BreakThrough Digest Medical News |
- New gene transfer strategy shows promise for limb girdle and other muscular dystrophies
- HPV vaccine reduces infection, even in unvaccinated
- Cell differentiation as a novel strategy for the treatment of an aggressive type of skin cancer
- Small molecule may play big role in Alzheimer’s disease
- Overweight? There’s a vaccine for that
| New gene transfer strategy shows promise for limb girdle and other muscular dystrophies Posted: 08 Jul 2012 09:00 PM PDT The challenge of treating patients with genetic disorders in which a single mutated gene is simply too large to be replaced using traditional gene therapy techniques may soon be a thing of the past. A Nationwide Children’s Hospital study describes a new gene therapy approach capable of delivering full-length versions of large genes and improving skeletal muscle function. The strategy may hold new hope for treating dysferlinopathies and other muscular dystrophies.
A group of untreatable muscle disorders known as dysferlinopathies are caused by mutations in the dysferlin gene. Patients with these disorders, including limb girdle muscular dystrophy type 2B, are typically diagnosed in their early twenties. Approximately one-third will become wheelchair dependent by their mid-30s. Gene therapy using adeno-associated virus (AAV) to deliver genes to cells has been pursued as an option for some patients with muscular dystrophy. However, AAV’s packaging limitations have served as obstacles in using gene therapy to deliver large genes like dysferlin. Scientists in the past have attempted to work around AAV’s packaging limitations by inserting a small version of large genes into the viral vector to induce gene expression. Some have also used more than one viral vector at a time to deliver a large gene. However, micro and mini versions of large genes don’t always have the power of full-length gene expression and an increased viral load can lead to negative side effects. “We have had success in the clinic using AAV gene therapy with limb girdle muscular dystrophy type 2D, which is caused by mutations in the alpha-sarcoglycan gene,” said Louise Rodino-Klapac, PhD, principal investigator in the Center for Gene Therapy at The Research Institute of Nationwide Children’s Hospital. “However, the dysferlin gene is very large, about six times larger than the alpha-sarcoglycan gene and can’t fit into a traditional AAV vector.” A 2008 study identified AAV5, an AAV serotype that could package large transcripts. “This made us wonder whether it could be used for gene replacement requiring inserts as large as the dysferlin gene,” said Dr. Rodino-Klapac. In their 2012 study appearing in PLoS ONE, Dr. Rodino-Klapac’s team used AAV5 to package a full-length, intact dysferlin gene and directly deliver it to the diaphragm of dysferlin-deficient mice. They also injected the leg muscles of dysferlin-deficient mice using both intramuscular and vascular approaches to further evaluate whether the gene delivery could improve skeletal muscle function. They found that both the intravascular and intramuscular delivery approaches led to full-length, intact dysferlin gene expression in the leg and diaphragm muscle cells of the mice. More importantly, they saw that the newly-restored dysferlin repaired membrane deficits previously seen in the dysferlin-deficient mice. “Our findings demonstrate highly favorable results with full restoration of dysferlin without compromise in function,” said Dr. Rodino-Klapac. “With regard to neuromuscular diseases, these studies provide new perspective for conditions caused by mutations of large genes. Duchenne muscular dystrophy is the most common severe childhood muscular dystrophy and would seem to benefit from expression of the larger transcripts than mini- and micro-dystrophins that only partially restore physiologic function in mouse models of the disease.” Dr. Rodino-Klapac and her team are currently defining a path for a dysferlin clinical gene therapy trial. “We have shown that AAV5-dysferlin delivery is a very promising therapeutic approach that could restore functional deficits in dysferlinopathy patients,” she says. ### Grose WE, Clark KR, Griffin D, Malik V, Shontz KM, Montgomery CL, Lewis S, Brown RH Jr, Janssen PM, Mendell JR, Rodino-Klapac LR. Homologous Recombination Mediates Functional Recovery of Dysferlin Deficiency following AAV5 Gene Transfer. PLoS One. 2012;7(6):e39233. Epub 2012 Jun 15. For more information on the Center for Gene Therapy, visit http://www.nationwidechildrens.org/center-for-gene-therapy Contact: Erin Pope |
| HPV vaccine reduces infection, even in unvaccinated Posted: 08 Jul 2012 09:00 PM PDT The HPV vaccine not only has resulted in a decrease in human papillomavirus infection in immunized teens but also in teens who were not immunized. The study is believed to be the first to show a substantial decrease in HPV infection in a community setting as well as herd protection ? a decrease in infection rates among unimmunized individuals that occurs when a critical mass of people in a community is immunized against a contagious disease.
