Gene Therapy Boosts Brain Repair for Demyelinating Diseases

Our bodies are full of tiny superheroes -- antibodies that fight foreign invaders, cells that regenerate, and structures that ensure our systems run smoothly. One such structure is myelin -- a material that forms a protective, insulating cape around the axons of our nerve cells so that they can send signals quickly and efficiently. But myelin, and the specialized cells called oligodendrocytes that make it, become damaged in demyelinating diseases like multiple sclerosis (MS), leaving neurons without their myelin sheaths. As a consequence, the affected neurons can no longer communicate correctly and are prone to damage. Researchers from the California Institute of Technology (Caltech) now believe they have found a way to help the brain replace damaged oligodendrocytes and myelin. The therapy, which has been successful in promoting remyelination in a mouse model of MS, is outlined in a paper published February 8 in The Journal of Neuroscience. "We've developed a gene therapy to stimulate production of new oligodendrocytes from stem and progenitor cells -- both of which can become more specialized cell types -- that are resident in the adult central nervous system," says Benjamin Deverman, a postdoctoral fellow in biology at Caltech and lead author of the paper. "In other words, we're using the brain's own progenitor cells as a way to boost repair." The therapy uses leukemia inhibitory factor (LIF), a naturally occurring protein that was known to promote the self-renewal of neural stem cells and to reduce immune-cell attacks to myelin in other MS mouse models. "What hadn't been done before our study was to use gene therapy in the brain to stimulate these cells to remyelinate," says Paul Patterson, the Biaggini Professor of Biological Sciences at Caltech and senior author of the study. According to the researchers, LIF enables remyelination by stimulating oligodendrocyte progenitor cells to proliferate and make new oligodendrocytes. The brain has the capacity to produce oligodendrocytes, but often fails to prompt a high enough repair response after demyelination. "Researchers had been skeptical that a single factor could lead to remyelination of damaged cells," says Deverman. "It was thought that you could use factors to stimulate the division and expansion of the progenitor population, and then add additional factors to direct those progenitors to turn into the mature myelin-forming cells. But in our mouse model, when we give our LIF therapy, it both stimulates the proliferation of the progenitor cells and allows them to differentiate into mature oligodendrocytes." In other words, once the researchers stimulated the proliferation of the progenitor cells, it appeared that the progenitors knew just what was needed -- the team did not have to instruct the cells at each stage of development. And they found that LIF elicited such a strong response that the treated brain's levels of myelin-producing oligodendrocytes were restored to those found in healthy populations. The researchers note, too, that by placing LIF directly in the brain, one avoids potential side effects of the treatment that may arise when the therapy is infused into the bloodstream. "This new application of LIF is an avenue of therapy that has not been explored in human patients with MS," says Deverman, who points out that LIF's benefits might also be good for spinal-cord injury patients since the demyelination of spared neurons may contribute to disability in that disorder. To move the research closer to human clinical trials, the team will work to build better viral vectors for the delivery of LIF. "The way this gene therapy works is to use a virus that can deliver the genetic material -- LIF -- into cells," explains Patterson. "This kind of delivery has been used before in humans, but the worry is that you can't control the virus. You can't necessarily target the right place, and you can't control how much of the protein is being made." Which is why he and Deverman are developing viruses that can target LIF production to specific cell types and can turn it on and off externally, providing a means to regulate LIF levels. They also plan to test the therapy in additional MS mouse models. "For MS, the current therapies all work by modulating or suppressing the immune system, because it's thought to be a disease in which inflammation leads to immune-associated loss of oligodendrocytes and damage to the neurons," says Deverman. "Those therapies can reduce the relapse rate in patients, but they haven't shown much of an effect on the long-term progression of the disease. What are needed are therapies that promote repair. We hope this may one day be such a therapy." The work done in this study, "Exogenous Leukemia Inhibitory Factor Stimulates Oligodendrocyte Progenitor Cell Proliferation and Enhances Hippocampal Remyelination," was funded by the California Institute for Regenerative Medicine, the National Institutes of Neurological Disorders and Stroke, and the McGrath Foundation.

