January 6, 2006

Research Summary 2005: Advances Give Renewed Hope for the Coming Year

The following is a recap of key findings published in 2005 that point the way toward new therapies for the nerve wasting disease, amyotrophic lateral sclerosis (ALS, also called Lou Gehrig’s disease).

• Belgian researchers led by Peter Carmeliet M.D., Ph.D. report in the January issue of Nature Neuroscience that direct delivery of the trophic factor, vascular endothelial growth factor (VEGF), increased survival in a rat model of ALS, improving motor performance and prolonging survival by 22 days. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15568021&query_hl=7

• Key genes governing the ability of developing brain cells to connect properly to the spinal cord could produce new insights for repair of damage in ALS, according to findings in the January 20 issue of Neuron, from the lab of Jeffrey Macklis, M.D., D.HST of Harvard, who suggests these genes also provide the first markers for the specific neurons that die in ALS. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15664173&query_hl=11

• Scientists show for the first time that human stem cells can be made to become motor neurons similar to those destroyed by ALS. The team at the Waisman Center at the University of Wisconsin led by Su-Chun Zhang details the sequence of molecular events that guide embryonic stem cells into becoming the cells that make muscles contract, as reported online January 31 in Nature Biotechnology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15685164&query_hl=16

• An already marketed drug unexpectedly alters the levels of a protein that regulates the nerve cell messenger, glutamate, and will enter clinical testing in 2006, due to a screening effort led by investigator Jeffrey Rothstein, M.D., Ph.D. at Johns Hopkins, whose team published in the January issue of Nature that ceftriaxone increases levels of the glutamate transporter protein at concentrations known to reach the brain. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15635412&query_hl=19

• Harvard epidemiologists reported in the January 11 issue of Neurology that men who served in the military have an increased relative risk of dying from ALS. The risk for veterans was 1.5 times that seen for the men who did not serve. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=retrieve&db=pubmed&list_uids=15642900&dopt=Abstract

• Scientists identify several promising molecules that keep in a safe form the mutant protein implicated in inherited ALS, as published online February 17 in the Proceedings of the National Academy of Sciences. The effective molecules give leads toward designing new therapeutics to treat the disease, according to team leader, Harvard investigator Peter Lansbury, Ph.D. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15738401&query_hl=24

• Researchers from the Swiss Federal Institute of Technology and French collaborators report March 13 online in Nature Medicine that ALS mice injected in the spinal cord with an RNA- silencing therapeutic showed improved motor skills. A British company, Oxford Biomedica Ltd. in Oxford, U.K., publishing in the same issue, demonstrates that muscle delivery of an RNA treatment to silence the mutant gene for SOD1 led to increased survival in mice. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15768028&query_hl=28 http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15768029&query_hl=30

• Research published in the April issue of Human Gene Therapy shows that stem cells taken from the outer layer of the human fetal brain can be prompted to turn into vital support cells for motor neurons and be engineered to make a factor that helps surrounding nerve cells to survive. Clive Svendsen, Ph.D., the University of Wisconsin investigator directing the research, said “We look forward to continual interactions with ALSA as we carefully take stem cells towards the clinic." http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15871682&query_hl=32

• A third team reported success with the new gene silencing approach. Mice show better grip strength if treated with the RNA therapeutic, according to the report online April 25 in the Annals of Neurology by Timothy Miller M.D. and Don Cleveland, Ph.D. of the Ludwig Institute at the University of California, San Diego and collaborators.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15852369&query_hl=35

• SOD1 mutant mice that recreate the symptoms of ALS in the laboratory display an early, subtle change in their walking gait that should help investigators find new treatments for ALS, according to a report in the May 2005 Muscle and Nerve by researchers at The Jackson Laboratory. New treatments may provide the best impact if they are applied as early in the course of the disorder as possible. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15880561&query_hl=37

• Abnormal deposits of the mutant SOD1 protein involved in some inherited forms of ALS appear in the mitochondria, the cell’s power supply. Information about the role of mitochondria in ALS is detailed by Giovanni Manfredi, M.D., Ph.D. at Cornell’s Weill medical college in New York City. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15758154&query_hl=7

• Reporting in the September 29 online Journal of Neurochemistry, University of Pittsburgh researcher Robert Bowser, Ph.D. and collaborators detailed findings on potential biomarkers for ALS. A predictive panel of biomarkers would allow more rapid and accurate diagnosis for patients who often undergo months of tests and uncertainty before finding out whether they have ALS. Bowser’s work is part of a consortium effort funded by ALSA to find biomarkers for ALS. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16191107&query_hl=7

• Findings in the October 10 Journal of Cell Biology shed new light on why ALS kills cells. Northwestern University researcher Richard Morimoto, Ph.D. and colleagues could see with a new microscope technique that the proteasomes, which work within cells to either refold defective protein or trash it, are trapped in the mesh of aggregated, mutated SOD1. Cells that visibly formed SOD1 aggregates died within a day. Certain drugs exist or are being designed that either boost the performance of the proteasome or interrupt aggregates. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16216923&query_hl=12

• Laval University researcher Jean-Pierre Julien and colleagues showed that helper molecules called chromogranins are found together with mutant SOD1. Abnormal SOD1 may actually be secreted by cells, according to the results presented in posters at the Society for Neuroscience meeting. Julien’s group in Quebec, Canada found clusters of the mutant protein where one finds proteins that are going to be exported. The findings have been published in the December 18 online Nature Neuroscience.http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16369483&query_hl=1&itool=pubmed_docsum