The Cincinnati Children’s Hospital Medical Center study will be published online July 9 in the eFirst pages of Pediatrics. “Infection with the types of HPV targeted by the vaccine decreased in vaccinated young women by 69 percent,” says Jessica Kahn, MD, MPH, a physician in the division of Adolescent Medicine at Cincinnati Children’s and lead author of the study. “Two of these HPV types, HPV-16 and HPV-18, cause about 70 percent of cervical cancer. Thus, the results are promising in that they suggest that vaccine introduction could substantially reduce rates of cervical cancer in this community in the future.” The first HPV vaccine was licensed for use in the United States in June 2006. The U.S. Advisory Committee on Immunization Practices has recommended vaccination of girls and women between the ages of 11 and 26 to reduce rates of HPV infection, which ultimately can lead to cervical cancer. In 2006 and 2007, Dr. Kahn and colleagues at Cincinnati Children’s recruited 368 young women between the ages of 13 and 16 from two primary care clinics in the city of Cincinnati. The young women had sexual contact but none were vaccinated. In 2009 and 2010, they recruited a different group of 409 young women in the same age range, more than half of whom had received at least one dose of the vaccine. The researchers compared pre- and post-vaccination HPV prevalence rates. The prevalence of vaccine-type HPV decreased 58 percent overall, from 31.7 percent to 13.4 percent. The decrease was high among vaccinated participants (69 percent), but also was substantial for those who were unvaccinated (49 percent). Dr. Kahn says the decrease in vaccine-type HPV among vaccinated participants was “especially remarkable,” given that participants were sexually experienced, many were exposed to vaccination-type HPV before vaccination, and only one dose of the vaccine was required to be considered vaccinated. Dr. Kahn emphasizes that despite the evidence of herd immunity demonstrated in her study, vaccination of all young women between the ages of 11 and 26 is important to maximize the health benefits of vaccination. Although vaccine-type HPV decreased, the overall prevalence of HPV (including types not targeted by the vaccine) in the study was “extremely high,” says Dr. Kahn. “Nearly one in four unvaccinated study participants was already positive for at least one high-risk HPV type.” Most participants in the study were young, black women, many with Medicaid insurance. Given this, and the fact that the study was a relatively small one conducted in a single city, larger studies with more representative samples are needed to definitively determine the public health impact of the HPV vaccine, says Dr. Kahn. ### The study was funded by the National Institutes of Health. Contact: Jim Feuer |
| Cell differentiation as a novel strategy for the treatment of an aggressive type of skin cancer Posted: 08 Jul 2012 09:00 PM PDT
Skin squamous cell carcinoma (SCC) is a subtype of very aggressive skin cancers that usually develops in sunexposed body regions, but can also affect a large number of organs such as the bladder, esophagus, lungs etc. However, little is known about the biology of these cells, which consequently makes difficult the generation of new specific therapies; actually, the standard treatments are based on surgery and subsequent radiotherapy.
Researchers at the Spanish National Cancer Research Centre (CNIO) led by Erwin Wagner, vice-director of Basic Research and director of BBVA Foundation-CNIO Cancer Cell Biology Programme, have discovered a molecular mechanism that favours the disappearance and inhibition of SCC development. The authors propose that these mechanisms could be crucial for the development of targeted therapies that could potentially overcome drug resistance. The study, which also involves the participation of medical researchers at the Medical University of Vienna, Austria, is published today on the online edition of The Journal of Clinical Investigation. “The guardian of the genome” p53, decreases cell division in favour of cell differentiation Using in vitro models, mouse genetic models and human tumors, researchers have uncovered the molecular signals by which the p53 protein, also called “the guardian of the genome”, prevents the formation of skin SCC tumors. “We demonstrate for the first time that p53 promotes differentiation [cell functional specialization] of keratinocytes [the most predominant cell type in the epidermis], thus avoiding their division and providing a protective effect against tumors”, states Juan Guinea Viniegra, “Ramón y Cajal” investigator at the CNIO and first author of the work. The alteration of these pathways decreases cell differentiation and hence produces an increase in cell division. “We found that samples from patients with skin SCC show reduced activity of proteins that promote cell differentiation and an overactivation of inhibitory signals,” says Guinea. An additional contribution of this work is the use of compounds that induce cell differentiation at the expense of cancer cell division. “The next step is to test these molecules in mouse models of skin cancer and assess whether they impair cell division and tumor development”, reveals the author. Treatment of tumors based on differentiation therapies is a new avenue in the development of innovative cancer treatments. These therapies, unlike conventional ones, seek to transform cancer cells into differentiated cells, which remain in the body with few possibilities to divide and likely avoiding the appearance of drug resistance. ### Reference article:
Differentiation-induced skin cancer suppression by FOS, p53, and TACE/ADAM17. Juan Guinea-Viniegra, Rainer Zenz, Harald Scheuch, María Jiménez, Latifa Bakiri, Peter Petzelbauer, Erwin F. Wagner. The Journal of Clinical Investigation (2012). DOI: :10.1172/JCI63103 Contact: Nuria Noriega |
| Small molecule may play big role in Alzheimer’s disease Posted: 08 Jul 2012 09:00 PM PDT
Alzheimer’s disease is one of the most dreaded and debilitating illnesses one can develop. Currently, the disease afflicts 6.5 million Americans and the Alzheimer’s Association projects it to increase to between 11 and 16 million, or 1 in 85 people, by 2050.
