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Ready or Not: Stem Cell Therapies Poised to Enter Trials for Alzheimer. All the same, they have been slow to make real inroads in the understanding and treatment of Alzheimer’s disease. That is about to change, according to scientists who spoke at “Accelerating the Cure for Alzheimer’s Disease through Regenerative Medicine.” Held November 6 at Duke University, Durham, North Carolina, the symposium was co- chaired by Murali Doraiswamy and Joanne Kurtzberg. Kurtzberg is a pediatrician and cell therapy expert at Duke. The first clinical trials of stem cells for AD are expected to begin in 2. Some cautioned that many questions remain about how stem cells affect the Alzheimer’s brain. Graduate Programs in which CRB Faculty Participate. Training Program (PGTP) Stem Cell and Regenerative. Wisconsin Stem Cell & Regenerative Medicine. Accelerating the Cure for Alzheimer's Disease through Regenerative Medicine. Stem Cell Laboratory at Duke Medicine. UC San Diego Stem Cell Program and. They debated whether the move into the clinic is premature, noting the need for more research into where in the brain stem cells go and how long they last. On this, attendees were intrigued by some success tracking injected cells with MRI. In addition to therapeutic applications, induced stem cells made from patients with AD and related disorders are helping shed light on disease mechanisms and enabling screens for potentially therapeutic compounds. Research on stem cells remains limited, however, in part because it is largely supported by state initiatives, such as the California Institute for Regenerative Medicine, and private foundations, such as the New York Stem Cell Foundation. Can Stem Cells Treat Alzheimer’s? Therapies based on stem cells have had some success in other diseases. Transplants of cord blood, for example, are approved by the Food and Drug Administration to treat leukemia and inborn errors of metabolism, Kurtzberg said in a talk in which she described treatments pioneered by the Duke Stem Cell and Regenerative Medicine Program. Molecular Medicine (MolMed) - Regenerative Medicine. The program is directed at. Clinicians irradiate the patient’s bone marrow before administering cord blood, then stem cells in the donated blood engraft and replace unhealthy cells. In the last 2. 5 years, more than 3. Kurtzberg noted. In Alzheimer’s disease, however, neurons die off in massive numbers throughout the brain, making cell replacement impractical. This has caused many researchers to overlook stem cell therapy as an option for AD, Mahendra Rao said in his keynote address. Rao leads regenerative medicine at the New York Stem Cell Foundation Research Institute, New York City. Nonetheless, stem cells have demonstrated the ability to improve cognition in animal models.
Rather than replacing neurons, they may benefit the brain in other ways, such as by modulating inflammation, stimulating remyelination, and supplying trophic support. Would injected cells succumb to the surrounding disease, as has been found to happen with fetal neuron grafts in Parkinson’s patients (see Apr 2. Jun 2. 01. 4 news story)? Quite the opposite, Rao believes. Injected stem cells, which often mature into glia, may help modify the brain environment, thus lowering its toxicity. One example of how stem cells can promote neuron health came some time ago from Frank La. Ferla of the University of California, Irvine. La. Ferla injected mouse neural stem cells into the brains of animals that modeled hippocampal sclerosis and Alzheimer’s disease. Treated mice improved cognitively but, in synch with what Rao said, injected cells neither became neurons nor lowered A. Instead, they promoted formation of synapses in the CA1 region of the hippocampus, an effect La. Ferla traced to stem cells releasing brain- derived neurotrophic factor (BDNF). Knocking down this growth factor in the cells before injecting them abrogated the treatment benefit (see Jul 2. Could stem cells slow disease progression? When La. Ferla modified neural stem cells to express the A. It is not clear if this step improves cognition further, La. Ferla said in answer to an audience question. Stem cells may also replace sick glia. Kurtzberg described the use of cord blood stem cells to treat Krabbe’s disease in children. This genetic disorder is caused by the lack of the enzyme galactosylceramidase, which helps maintain the myelin wrapped around axons. Babies born with this condition develop muscle weakness and seizures, and most die before they are 2 years old. However, those who receive cord blood transplants around one month of age, before symptoms appear, survive and generally thrive, with only mild development delays, Kurtzberg said (see Escolar et al., 2. Most of the stem cells that engraft in the brains of these children become glia. Studying engrafted cells in postmortem samples, Kurtzberg’s group found that they shared properties of microglia and oligodendrocytes. In mouse models, these cells secrete soluble anti- inflammatory factors, stimulate neurogenesis, and promote remyelination. The researchers are now generating these cells in vitro and are about to begin a Phase 1 trial to test whether delivering them into cerebrospinal fluid, in addition to the standard cord blood transplant, is