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USE OF STEM CELLS IN PATIENTS WITH ALS - A PILOT PROJECT INITIAL FINDINGS AND CONCERNS RAISED

November 26, 2002

At the 13th International Symposium on ALS/MND held November 17-19, in Melbourne, Australia, L. Mazzini, MD and colleagues from Italy reported initial results (6-month) from a pilot clinical trial using stem cells.

The study presentation raised a number of questions and criticisms of the study design and methods from the researchers and clinicians present.

Serious concerns from the scientists in the audience include:

1. There was no scientific basis offered as rationale to conduct the study.

2. It is doubtful that the 1.5 milliliters of stem cells were actually injected, as this volume is very large for the space of the spinal cord.

3. There is not clear evidence that the small change in proximal muscle strength reported can be attributed to an effect of the stem cells. It is not certain that the stem cells actually were delivered into the spinal cord. Other variables, such as the trauma of the injection, could account for the muscle function changes.

As reported by Mazzini, the aims of this 12-month study-still in process-are to:

1. Verify the safety and tolerability of injecting autologous mesenchymal stem cells into the spinal cord

2. Examine the effects of the injection of stem cells, and

3. Evaluate the impact of the stem cell injection on quality of life

In this trial of a small number of people with ALS, bone marrow was collected from each patient (autologous) and the mesenchymal stem cells were extracted and later injected into the patient's spinal column.

Scientists in the audience raised doubt about whether the stem cells could have actually been injected into the spinal cord as described, given the large volume reported.

No major adverse events were reported in the first six months of the study. There were minor reports of pain as well as sensory, bladder, bowel and motor problems.

The study authors indicate that at both the 3-month and 6-month intervals after the stem cell injections, there was a slight improvement in muscle strength that was greater in the proximal muscles than in the distal muscles. Small improvement in neck flexor muscle strength was noted as well. There were a number of questions from attending scientists about whether there was adequate evidence that the muscle changes could be attributed to the stem cells and not from other factors such as the trauma of the procedure itself.

The investigators will continue the study and report the 12-month end of study findings in a future report. The authors indicate that the stem cell injection was safe and well tolerated, but they cautioned that further studies should be conducted to understand what role the stem cells may be playing. Many clinicians in the audience voiced concerns about safety of injection into the spinal cord and the feasibility and accuracy of this technique. It was noted that the changes in muscle strength could have been a temporary effect of the trauma of the injection or local tissue damage.

The authors stated that it was not clear why there was a difference in the muscle strength in the proximal muscles versus distal muscles. The potential use of stem cells as future carriers for drugs and other therapies was noted. The possibility that the stem cells are acting as neurotrophic/growth factor agents was discussed. Future trials may include newly diagnosed patients and people with a focal form of ALS.

In summarizing the Symposium's clinical presentations, Ed Byrne, MD, noted that as the field begins to start considering Phase I clinical trials of stem cells, investigators have to assure that the biological basis and scientific rationale for the potential treatment is sound. He urged that stem cells be tested in the ALS animal models to learn more about the actions and effects the stem cells are actually having.

Dr. Byrne commented that while there is very little evidence that stem cells can replace motor neurons, it might be possible that stem cells can have an indirect rescuing impact on the motor nerves by altering the environment around the neurons. He encouraged scientists to increase the research focus on how to stimulate stem cells that exist within each person's body (endogenous) to signal the motor nerves damaged by ALS.

Among the issues to consider before stem cell treatment is ready for ALS clinical trials, Dr. Byrne urged the attendees to address:

· Selection of the location of the body for transplantation and/or stimulation of the patient's own existing stem cells

· Technical approach challenges for injection or transplantation

· Need for clinical protocols

· Timing - earlier in the disease is probably better

· Quantification of results with objective tests

· Immunosuppression to prevent rejection response

· Need for follow-up care and treatment

· Long term follow-up or registry of patients who have received stem
cells

Noting that at this time there is little evidence in humans that stem cells provide a benefit in ALS, Dr. Byrne advised that the field should move cautiously.

For an article on the state of work in ALS on stem cells, visit ALSA's web
site at http://www.alsa.org/research/stem_cells.cfm>.