Cell death in the brain causes one to grow forgetful, confused and, eventually, catatonic. Recently approved drugs provide mild relief for symptoms but there is no consensus on the underlying mechanism of the disease. “We don’t know what the problem is in terms of toxicity,” said Joan-Emma Shea, professor of chemistry and biochemistry at the University of California, Santa Barbara (UCSB). “This makes the disease difficult to cure.” Accumulations of amyloid plaques have long been associated with the disease and were presumed to be its cause. These long knotty fibrils, formed from misfolded protein fragments, are almost always found in the brains of diseased patients. Because of their ubiquity, amyloid fibrils were considered a potential source of the toxicity that causes cell death in the brain. However, the quantity of fibrils does not correspond with the degree of dementia and other symptoms. New findings support a hypothesis that fibrils are a by-product of the disease rather than the toxic agent itself. This paradigm shift changes the focus of inquiry to smaller, intermediate molecules that form and dissipate quickly. These molecules are difficult to perceive in brain tissue. Shea’s group uses computer simulations to understand the formation of toxic entities in the brain. Since 2007, Shea has run thousands of simulations of amyloid peptides using the Ranger supercomputer at the Texas Advanced Computing Center (TACC) to better understand the structure, formation and behavior of amyloid accumulations. “We can identify the important structures or conformations that are adopted by these peptides at a resolution that exceeds what can be done experimentally,” she explained. “This helps us understand what structures lead to a self-assembly.” For decades, it was believed that fibrils were a toxic species, but increasingly researchers are looking at small, soluble precursor forms of the fibrils, known as oligomers. “These are difficult to detect experimentally because they tend to be transient species,” Shea said “There’s no consensus on how big they are. There are still a lot of debates.” Shea and Michael Bowers, professor of chemistry and biochemistry at UCSB and Shea’s experimental collaborator, believe the transient oligomers may be responsible for the onset of the disease through interactions with the cell membrane. “These oligomers may be toxic by inserting themselves into membranes and causing a damage to the membrane,” she said. “The membrane is critical for the cell viability.” In 2007, Shea and Bowers received a grant from the National Institutes of Health to investigate this theory. Together, they have spent the last five years looking at small peptide-based inhibitors that would prevent these oligomers from forming. “If you can prevent the oligomers from forming, you can limit toxicity,” Shea said. In a recent paper currently in press in Biophysical Journal, Shea and postdoctoral researcher Luca Larini studied the conformations adopted by small oligomers of peptide amyloids encountered within the cell. They found that hairpin-shaped forms of the peptide initiated the aggregation of oligomers that ultimately led to the formation of a fibril. Like an old slapstick routine where one person trips, another trips over them, and eventually a pile forms, the misfolded proteins in the brain cells of those with Alzheimer’s recruit other misfolded proteins and eventually grow into a large mass. Shea’s simulations have not only helped uncover the possible role of oligomers in the onset of Alzheimer’s, but they are aiding in research that is trying to stop oligomer formation in the first place. A paper in the November 2011 edition of Biochemistry, co-authored with the Bowers group, described how a class of small molecules known as c-terminal inhibitors was able to stop the formation of oligomers, possibly halting disease progression before it is too late. “Dr. Shea’s simulations put a molecular face on the cross sections and oligomer distributions that we experimentally measure,” said Bowers. ” Of significant importance is the simulation of the ABeta42 monomer structure that very nicely correlated with our experiments. Also of importance are calculations on the sites and mechanism of attachment of potential therapeutic agents that we are testing as ABeta aggregation inhibitors.” Simulations on Ranger helped researchers identify where the inhibitors bind and led to new ideas about how inhibition can be improved. “Dr. Shea is clearly at the top of the large cohort of simulators in her age group,” Bowers said. Through a related investigation, Shea and postdoctoral researcher Chun Wu solved the long-standing mystery of why Thioflavin T, a dye commonly used in brain imaging, is able to bind to amyloid proteins. Her molecular dynamics simulations identified the specific hydrophobic motif in the peptide to which the dye binds. This pinpoint conclusion now allows chemists and neurological experimentalists to create designer forms of the dye that can be used to improve their diagnostic