safe in children with Krabbe’s disease. The differentiated cells should engraft more quickly than do stem cells, which take months to provide the full benefit, and thus may improve outcomes, Kurtzberg noted. Cleanup Crew? Researchers led by Alexei Lukashev of the biotech company Stemedica International, Epalinges, Switzerland, presented a poster on the use of human adult mesenchymal stem cells to combat Alzheimer’s disease. First author Tristan Bolmont injected the cells into the bloodstream of 1. APP/PS1 mice once per week for 1. The amyloid load in the hippocampus of treated mice dropped by one- third compared with untreated controls. Meanwhile, more microglia clustered around plaques, while the number of pro- inflammatory microglia shrank, suggesting that the stem cells somehow influence this balance. In ongoing work, the authors are characterizing this, as well as testing behavior in treated mice. The cells appeared safe, with no increase in vascular amyloid or microhemorrhage. Human mesenchymal stem cells are currently in a Phase 1/2 clinical trial for stroke. Lukashev said he is applying for FDA approval for a Phase 2 Alzheimer’s study to start next year. Similar approaches by other groups are in trials for multiple sclerosis and amyotrophic lateral sclerosis (ALS) (see Oct 2. Other stem cell- based Alzheimer’s treatments are also on the threshold of the clinic. Ellen Feigal, who leads research and development at the California Institute for Regenerative Medicine (CIRM), noted that her organization has given out 1. Alzheimer’s projects; three of those are now applying for FDA approval for trials. Two academic studies identified small neuroprotective molecules through screens of stem cells; the third, led by Alexandra Capela at the biotech company Stem. Cells Inc., Newark, California, proposes to transplant neural stem cells into AD patients (see CIRM award). Conference attendees disagree whether the technology is ready for human study. Also, researchers do not yet know how many cells to deliver, where, and how often in order to optimize the response, he said. Bolmont conceded that questions remain, but said he felt many of them can be answered only by trials. Feigal urged that trials and research run in parallel. Clinical trials can inform research. It is a two- way street,” she said. Thomas Finn from the FDA spelled out potential safety concerns for which his agency will watch. They include whether intravenous injections of stem cells might block capillaries, causing embolisms and damaging brain tissue. Another question is whether stem cells might give rise to tumors, or make the wrong kind of cells or connections in the brain, leading to side effects like chronic pain. Where Did the Injection Go? In his talk, Jeff Bulte, a radiologist at Johns Hopkins University, Baltimore, discussed ways to label stem cells with contrast agents so that MRI can tracked them (see Ahrens and Bulte, 2. One such agent, superparamagnetic iron oxide (SPIO), is sensitive and appears safe, having been used in several clinical trials. In a human case study, SPIO maintained a signal for more than four months (see Janowski et al., 2. However, this compound has been pulled from the market for economic reasons, Bulte told Alzforum. Probes containing the stable isotope fluorine- 1. F) emit a bright signal but are less sensitive than SPIO (see Ruiz- Cabello et al., 2. Bulte’s own company, Sen. CEST LLC, Fulton, Maryland, develops chemical exchange saturation transfer (CEST) agents. Instead of using metal, the exchange of a proton between the agent and surrounding water creates the signal. All three approaches demonstrate potential for human use at this time, Bulte said. With all these labels, however, the signal fades over time. Bulte is experimenting with reporter genes that could give long- term information on injected cells, with the added advantage of turning off when cells die. As an example, he said that stem cells can be engineered to express a thymidine kinase from herpes simplex virus, which is then detected by a thymidine analogue probe using CEST (see Bar- Shir et al., 2. Bar- Shir et al., 2. Bulte also found that stem cells can be targeted to areas of inflammation by making them express the docking protein VLA- 4 on their cell surface. This molecule binds to VCAM- 1, which is expressed by inflamed endothelial cells. This way, stem cells penetrate into the brain three- to fourfold better, Bulte claimed (see Gorelik et al., 2. Such tracking technologies provide a glimpse into the life of injected cells. Using MRI labels, Bulte found that stem cells injected into carotid arteries fanned out across the brain more broadly than cells injected into the brain’s ventricles or parenchyma (see image above). In an animal study, injection of large cells by this route did not disrupt the integrity of blood vessels in the brain, Bulte said. Modeling Disease: What if Craig Had an Alzheimer Mutation? Short of treating disease, researchers hope that stem cells will at least model human disease more faithfully than do animals or cell lines. Free Books. Name: FATE REASON GERMAN PHILOSOPHY FICHTEFile Size: 5. Mb with total 5. 58 Pages. File Types: PDF Document. MD5: 4. 68. 4cddc. German Philosophy from Kant to Fichte. 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