Gene Therapy for ALS Mice and for Patients

1. What is the new discovery?
Researchers at the Salk Institute and Johns Hopkins have demonstrated that gene therapy can be used to deliver a new therapy to motor neurons that can substantially increase animal survival in a mouse model of ALS. Furthermore, when comparing two therapeutic proteins -- insulin-like growth factor 1 (IGF-1) and glial cell-derived neurotrophic factor (GDNF), IGF-1 was markedly more effective. Finally, the researchers discovered that IGF-1 can be given even late in the course of disease in the animal model -- when clinical disease was already underway -- and it was still potently capable of delaying disease progression.

2. What does this mean for ALS patients?
Over the last decade, pharmaceutical, biotech, and academic researchers have discovered various potent drugs or hormones that might be effective to treat ALS. However, a major limitation has been getting the drugs or protein into the brain or spinal cord, since these organs have a protective barrier, called the blood-brain barrier, that keeps out many drugs and hormones. Our study shows that gene therapy can be used to bypass this barrier and deliver the therapeutic agent to where it is needed. Thus, the study sets the stage for future clinical trials based on this gene therapy and makes it possible to reconsider the therapeutic potential of proteins previously discarded or ignored because of blood-brain barrier issues.

3. If this so exciting, are human trials planned?
Yes. Scientists from Salk and the scientists and clinicians from Johns Hopkins, along with Project ALS, are actively planning a clinical trial of this gene therapy in patients with ALS and are already conducting important meetings with appropriate regulatory agencies. Discussions are now underway with potential pharmaceutical and biotech partners to manufacture the IGF-1 gene therapy and perform the necessary and mandatory safety studies as outlined by the FDA. This process should take about a year, at which point, if all goes as planned, the first clinical trial of this treatment could begin.

4. What is being done to speed up this process to bring this to patients as quickly as possible?
There are a number of distinct obstacles to beginning a clinical trial. All new experimental therapies must be reviewed by the FDA before they can be tested in people. In addition, all experimental gene therapies undergo a separate and mandatory review by the Recombinant Advisory Committee (RAC). Furthermore, and most importantly, few companies and biopharmaceuticals actually manufacture gene therapies, a process that is quite expensive ($1.5 to 2 million) and time consuming (up to 6 to12 months). To jump start this process, Project ALS is dedicating an effort to fund these initial steps. Ultimately, government and other funding sources will be required to advance the design and execution of a clinical trial for patients. In the meantime, however, the investigators have met with FDA and various biopharmaceutical companies to move this process along as fast as possible.

5. Isn't IGF-1 also called Myotrophin? Wasn’t that already studied in ALS?
The artificially synthesized (also known as recombinant) IGF-1 protein was used in two ALS trials a number of years ago. Biotech company Cephalon synthesized the protein and ran the human trials. In this case, the large protein molecule was injected into patients' skin every day. The trial of Myotrophin in Europe failed to show efficacy in slowing disease, but the trial in the U.S. showed modest efficacy on some clinical measures, but did not improve patients' survival. Because of the experimental nature of IGF-1, and its limited efficacy, the FDA requested a third trial by the company, which was not carried out. However, a group of academic medical centers recently received funding from the NIH to carry out a repeat trial of recombinant IGF-1 protein in ALS. This will be a two year trial, organized through the Mayo Clinic and conducted at selected sites site in the U.S.

What’s different about the use of gene therapy compared to the previous trial of recombinant protein?
The original IGF-1 study involved the daily injection of the recombinant protein into the skin or muscle of patients for the duration of the clinical trial. Unfortunately, most of the injected protein was broken down and eliminated by the body, and very little got into the nervous system. Based on our study in mice, gene therapy is potentially a much more powerful and a simpler way to deliver a medical treatment to the brain and spinal cord. In this gene therapy, a specially modified virus carrying genetic instructions for IGF-1 is injected into muscle, where it is able to infect motor neurons and get them to make the IGF-1 protein. Essentially, this means a one time injection into muscle; the virus is then "picked up" by the nerves in that muscle and transported back into the spinal cord where it goes to work.

Once the virus enters a motor neuron or other cell in the spinal cord, the cell acts like a factory to rapidly produce the IGF-1 protein. IGF-1 protein then works within the motor neurons or can be secreted by motor neurons to help surrounding sick cells. In this manner, a continuous, large amount of the beneficial protein is synthesized within the spinal cord -- constantly providing therapy to the diseased nervous system.

7. Who do I contact about future clinical trials?
At this point, a clinical trial of IGF-1 gene therapy is still in the planning stages. If all goes well, we hope to be ready to initiate a trial in about 1 year, at which time more details will be available. Future information about this trial will be available on the websites of Project ALS and the Packard Center for ALS Research at Johns Hopkins. Typically, all clinical trials at Johns Hopkins are open and are filled on a first come, first served basis. Patients must be seen by Johns Hopkins Neuromuscular physicians to be eligible. To make an appointment to be seen by a physician in the ALS clinic, call 410-614-5972.

8. How do I learn more about ALS?
Information about ALS, the disease, practical medical management, research on its causes and the development of new treatments can be obtained from several sources. Websites that provide background information about ALS and ALS research include: Packard Center for ALS Research at Johns Hopkins – http://www.alscenter.org , Project ALS – www.projectals.org , and the ALS Association – http://www.alsa.org . These sites contain extensive additional links and patient materials.