Targeting HIV's Sugar Coating: New Microbicide May Block AIDS Virus from Infecting Cells

University of Utah researchers have discovered a new class of compounds that stick to the sugary coating of the AIDS virus and inhibit it from infecting cells -- an early step toward a new treatment to prevent sexual transmission of the virus. Development and laboratory testing of the potential new microbicide to prevent human immunodeficiency virus infection is outlined in a study set for online publication in the journal Molecular Pharmaceutics. Despite years of research, there is only one effective microbicide to prevent sexual transmission of HIV, which causes AIDS, or acquired immune deficiency syndrome. Microbicide development has focused on gels and other treatments that would be applied vaginally by women, particularly in Africa and other developing regions. To establish infection, HIV must first enter the cells of a host organism and then take control of the cells' replication machinery to make copies of itself. Those HIV copies in turn infect other cells. These two steps of the HIV life cycle, known as viral entry and viral replication, each provide a potential target for anti-AIDS medicines. "Most of the anti-HIV drugs in clinical trials target the machinery involved in viral replication," says the study's senior author, Patrick F. Kiser, associate professor of bioengineering and adjunct associate professor of pharmaceutics and pharmaceutical chemistry at the University of Utah. "There is a gap in the HIV treatment pipeline for cost-effective and mass-producible viral entry inhibitors that can inactivate the virus before it has a chance to interact with target cells," he says. Kiser conducted the study with Alamelu Mahalingham, a University of Utah graduate student in pharmaceutics and pharmaceutical chemistry; Anthony Geonnotti of Duke University Medical Center in Durham, N.C.; and Jan Balzarini of Catholic University of Leuven in Belgium. The research was funded by the National Institutes of Health, the Bill and Melinda Gates Foundation, the Catholic University of Leuven, Belgium, and the Fund for Scientific Research, also in Belgium. Synthetic Lectins Inhibit HIV from Entering Cells Lectins are a group of molecules found throughout nature that interact and bind with specific sugars. HIV is coated with sugars that help to hide it from the immune system. Previous research has shown that lectins derived from plants and bacteria inhibit the entry of HIV into cells by binding to sugars found on the envelope coating the virus. However, the cost of producing and purifying natural lectins is prohibitively high. So Kiser and his colleagues developed and evaluated the anti-HIV activity of synthetic lectins based on a compound called benzoboroxole, or BzB, which sticks to sugars found on the HIV envelope. Kiser and his colleagues found that these BzB-based lectins were capable of binding to sugar residues on HIV, but the bond was too weak to be useful. To improve binding, they developed polymers of the synthetic lectins. The polymers are larger molecules made up of repeating subunits, which contained multiple BzB binding sites. The researchers discovered that increasing the number and density of BzB binding sites on the synthetic lectins made the substances better able to bind to the AIDS virus and thus have increased antiviral activity. "The polymers we made are so active against HIV that dissolving about one sugar cube's weight of the benzoboroxole polymer in a bath tub of water would be enough to inhibit HIV infection in cells," says Kiser. Depending on the strain, HIV displays significant variations in its viral envelope, so it is important to evaluate the efficacy of any potential new treatment against many different HIV strains. Kiser and his colleagues found that their synthetic lectins not only showed similar activity across a broad spectrum of HIV strains, but also were specific to HIV and didn't affect other viruses with envelopes. The scientists also tested the anti-HIV activity of the synthetic lectins in the presence of fructose, a sugar present in semen, which could potentially compromise the activity of lectin-based drugs because it presents an alternative binding site. However, the researchers found that the antiviral activity of the synthetic lectins was fully preserved in the presence of fructose. "The characteristics of an ideal anti-HIV microbicide include potency, broad-spectrum activity, selective inhibition, mass producibility and biocompatibility," says Kiser. "These benzoboroxole-based synthetic lectins seem to meet all of those criteria and present an affordable and scalable potential intervention for preventing sexual transmission in regions where HIV is pandemic." Kiser says future research will focus on evaluating the ability of synthetic lectins to prevent HIV transmission in tissues taken from the human body, with later testing in primates. Kiser and his colleagues are also developing a gel form of the polymers, which could be used as a topical treatment for preventing sexual HIV transmission.

New Sensor Glove May Help Stroke Patients Recover Mobility

A new sensor glove may help stroke patients recover hand mobility by playing video games. 

People who have strokes are often left with moderate to severe physical impairments. Now, thanks to a glove developed at McGill, stroke patients may be able to recover hand motion by playing video games. The Biomedical Sensor Glove was developed by four final-year McGill Mechanical Engineering undergrads under the supervision of Professor Rosaire Mongrain.

It is designed to allow patients to exercise in their own homes with minimal supervision, while at the same time permitting doctors to monitor their progress from a distance, thus cutting down on hospital visits and costs.
Patients can monitor their progress thanks to software, which will generate 3D models and display them on the screen, while at the same time sending the information to the treating physician.
The glove was developed by the students in response to a design request from the startup company Jintronix Inc. The students met with company representatives once a week for several months to develop the glove, which can track the movements of the wrist, the palm and the index finger using several Inertial Measurement Units. Although similar gloves currently exist, they costs approximately $30,000. By using more accurate and less expensive sensors, the students were able to develop a glove that currently costs $1000 to produce.
Jintronix, Inc. has submitted the project to Grand Challenges Canada, which is an independent not-for-profit organization dedicated to improving the health and well-being of people in developing countries, in the hopes that they will receive funding for further development.