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From: alscenter@jhmi.edu To: The ALS Community Date: October 20, 2008

Subject: Robert Packard Center ALS News Network SWAMPING BAD CELLS WITH GOOD IN ALS ANIMAL MODELS HELPS SUSTAINBREATHING, NEW PACKARD STUDY SHOWS In a disease like ALS--one that's always fatal and that has a long history of research-resistant biology--finding a proof of principle in animal models is significant. This week, Packard Center researchers report that transplanting a newline of stem cell-like cells into rat models of the disease clearly shifts key markers of neurodegenerative disease in general and ALS in particular--slowing the animals' neuron loss and extending life. The new work supports an earlier Packard-proposed hypothesis that artificially outnumbering unhealthy cells with healthy ones in targeted parts of the spinal cord could preserve limb strength, breathing and can increase survival. An account of the work appears online this week in Nature Neuroscience. Two parts of the study hold special interest: One is that the target area for the added cells--parts of the cervical spinal cord that control the diaphragm muscles largely responsible for breathing--reap the most benefit. Forty-seven percent more motor neurons survived there than in untreated model animals. Respiratory failure from diaphragm weakness is the usual cause of death in ALS, also called Lou Gehrig's disease. "While the added cells, in the long run, didn't save all of the nerve to the diaphragm, they did maintain its nerve's ability to function and stave off death significantly longer," says neuroscientist Nicholas Maragakis, who led the research team. Maragakis is an associate professor with the Johns Hopkins University School of Medicine. "We intentionally targeted the motor neurons in this region," he says,"since we knew that, in ALS, their death results in respiratory decline." Also significant is that the transplanted cells, called glialrestricted precursors (GRPs), address a well-known flaw in people with ALS and in its animal models. Both humans and models are stunted in their ability to clear away the neurotransmitter glutamate. And excess glutamate--common in ALS--over stimulates the motor neurons that spark muscle movement, causing death. The event, called excitotoxicity, also occurs in stroke and other neurological diseases. So on a more basic level, the study adds clout to the principle--in live animals-- that excitotoxicity is a major bad guy in ALS and that finding more effective ways to avoid or lessen it could help protect the nervous system. In their research, the team transplanted some 900,000 GRPs overall to specific sites in the cervical spinal cord of each model rat in early stages of disease. The glial restricted precursors the scientists used began life as what's called astrocyte progenitor cells from healthy ratspinal cord tissue. Following transplant, they transformed into mature,healthy astrocytes, found living alongside sick motor neurons. Astrocytes are the most common cells in the central nervous system.Work at Hopkins and elsewhere has shown their crucial role in keepingthe CNS in healthy balance. Not only are the cells studded withtransporter molecules that mop up glutamate; they also maintain properion levels and nutrient support of nerve cells. The study showed that at least a third of the added GRPs "tookroot"after their injection. With time, almost 90 percent of the GRPs haddifferentiated into astrocytes. Unlike the model rats' own astrocytes,the new ones continued to appear healthy. None of the GRPs damaged the spinal cord or formed tumors--a worry withsome stem cell therapies. Transplanting alternate GRPs--those that the team engineered to lackglutamate transporters--offered none of the protective properties. "Our findings demonstrate that astrocyte replacement, bytransplantation, is both possible and useful," Maragakis explains. "Thistargeted cell delivery to the cervical spinal cord is a promisingstrategy to slow that loss of motor neurons in ALS. We hope at somepoint it will translate to the clinic." Earlier research by U.S. scientists suggests that, while astrocytes godownhill in ALS, they may not be a primary cause of the disease. Theidea is more that they're involved in its progression. Diseasedastrocytes, studies show, may make motor neurons more susceptible todeath by excitotoxicity. Amyotrophic lateral sclerosis (ALS) is a motor neuron disorder thataffects roughly 30,000 people in this country. It's characterized by arapid decline in motor neurons, with death from respiratory failuretypically occurring from two to five years after diagnosis. Most patients have the sporadic form, having no family history of thedisease. As many as 10 percent of ALS patients have the familial form.One in five with familial ALS have a defective gene called SOD1. It'sthat gene that's used to make the classic animal models of the disease. Transgenic mice and rats with mutant human SOD1 genes reflect many,though not all, of the human features of the disease. Principal researchers in this study are all members of the RobertPackard Center for ALS Research at Johns Hopkins, which funded the workalong with grants from the ALS Association and the NIH. The researchteam included Angelo Lepore, Britta Rauck, Christine Dejea, Andrea Pardoand Jeffrey Rothstein, of Johns Hopkins. Mahendra Rao is with theInvitrogen Corp., of Carlsbad, CA. ___________________________________ About The Robert Packard Center for ALS Research at Johns Hopkinswww.alscenter.org Located in Baltimore, the Robert Packard Center for ALS Research atJohns Hopkins is a worldwide collaboration of scientists aimed atdeveloping therapies and a cure for amyotrophic lateral sclerosis (ALS),also known as Lou Gehrig’s disease. The Center is the only institution of its kind dedicated solely to thedisease. Its research is meant to translate rapidly from the lab benchto the clinic, largely by eliminating time spent waiting for grants andlowering institutional barriers to sharing scientific results. Scientists and clinician members of the Packard Center have moved drugsreliably and rapidly from preclinical experiments to human trials.Direct or indirect links to international biotech or pharmaceuticalcompanies bring the infrastructure and experience needed to makepromising drugs into therapies. Packard scientists are the first to propose and test a combinationapproach to drug therapy, a tactic that has worked for AIDS, cancer andother diseases. ALS is a progressive, disabling neuromuscular disease that causescomplete paralysis and loss of function - including the ability to eat,speak and breathe. ALS progresses quickly and is not curable. Mostpatients die within five years of diagnosis. _________________________________________Rebecca BergerResearch Program CoordinatorRobert Packard Center for ALS Research at Johns Hopkins5801 Smith Avenue | McAuley Suite 110Baltimore, MD 21209410.735.7678 direct410.735.7680 faxrberger6@jhmi.edu www.alscenter.org ************************************************** ******************************Click on the link below to unsubscribemailto:sympa@lists.johnshopkins.edu?sub ject=unsubscribe%20alscenter&body=PLEASE%20SEND%20 THIS%20EMAIL%20OUT%20FOR%20UNSUBSCRIBING Please follow the instructions below if the above link does not work: Compose an email to: sympa@lists.johnshopkins.edu With Subject: unsubscribe alscenterNote: 'unsubscribe alscenter' should be on the SUBJECT line, NOT IN THE MESSAGE BODY. To contact the list owner: mailto:alscenter-request@lists.johnshopkins.edu******************** ************************************************** **********