in a 10-μL volume, for a total dosing range of 500,000 to 1.5 million cells. The procedure was well tolerated by all patients, with minimal perioperative or postoperative complications, Dr. Feldman said.

Preliminary Signs of Activity

Efficacy outcomes were mixed in the earlier tiers of the study, but for ambulatory patients receiving both bilateral lumbar and unilateral cervical injections, outcomes were promising.

Of 12 patients in the earlier cohorts, 6 showed relatively steep declines in revised ALS Functional Rating Scale (ALSFRS-R) scores, while 6 had slower declines. In the final cohort, however, stabilization was noted in all 3 patients. Scores over 1.5 years remained essentially the same as at baseline, about 32 to 45 points, Dr. Feldman reported. "Though these are very small numbers, we see a flattening of the curve," she noted.

Patients with bulbar signs essentially failed to respond."The data suggest that transplantation in subjects early in the disease course, with no bulbar signs, carries less risk," she said.

Analysis of the final cohort's outcomes have yielded early insight into potential windows of stem cell biological activity and suggests that some clinical endpoints closely correlate with response to the treatment, she said.

Forced vital capacity, grip strength, and hand-held dynamometry were the most robust measures, and at least 1 patient reported improvement in spasticity. Autopsies of some patients have shown "clusters of stem cells in the cord," she added.

Phase 2 Design

Three patients have been enrolled in the phase 2 trial. They have received 5 cervical injections per side with 200,000 cells per injection, for a total of 2 million cells. The plan is to advance to 10 cervical injections per side in increments of 3 patients per cohort, advancing from 4 to 6 to 8 million cells total.

The final cohort will receive bilateral cervical injections (8 million cells) followed by bilateral lumbar injections (8 million cells).

 
The spinal cord is precious real estate. Dr. Eva Feldman
 

"But challenges lie in developing a safe, accurate and effective cellular therapy for ALS," Dr. Feldman acknowledged. The researchers will be evaluating spacing and depth of the injections, optimal number of cells to inject, injection rate, cellular viability and migration, the risks and benefits of immunosuppression, and other relevant issues.

"The spinal cord," Dr. Feldman concluded, "is precious real estate."

Mark Tuszynski, MD, PhD, professor and founding director of the University of California, San Diego, Translational Neuroscience Institute, commented on the presentation for Medscape Medical News.

"Stem cells in ALS have the potential to secrete growth factors to help cells divide and potentially restore lost connections and form new connections. It's early days in the research, but there is certainly hope," he said. "We have to acknowledge that most research that enters the clinical trial arena takes a long time to come to fruition. With new interventions, things have to fail before we learn how to do them right, but we are optimistic here. Time will tell."

The study was supported by Neuralstem. Dr. Feldman is an unpaid consultant for Neuralstem. Dr. Tuszynski has disclosed no relevant financial relationships.

American Neurological Association (ANA) 2013 Annual Meeting. Symposium lecture. Presented October 15, 2013.

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