February 16, 2007

Researchers Give Clinical Progress Report in TREAT ALS Trials

Roberta Friedman, Ph.D., Research Department Information Coordinator

[Quick Summary: Clinical researchers gave progress updates at The Association’s Leadership and Clinical meeting on the possible use of gene therapies for ALS as well as ongoing combination therapy now being tested in the disease and markers of disease progression that may serve to streamline clinical trials.]
Paul Gordon, M.D., Columbia University
Challenges to those working on a solution to ALS (amyotrophic lateral sclerosis, also known as Lou Gehrig’s Disease) are the nature of the therapeutic target, the motor neuron that is dying. This cell has complex and demanding biology with far flung connections to other cells and metabolic demands that are hard to address. The real problem is to get therapeutics to where they are needed to aid the motor neuron, said Lucie Bruijn, Ph.D., vice president and science director of The ALS Association, as she introduced the speakers at the research update session at the 2007 Leadership and Clinical Conference in Newport Beach, Calif., January 25 – 27, 2007.

Many aspects of the molecular support systems within and surrounding the motor neuron are failing in ALS. It may be simplistic to think that a single compound will be able to make a difference. That is why the TREAT ALS (Transitional Research Advancing Therapy for ALS) initiative is testing combinations of therapies as well as testing many different approaches simultaneously in its drug development efforts.

Researchers provided progress reports and outlined their strategies in pilot clinical trials as well as the basic research that stands to enter soon into clinical testing. Another effort detailed in the reports was the search for new measures that will help streamline clinical trials to speed testing and decrease the time and number of patients required.

Gene Therapy: Promising Approach for ALS

Nicholas Boulis, M.D., of the Cleveland Clinic spoke about the rationale behind possible gene therapy for the disease. Many gene therapies rely on a disarmed virus. Scientists can take out the disease causing genes and replace with a gene construct to direct manufacture of a therapeutic protein. In this way, the body itself is able to produce the therapy and deliver it exactly where it is needed.

A virus is simply nature’s way to deliver a genetic signal, Boulis said, and progress in the last decade has come from investigating which viruses best target the nerves with the fewest unwanted effects such as inflammation. Genetic manipulations can improve nature’s design by combining elements from more than one virus to improve the ability to enter nerve cells.

Gene therapy approaches have protected challenged cells growing in lab dishes and in mice that have a genetic mutation that produces symptoms of ALS. The therapeutic gene delivered in these instances makes a growth factor such as IGF-1 (insulin-like growth factor). But in people the motor neurons are much longer, so this will be more challenging for ALS patients. To meet that challenge, Boulis and his colleagues have created a combination virus that has aspects of both a rabies and a lentivirus with funding from The ALS Association. This virus can deliver therapeutic genes to increase growth of nerve fibers. Another designed virus is modified by tagging with the tetanus toxin that also targets nerve cells to improve binding and uptake into nerve cells. Ongoing collaboration with the biotech company, Ceregene, will seek to better target gene therapy for ALS.

Boulis said that his expertise as a neurosurgeon will help in planning and testing surgical delivery of gene therapy for ALS. He demonstrated how one can listen in to the nerves firing as a delivery probe advances into the spinal cord to reach the desired region for therapeutic delivery. Another plan to investigate is delivery into the blood supply of the spinal cord together with a compound that can temporarily open up the normal barrier that protects the cord.

He is also collaborating with Clive Svendsen, Ph.D., at the University of Wisconsin in Madison, to develop a gene transfer plan. They will modify support cells, called astrocytes, to increase production of the growth molecule, GDNF (glial derived neurotrophic factor). The astrocytes are derived from stem cells. Placed properly into targeted areas of the spinal cord, these cells could provide support for the motor neurons. They are seeking approval from the Food and Drug Administration to proceed with patient testing.

Combination Trial Progressing Rapidly

Paul Gordon, M.D., of Columbia University, gave a progress report on a trial that is testing two different combinations of therapeutics with TREAT ALS funding (see for more details http://www.alsa.org/research/grants....action=detail). Enrollment in this trial was far brisker than anticipated, Gordon remarked, probably due to the lack of a placebo—all patients enrolling will receive a combination of drugs. Eighteen people have completed the trial, and results are expected to be available after March 2007. The FDA has required stringent safety monitoring with frequent checks of liver function, as one patient, with already compromised liver function, had an adverse reaction.

The combinations under investigation are celecoxib at a relatively high dose that might impair liver function, although this is an FDA approved dose, together with creatine, as well as creatine and minocycline. Both combinations were additively beneficial in the SOD1 mutant mouse prolonging survival.

The design of this combination trial allows the investigators to detect which combination might be better, with 80 percent certainty, despite only 120 patients at most enrolled. But the trial can stop if one treatment arm rises above another. The outcome measure followed is the ALS functional rating scale, a measure of respiratory function. A difference between treatment arms of three quarters of a standard deviation (a statistical measure) will halt the trial.

This type of trial design can be used to study up to a dozen different treatments in 20 months, Gordon said. That is because the trial is asking only for a good probability that a compound is better than the others. Traditional clinical trials ask for definitive proof that a drug is effective. However, this is a pilot study. Any treatment emerging from such a study would have to undergo the more rigorous testing in a traditional clinical trial with placebo to know that it is indeed changing the clinical course of the disease.

Surrogate Measures for ALS Clinical Trials

Seward Rutkove, M.D., of Beth Israel Deaconess Medical Center in Boston, is investigating a new technique to measure the response of muscle to provide a reproducible and easily followed indication of a person’s motor function in ALS. Electrical impedance myography (EIM) is painless and indicates the health of the muscle tissue providing a signature signal of the way the muscle is changing as it atrophies in the disease, Rutkove said. The technique is easy to carry out once practitioners have been trained to perform it, he added.

One question under investigation in a currently funded study of the technique, through the TREAT ALS initiative, is to see if the procedure can be simplified by using fewer recording electrodes. Rutkove says that it looks as if using just two can actually give better data.

Jeremy Shefner, M.D., Ph.D., of the State University of New York Upstate medical center then spoke about a more established marker of muscle function, called motor unit number estimation, or MUNE. This method estimates how many nerve fibers are still functioning along with their innervated muscle fibers, which is called a motor unit. As nerve cells die, neighboring ones attempt to take over their empty muscle fibers. So strength of the contraction can be preserved for a while despite the drop out of motor neurons.

The ability of MUNE to provide a reproducible and standardized measure of declining motor function is under investigation in a TREAT ALS sponsored trial, ongoing at eight centers and designed to enroll 120 patients. The trial will also use strength testing and the ALS functional rating scale for comparison.

By carefully comparing various outcome measures in these clinical trials, The ALS Association intends to provide the research community with a way to definitively test new candidate therapies in the search for effective treatment of ALS.



The ALS Association, National Office
27001 Agoura Road, Suite 150
Calabasas Hills, CA 91301-5104
Phone: (818) 880-9007
Fax: (818) 880-9006


In the past decade, The ALS Association has awarded nearly $40 million to fund research to find the causes and a cure for ALS. Learn more about The Association’s research and grant programs along with the groundbreaking TREAT ALS initiative at www.alsa.org/research.