ability. These results were reported in the Biophysical Journal in March 2011. “Now that we’ve established where these molecules bind, we can start tweaking the molecule to try to make binders that have a greater affinity for the fibril. That could be something that would be beneficial for medicine as a better imaging agent,” she said. Shea’s simulations of peptide interactions, dyes binding to fibrils, and inhibitors stopping the accumulation of amyloids provide great insights to scientists. The projects required more than 13 million hours of compute time on TACC’s Ranger and Lonestar supercomputers since 2009. “The number of atoms is huge?we need a lot of computational resources to simulate them,” Shea said. “Nothing that we’re doing here is something that we could do on our home clusters. The scale of it is intractable.” Ranger is one of the top 50 most powerful supercomputers in the world, Funded by the National Science Foundation and deployed in 2008, Ranger helps scientists around the country make discoveries by offering free compute time to academic researchers. The system is part of the Extreme Science and Engineering Discovery Environment (XSEDE), the NSF-funded effort to provide cyberinfrastructure and computing power to the nation’s scientists. In February, Ranger will be decommissioned to make way for Stampede, a new supercomputer 20 times more powerful. Such a system will be required to answer further important questions about Alzheimer’s disease. “With growing computational resources and capabilities, we’ll be able to look at how these proteins interact with membranes,” Shea said. “We’re far away from simulating a whole cell, but we can start incorporating additional elements that may turn out to be important.” Contact: Faith Singer-Villalobos |
| Overweight? There’s a vaccine for that Posted: 07 Jul 2012 09:00 PM PDT
New vaccines promote weight loss. A new study, published in BioMed Central’s open access journal, Journal of Animal Science and Biotechnology, assesses the effectiveness of two somatostatin vaccinations, JH17 and JH18, in reducing weight gain and increasing weight loss in mice.
Obesity and obesity-related disease is a growing health issue worldwide. Somatostatin, a peptide hormone, inhibits the action of growth hormone (GH) and insulin-like growth factor (IGF-1), both of which increase metabolism and result in weight loss. Vaccination with modified somatostatin causes the body to generate antibodies to somatostatin, effectively removing this inhibition without directly interfering with the growth hormones and subsequently increasing energy expenditure and weight loss. Keith Haffer from Braasch Biotech LLC, tested the vaccinations in two groups of ten diet-induced obese male mice compared with a control group of ten mice which received saline injections. Mice in all groups had been fed a high fat diet for eight weeks prior to the study and continued to eat the same food for the duration of the six-week study. The vaccinations were administered twice – at the start of the study followed by a booster vaccination on day 22. Four days after the first injection of modified somatostatin, the vaccinated mice had a 10% drop in body weight (not seen in the control mice). At the end of the study, results showed that both vaccines induced antibodies to somatostatin and significantly reduced body weight, sustaining a 10% lower body weight, without affecting normal levels of the growth hormone IGF-1, or insulin levels. “This study demonstrates the possibility of treating obesity with vaccination”, Keith explained. He continued, “Although further studies are necessary to discover the long term implications of these vaccines, treatment of human obesity with vaccination would provide physicians with a drug- and surgical- free option against the weight epidemic.” ### Notes to editors
1. Effects of Novel Vaccines on Weight Loss in Diet-Induced-Obese (DIO) Mice Please name the journal in any story you write. If you are writing for the web, please link to the article. All articles are available free of charge, according to BioMed Central’s open access policy. Article citation and URL available on request on the day of publication. 2. Journal of Animal Science and Biotechnology is an open access, peer-reviewed journal that encompasses all aspects of animal science and biotechnology. That includes domestic animal production, animal genetics and breeding, animal reproduction and physiology, animal nutrition and biochemistry, feed processing technology and bioevaluation, animal biotechnology, and meat science. 3. BioMed Central is an STM (Science, Technology and Medicine) publisher which has pioneered the open access publishing model. All peer-reviewed research articles published by BioMed Central are made immediately and freely accessible online, and are licensed to allow redistribution and reuse. BioMed Central is part of Springer Science+Business Media, a leading global publisher in the STM sector. Contact: Hilary Glover |
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