Stem Cell Therapy Safe in ALS Patients, Review Finds; Evaluating Effectiveness is Next

Stem cell therapy seems to be safe in patients with amyotrophic lateral sclerosis (ALS) and clinical trials evaluating its effectiveness are on the way, according to a review study.

The review, “Stem cell transplantation for amyotrophic lateral sclerosis,” was published in the journal Current Opinion in Neurology.

Over the past years, there has been much excitement and hope around the therapeutic potential of stem cells in a variety of neurodegenerative diseases, including ALS.

Stem cells have the remarkable potential to develop into many different cell types in the body and to replicate rapidly. These properties highlight their potential to replace cells that are lost or to provide protective, immunomodulatory (that regulate immune responses), and survival signals to the remaining cells.

Currently, no stem cell treatment, in which stem cells are transplanted into the patient, has been approved for ALS, and the evaluation of its safety and effectiveness is only in its first steps. “In the case of amyotrophic lateral sclerosis (ALS), there are no approved stem cell treatments and there are only a few legitimate clinical trials of stem cells to date,” the authors wrote.

Researchers at the Cedars-Sinai Medical Center, in Los Angeles, and the Emory University School of Medicine, in Atlanta, reviewed current knowledge and recent efforts to develop and evaluate stem cell therapies for ALS.

Because the reconstruction of complete motor nerve circuits in adult patients is very complex, current stem cell approaches in ALS aim to use them to improve the function of motor nerve cells and prolong their survival.

This is done through the regulation of immune responses, secretion of important molecules, and/or production of brain cells that support motor nerve cells.

The authors noted that the best source of stem cells (bone marrow-derived mesenchymal stem cells or immune cells, or fetal-derived nerve stem cells) and the best delivery method — directly into the brain, cerebrospinal fluid (the fluid that bathes the spinal cord and brain), muscle, or blood — is still unclear.

Mesenchymal stem cells have the potential to differentiate into cells that produce key factors for the healthy function and survival of nerve cells or signals that regulate immune responses, such as inflammation.

Four recent Phase 1 or 2 clinical trials have mainly evaluated the safety, but also some preliminary measures of effectiveness, of transplanting the patient’s own mesenchymal stem cells intrathecally (directly into the cerebrospinal fluid).

The results showed this approach appears to be safe and well-tolerated — although associated with temporary infusion reactions — and to temporarily increase the levels of key factors for nerve cells’ survival and anti-inflammatory molecules.

However, since these studies were small and not placebo-controlled, the effectiveness of this approach remains unproven.

Next phase of research

Nevertheless, the dosing and safety knowledge gathered so far is sufficient to promote the development of randomized placebo-controlled Phase 3 trials.

One such Phase 3 study is underway (NCT03280056) and will evaluate the safety and effectiveness of BrainStorm Cell Therapeutics’ therapy candidate NurOwn, every two months in ALS patients, compared to placebo. The trial is recruiting up to 200 participants at six U.S. sites. BrainStorm plans to complete the study by July 2019.

A couple of Phase 1 clinical studies evaluating the safety of transplanting the patient’s own bone marrow- or blood-derived immune cells intrathecally (into the spine) or directly into the blood also highlight that this may be a safe approach, but its effectiveness remains to be clarified.

Fetal-derived nerve stem cells, such as neural progenitor cells — cells with the potential to generate nerve cells and their supporting cells — are another potential source of therapeutic stem cells in ALS.

Their use aims to replace interneurons (nerve cells that connect sensory and motor nerve cells), release potent growth factors, and reduce toxic inflammation.

Phase 1 and 2 clinical trials also have demonstrated the safety of delivering neural progenitor cells into the spinal cord of ALS patients, and Phase 3 studies to evaluate the effectiveness of this approach are currently being planned.

Additionally, induced pluripotent stem cells (iPSCs), or stem cells derived from tissues of adult patients, have the advantage to allow researchers to generate iPSCs-derived neural progenitors from the patient and avoid ethical concerns with fetal or embryonic tissues.

Preclinical and clinical studies also have highlighted the importance of the location of stem cell delivery to treat ALS, as different locations throughout the spinal cord, or administration into the spinal cord vs muscle, have shown distinct results. So, additional studies are needed to clarify the best delivery location of stem cell therapy.

“With clinical trials recently demonstrating that stem cell transplantation can be safe and well tolerated in ALS, the field is positioned to complete pivotal controlled trials to determine efficacy,” the researchers wrote.

They also noted that the major challenge is to “design pivotal phase 3 trials that include appropriate controls to definitively demonstrate clinical value, but that simultaneously maintain cost effectiveness and do not place control subjects at undo risk without benefit.”