Research Update – from ALSA's National Office
October 26, 2006
Report on Progress Toward ALS Therapies Presented at Neuroscience 2006
Roberta Friedman, Ph.D., Research Department Information Coordinator for The ALS Association
Researchers seeking leads on effective therapies for ALS presented progress in their efforts at the meeting in Atlanta, Ga., of the Society for Neuroscience. Evidence is building that finding a way to mimic certain hormones or growth factors which support cell survival might help in ALS.A growth factor known to support the health of cells is able to prolong survival and preserve motor function in mice with the SOD1 mutation which model ALS. Granulocyte colony stimulating factor (G-CSF) had this beneficial ability as reported by German investigators at a biotech company, Axaron, at last year’s meeting of the Society for Neuroscience. This finding was supported by new results showing that G-CSF increased the number of surviving motor neurons in the mice and helped keep the surviving cells looking normal under the microscope.
Christine Haenggeli, M.D., and colleagues at Hopkins are testing a gene therapy that delivers IGF-1 by viral vector directly into the spinal cord of SOD1 mutant mice, producing a modest increase in lifespan of a week or two. Peter Carmeliet’s group is also trying to use vector delivery of the trophic factor, VEGF (see trophic factors). The nerve muscle junction was preserved by this VEGF gene transfer. Brian Kaspar, Ph.D., at Columbus Children’s Research Institute, Ohio, and collaborators at the biotech company, Genzyme, tested direct delivery of IGF-1 to the deep cerebellar nuclei in SOD1 mice finding this treatment to promote motor neuron survival and to improve retention of motor skills while extending lifespan by a couple of weeks.
Cell Therapies
Jeffrey Rosenfeld, M.D., Ph.D., at Carolinas Medical Center in Charlotte, is investigating Sertoli cells, the nurse cells from the testes which secrete helper molecules including several trophic factors. These cells can survive implants into mice spinal cord at least until three weeks but beyond that is undetermined.
Stem cells that produce the supportive cells of the nervous system, called astrocytes, have been transplanted into the cervical spinal cord in mutant SOD1 rats. Investigators at Johns Hopkins did not find any change in survival although the treatment gave some delay in loss of diaphragm function. The injection was at the level of the spinal cord innervating this muscle. The findings agree with results reported just as the meeting got underway from a Hopkins team publishing on injections of stem cells into the lower spinal cord that did not help the diaphragm strength but did appear to briefly improve strength in the lower limbs.
Rosenfeld’s group is also testing a combination therapy that includes a compound called huperzine A. Neuron-like cells growing in lab dishes can resist toxic challenges and survive longer in dishes when given the combination therapy. A combined therapy with drugs shown to extend survival in the SOD1 mouse model is underway in ALS patients funded through TREAT ALS.
Muscle Not Likely a Target
Chien-Ping Ko, Ph.D., at the University of Southern California, reported that male SOD1 mice given dihydrotestosterone maintained motor performance beyond the time when untreated SOD1 mutant mice were severely impaired. Testosterone itself did not give any benefit. Nor did female SOD1 mutant mice improve with either hormone. Erika Holzbaur, Ph.D., and colleagues at Wyeth Pharmaceuticals have developed and tested an antibody to inhibit myostatin, a treatment that increased muscle mass and strength up until the late stage of disease in SOD1 mutant rodents but did not extend lifespan.
Another molecule called follistatin that can increase muscle mass did not help prolong survival but did maintain grip strength in the mouse model of ALS, as reported by Kaspar, collaborating with Don Cleveland, Ph.D., of the University of California, San Diego.
Role of Glial Cells
Other research presented at the meeting was directed at the microglia, the immune cells of the nervous system implicated in ALS, Laval University researcher Jean-Pierre Julien, Ph.D., and colleagues tested the drug called ganciclovir which can eliminate proliferating microglia. They found a 1.5 fold decrease in the number of activated microglia but no difference in loss of motor neurons in SOD1 mice.
Researchers at Simon Fraser University in British Columbia found that there is a significant increase in the number of microglia coming in from the bone marrow which are still able to divide. If these marrow-derived cells can be taken from blood and re-injected to enter the brain and spinal cord, they might prove ideal candidates for gene delivery. Please see related news story from the meeting for more information about the tissues to target in ALS (see models of ALS).
Clues from Cannabinoids
Evidence presented in two posters at the meeting show aspects of drugs based on cannabinoid compounds (part of the complex mix present in marijuana) that are suggestive for ALS. In findings from a group at the University of Arkansas, Little Rock, a selective drug that acts at a particular cannabinoid receptor increased lifespan by a couple of weeks in SOD1 mice. The beneficial effect occurred when the drug treatment was started at symptom onset in the mice. Most likely, the cannabinoid effect is through modulation of inflammation, concluded the researchers, led by John Crow, Ph.D., and Paul Prather, Ph.D.
Another team led by Eric Beattie, Ph.D., at California Pacific Medical Center in San Francisco, has also published similar findings with the same cannabinoid drug, which is only available to investigators and has the code name AM1241. A role in ALS for cannabinoids is still uncertain. Use of marijuana will not likely reproduce effects seen with single cannabinoid compounds.
Gene Silencing, a Nobel-Winning Approach with Promise
The gene silencing technique that has come from the science awarded a Nobel Prize this year, called RNA interference, is being applied to ALS. Confirming the promise of this approach, Japanese researchers working with Hidehiro Mizusawa, M.D., Ph.D., at Tokyo Medical and Dental University lowered production of the mutant SOD1 well before any symptoms appear in mice. Scientists now need to show that the RNA interference could increase lifespan by lowering production after symptoms begin, before the approach can be investigated further as a treatment or a gene therapy.
Progress with Biomarkers
The protein, transthyretin, protects neurons. In ALS patients, it is among a set of molecules that appear to differ from the usual amount in the cerebrospinal fluid that bathes the brain and spinal cord. As presented by the team working with Robert Bowser, Ph.D., at the University of Pittsburgh, on the biomarker project funded by The ALS Association, some ALS patients might have an altered form of transthyretin.
Reducing the amount of transthyretin increases the deposits of amyloid, a key protein implicated in that disorder of aging. Mice modeling Alzheimer’s had more amyloid deposits if they could not make transthyretin. This suggests transthyretin might play a role in neurodegeneration in general.
Other biomarkers found by both the Bowser team and another group are of interest, as presented in a poster by the team at Mount Sinai Medical Center in New York led by Guilio Pasinetti, M.D., Ph.D. They reported on cystatin C and a protein related to chromogranin (it is called VGF). Both are lower than normal in spinal fluid of ALS patients, and in mice that model the disease by expressing mutant SOD1. Chromogranins have been implicated in ALS, as presented at last year’s meeting of the Society for Neuroscience by Julien, funded by ALS Canada and The ALS Association.
The collective findings on potential biomarkers of ALS highlights the importance of verifying that these can serve as surrogate markers of the disease and lends hope that such biomarkers could in fact add to the arsenal of potential treatments being explored to help patients.