“Induced pluripotent stem cells” are poised to become a powerful tool for understanding the ALS disease process and for rapidly discovering drugs to treat the disease. That was the message from Ashkan Javaherian, Ph.D., Senior Scientist at the biotechnology firm iPierian, a company at the forefront of this technology, which uses skin cells from ALS patients as the starting point for growing millions of motor neurons in culture.
Dr. Javaherian presented these new developments in an ALS Association Research Webinar in April. The full webinar, including a Q&A session with participants, is available at https://alsa.webex.com/alsa/ldr.php?AT=pb&SP=MC&rID=62325022&rKey=e7183ff99c9d3e26
“This is a very new technology, and it has been quickly applied to ALS. It’s extremely exciting,” said ALS Association Chief Scientist Lucie Bruijn, Ph.D., who hosted the webinar.
“A fundamental challenge in neurodegenerative diseases is the lack of appropriate disease models,” Dr. Javaherian explained, especially in ALS. Motor neurons cannot be simply isolated from humans the way blood or skin cells can, and unlike many other cell types, motor neurons don’t divide. Both these factors have made it hard to create enough motor neurons to study in the lab.
Stem cells have the ability to grow into all the types of cells of the body, including motor neurons. But research with stem cells derived from embryos has been hampered due to ethical controversies.
In 2007, however, a new technique was developed that allowed researchers to convert skin cells into stem cells, called induced pluripotent stem cells (iPS cells). “What is so special about these cells is that when grown in culture, they renew themselves, and can produce an unlimited supply of more iPS cells, and they also have the potential to produce cells of every organ type,” he said.
That development immediately suggested that it might be possible to use skin cells from ALS patients to develop iPS cells, and from them the millions of motor neurons needed to conduct research and search for treatments. This has been the mission of iPierian, Dr. Javaherian added.
The traditional path to drug discovery begins with a gene from patients, which is inserted into a mouse, which is then used to test new drugs, which can then be brought back to humans for further testing.
With iPS cells, that path is potentially quite different. Skin cells from many different patients can be isolated, converted to stem cells, and used to grow many different lines of motor neurons. Each can be tested against thousands of drugs in a “high-throughput screen.” The goal is to find a compound that reverses some aspect of the disease, such as cell death, signs of stress, or expression of some disease-related protein.
With enough patient-derived cell lines, he said, “we can do an ‘in vitro clinical trial’ before a patient-based trial, increasing the potential that one of the drugs brought to humans will work.” This does not necessarily circumvent the animal testing that is important for safety however it improves the likelihood that the compound works in humans.
The company began by focusing on the disease spinal muscular atrophy (SMA), another motor neuron disease, caused by a faulty gene. But they are moving ahead with an ALS program now, collecting patient skin cells and developing iPS cells and motor neurons.
Ninety percent of all ALS cases are sporadic (that is, not inherited), and it is likely that there are multiple causes of motor neuron loss in this large group of patients. This increases the importance of having multiple cell lines to test, because a single treatment may work in some cells and not others. “This is a powerful system for modeling a disease when we don’t know which genes are involved,” Dr. Javaherian said.
The group is still collecting cells, primarily at two medical centers in the San Francisco area. Patients in other areas may nonetheless be able to donate (see below).
Currently, cell lines are being developed and motor neurons made, and the scientists are testing different markers to use in the high-throughput screen. At that point, up to 200,000 different compounds will be tested to determine their effects on patient-derived motor neurons. Dr. Javaherian estimated they were still several years away from a clinical trial based on the iPS screens.
Dr. Bruijn stated that this is potentially a powerful way to find new drug candidates quickly, and to find treatments that may be useful in sporadic ALS. “This is a technology with a lot of promise,” she added and noted that the motor neurons derived from iPS cells are unlikely to be a valuable source for cell-based therapies, since they may retain the characteristics that made them vulnerable to disease. It is also important to note, she said, that cell-based treatment for ALS is an unproven therapeutic strategy.
If you are interested in donating cells, currently, two sites are accepting cells from ALS patients for conversion into iPS cells. These are:
California Pacific Medical Center
2324 Sacramento Street, Suite 150
San Francisco, CA 94115
Contact: Jonathan Katz, M.D.
University of California at San Francisco
The ALS Research Center at UCSF is located at:
350 Parnassus Ave. Suite 500
San Francisco, CA 94117
Contact: Catherine Lomen-Hoerth, M.D., Ph.D.
Patients in other areas interested in donating through their own physician should contact the ALS Association at 1-800-782-4747.
The donation procedure is performed during a routine clinical visit. A topical anesthetic is applied to the skin, and the doctor takes a small “punch biopsy,” which removes a piece of skin two to three millimeters long. It does not require a stitch, heals within a week, and may leave a small scar.