ENCALS 2014: Stem Cell Therapy for ALS: Theory and Practice

Dr. Neta Zach, Chief Scientific Officer of Prize4Life-Israel, attended the European Network for a Cure for ALS (ENCALS) Meeting on May 22-24th in Leuven, Belgium, and brings us the highlights of an intriguing presentation by Jonathan Glass, M.D., the invited speaker of the Thierry Latran Foundation and Professor, Neurology and Pathology, Emory University School of Medicine, Atlanta, Georgia on “Stem Cell Therapy for ALS: Theory and Practice”.

ALS patients often approach their physicians and request treatment with stem cell therapy. Despite the fact that these treatments are still unapproved and information is still lacking about their safety and efficacy, they are almost magically attractive to patients. But what are the facts about the benefits of stem cell therapy?

The notion of stem cells dates back well before DNA, to the idea of the Stammzellen suggested by Biologist Ernst Haeckl, who studied the evolution of cells in the 18th century. The first actual stem cells were isolated in 1981.

Surveying the current literature on stem cell therapy reveals many promising findings, but also much heterogeneity in the reported literature rendering it difficult to reach unequivocal conclusions about safety and efficacy of the treatments. The studies vary in the sources from which stem cells are harvested, such as umbilical cord, bone marrow, nasal epithelium and fetal cells. There is also a diversity of therapeutic applications: 1) Cell replacement, where stem cells undergo directed differentiation into healthy, mature cells to replace the diseased cells; 2) Trophic support, in which the stem cells undergo differentiation into cells secreting neurotrophic factors to support the damaged cells; or 3) Immunomodulation, where the differentiated stem cells secrete factors that can combat neuroinflammation. Stem cells have been suggested as beneficial for a wide range of neurological diseases including ALS, Alzheimer’s disease, autism, cerebral palsy and more. Similarly, there is tremendous variation with respect to mode of delivery of the cells and some published studies do not even report on the mode of administration, making the studies overall difficult to compare.

On the ALS stem cell clinical trial front, there are two ongoing studies in the United States: one sponsored by Neuralstem (Dr. Glass is the Site Investigator for the Neuralstem stem cell therapy trial at Emory University Hospital in Atlanta, Georgia, more detail below) and  a Phase II trial sponsored by Brainstorm Cell Therapeutics (see April 2014 Drug News).


Outside the U.S.,  there are several studies registered on ClinicalTrials.gov. including trials from Spain, Italy, and Turkey that have already been published in peer-reviewed journals.

The Italian stem cell trial was conducted in 2012. Stem cells were administered to 19 subjects via intralaminar injection into the spinal cord. Cells were injected at different levels of the spinal cord in two sessions, and patients were followed for one year following the procedure. Of the 19 subjects, seven have since passed away (all for reasons unrelated to the surgery), but six have reached a plateau in disease progression.

The Spanish stem cell study was also conducted in 2012, and recruited 11 patients. The stem cells administered in this trial were bone marrow derived, and were transplanted via spinal cord injection with a one-year follow up. The primary endpoints examined for survival and the ALS Functional Rating Scale (ALSFRS). In the period since the conclusion of the trial, seven patients have died (within an average of 3.2 years of disease onset) and four are still alive (within an average of 5.6 years of disease onset). Autopsies of the deceased patients indicate that the transplanted stem cells survived in the spinal cord. The researchers make no claims about efficacy, only that the treatment is safe in humans. The team is now repeating the study (for details click here) with 63 patients, including control subjects who will receive only saline injections. 

The trial conducted in Turkey dates back to 2009, but the publication lacks some important details about the study design.  The patient pre-treatment status is merely describes as “terminal illness” with a subset of the 13 subjects having already undergone tracheostomy. Subjects received multiple injections to spinal cord segments C1-2 (a relatively dangerous injection site), with addition IV injections. In the follow up period since treatment, three subjects died (for reasons other than the treatment), one remains stable and the other nine improved, but no clear metric of improvement is provided.

Dr. Glass proceeded to discuss the Neuralstem stem cell therapy trial in detail. The NSI-566/ALS Phase II trial commenced in September 2013, and expanded to three sites, including the Phase I site at Emory University Hospital lead by Dr. Glass. The Neuralstem trial uses fetal derived stem cells from human embryonic spinal cord (8 weeks of gestation). Since spinal cord injections pose serious safety risks independent of the stem cells, the research team has invested major efforts to develop the surgical tools to ensure sterile, stable and accurate injections.

In the preclinical studies, performed primarily at John Hopkins University in Baltimore, Maryland, they found that 70% of injected cells expressed markers of adult cells, and the treatment improved survival and attenuated motor neuron death in a rat model of ALS.

Despite promising preclinical results, translation to humans is not straightforward. Even in a terminal illness such as ALS, the surgical intervention can cause further damage such as pain and loss of bladder control, and the injected materials can have toxic side effects. Therefore, the trial was designed with a progressive level of intervention. The first 15 patients were divided into groups of distinct treatment paradigms: the first group of three patients were already unable to walk, and received unilateral lumbar injections; the second group included three patients that were still able to walk and received similar treatment; the third group received bilateral injections; the fourth were three ambulatory patients receiving unilateral cervical  injection;  and finally, the fifth group included three ambulatory patients with bilateral cervical injections. The investigators found that even 10 injections at the same site were well tolerated by patients.

As performance measures, the investigators examined outcomes using ALSFRS, as well as electrical impedance myography (EIM, the winner of Prize4Life’s $1M ALS Biomarker prize). The treatment slowed disease progression, and was more effective in the patients who received more invasive treatment. Specifically, five patients in the stem cell trial, who were not on mechanical ventilators at the time of surgery, exhibited decreased progression of disease, as compared to the predicted progression based on current understanding of typical disease course.

Intriguingly, one patient in the fourth group (who received unilateral cervical injections) exhibited dramatic improvement, with a partial reversal of ALS symptoms, and an increase of 1.4 ALSFRS points on average per month. Even more dramatically, improvement was dependant on continuation of treatment, and the condition of the patient deteriorated when treatment was discontinued. The team was stunned by this unexpected outcome. Ultimately, it appeared that the observed improvement was not due not to the injected stem cells, but rather to the immunosuppression protocol that accompanied the surgeries. Given that ALS an extraordinarily heterogeneous disease, it is possible that there exists a subset of patients with a particularly immune-responsive disease that has not been previously described. The investigators hypothesized that the immunosuppressants given to trial participants are neuroprotective by increasing the ratio of regulatory T cells and other protective immune mediators to neurotoxic immune modulators.

To further test this hypothesis, The ALS Association, ALS Therapy Alliance (ATA) and Northeast ALS (NEALS) Consortium, in conjunction with Dr. Glass, are now conducting a 30 patient clinical trial testing an immunosuppression protocol in ALS patients. Hopefully, the prior dramatic effects will be reproduced in additional subjects! In addition to monitoring survival and motor function, the investigators are also carefully monitoring the patient immune profiles throughout the course of treatment in order to better understand the processes affected by immunosuppression, and how they can inform our understanding of the disease. – Neta Zach.

conf-European Network to Cure ALS (ENCALS) Meeting disease-als stem cells topic-clinical topic-newmethods topic-randd
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