BreakThrough Digest Medical News |
- First pre-clinical gene therapy study to reverse Rett symptoms
- UCLA study suggests iron is at core of Alzheimer’s disease
- Ingredient in turmeric spice when combined with anti-nausea drug kills cancer cells
| First pre-clinical gene therapy study to reverse Rett symptoms Posted: 19 Aug 2013 09:00 PM PDT The concept behind gene therapy is simple: deliver a healthy gene to compensate for one that is mutated. New research published today in the Journal of Neuroscience suggests this approach may eventually be a feasible option to treat Rett Syndrome, the most disabling of the autism spectrum disorders. Gail Mandel, Ph.D., a Howard Hughes Investigator at Oregon Health and Sciences University, led the study. The Rett Syndrome Research Trust, with generous support from the Rett Syndrome Research Trust UK and Rett Syndrome Research & Treatment Foundation, funded this work through the MECP2 Consortium.
In 2007, co-author Adrian Bird, Ph.D., at the University of Edinburgh astonished the scientific community with proof-of-concept that Rett is curable, by reversing symptoms in adult mice. His unexpected results catalyzed labs around the world to pursue a multitude of strategies to extend the pre-clinical findings to people. Today’s study is the first to show reversal of symptoms in fully symptomatic mice using techniques of gene therapy that have potential for clinical application. Rett Syndrome is an X-linked neurological disorder primarily affecting girls; in the US, about 1 in 10,000 children a year are born with Rett. In most cases symptoms begin to manifest between 6 and 18 months of age, as developmental milestones are missed or lost. The regression that follows is characterized by loss of speech, mobility, and functional hand use, which is often replaced by Rett’s signature gesture: hand-wringing, sometimes so intense that it is a constant during every waking hour. Other symptoms include seizures, tremors, orthopedic and digestive problems, disordered breathing and other autonomic impairments, sensory issues and anxiety. Most children live into adulthood and require round-the-clock care. The cause of Rett Syndrome’s terrible constellation of symptoms lies in mutations of an X-linked gene called MECP2 (methyl CpG-binding protein). MECP2 is a master gene that regulates the activity of many other genes, switching them on or off. “Gene therapy is well suited for this disorder,” Dr. Mandel explains. “Because MECP2 binds to DNA throughout the genome, there is no single gene currently that we can point to and target with a drug. Therefore the best chance of having a major impact on the disorder is to correct the underlying defect in as many cells throughout the body as possible. Gene therapy allows us to do that.” Healthy genes can be delivered into cells aboard a virus, which acts as a Trojan horse. Many different types of these Trojan horses exist. Dr. Mandel used adeno-associated virus serotype 9 (AAV9), which has the unusual and attractive ability to cross the blood-brain barrier. This allows the virus and its cargo to be administered intravenously, instead of employing more invasive direct brain delivery systems that require drilling burr holes into the skull. Because the virus has limited cargo space, it cannot carry the entire MECP2 gene. Co-author Brian Kaspar of Nationwide Children’s Hospital collaborated with the Mandel lab to package only the gene’s most critical segments. After being injected into the Rett mice, the virus made its way to cells throughout the body and brain, distributing the modified gene, which then started to produce the MeCP2 protein. As in human females with Rett Syndrome, only approximately 50% of the mouse cells have a healthy copy of MECP2. After the gene therapy treatment 65% of cells now had a functioning MECP2 gene. The treated mice showed profound improvements in motor function, tremors, seizures and hind limb clasping. At the cellular level the smaller body size of neurons seen in mutant cells was restored to normal. Biochemical experiments proved that the gene had found its way into the nuclei of cells and was functioning as expected, binding to DNA. One Rett symptom that was not ameliorated was abnormal respiration. Researchers hypothesize that correcting this may require targeting a greater number of cells than the 15% that had been achieved in the brainstem. “We learned a critical and encouraging point with these experiments ? that we don’t have to correct every cell in order to reverse symptoms. Going from 50% to 65% of the cells having a functioning gene resulted in significant improvements,” said co-author Saurabh Garg. One of the potential challenges of gene therapy in Rett is the possibility of delivering multiple copies of the gene to a cell. We know from the MECP2 Duplication Syndrome that too much of this protein is detrimental. “Our results show that after gene therapy treatment the correct amount of MeCP2 protein was being expressed. At least in our hands, with these methods, overexpression of MeCP2 was not an issue,” said co-author Daniel Lioy. Dr. Mandel cautioned that key steps remain before clinical trials can begin. “Our study is an important first step in highlighting the potential for AAV9 to treating the neurological symptoms in Rett. We are now working on improving the packaging of MeCP2 in the virus to see if we can target a larger percentage of cells and therefore improve symptoms even further,” said Mandel. Collaborators Hélène Cheval and Adrian Bird see this as a promising follow up to the 2007 work showing symptom reversal in Rett mice. “That study used genetic tricks that could not be directly applicable to humans, but the AAV9 vector used here could in principle deliver a gene therapeutically. This is an important step forward, but there is a way to go yet.” “Gene therapy has had a tumultuous road in the past few decades but is undergoing a renaissance due to recent technological advances. Europe and Asia have gene therapy treatments already in the clinic and it’s likely that the US will follow suit. Our goal now is to prioritize the next key experiments and facilitate their execution as quickly as possible. Gene therapy, especially to the brain, is a tricky undertaking but I’m cautiously optimistic that with the right team we can lay out a plan for clinical development. I congratulate the Mandel and Bird labs on today’s publication, which is the third to be generated from the MECP2 Consortium in a short period of time,” said Monica Coenraads, Executive Director of the Rett Syndrome Research Trust and mother of a teenaged daughter with the disorder. ### Publication Title:
Systemic delivery of MeCP2 rescues behavioral and cellular deficits in female mouse models of Rett syndrome. About the Rett Syndrome Research Trust
The Rett Syndrome Research Trust is a non-profit exclusively devoted to global research on Rett Syndrome and related MECP2 disorders. Our goal is to heal children and adults who will otherwise suffer the effects of these disorders for the rest of their lives. To learn more about the Trust, please visit http://www.ReverseRett.org Our partners in supporting this work are parents’ organizations worldwide including RSRT UK, Rett Syndrome Research & Treatment Foundation (Israel), Stichting Rett Syndrome (Holland), Rett Syndrom Deutschland e.V., Skye Wellesley Foundation (UK) and American organizations, The Kate Foundation for Rett Syndrome Research, Girl Power 2 Cure, Eva Fini Fund at RSRT, Rocky Mountain Rett Association and the New Jersey Rett Syndrome Association. About the MECP2 Consortium
The MECP2 Consortium, launched by the Rett Syndrome Research Trust in 2011 with a $1 million lead gift by Trustee Tony Schoener and his wife Kathy, fosters novel alliances among leading scientists to interrogate the molecules at the root of Rett Syndrome. Consortium members include Adrian Bird of the University of Edinburgh, Michael Greenberg of Harvard University and Gail Mandel of Oregon Health and Sciences University. Contact: Monica Coenraads |
| UCLA study suggests iron is at core of Alzheimer’s disease Posted: 19 Aug 2013 09:00 PM PDT Alzheimer’s disease has proven to be a difficult enemy to defeat. After all, aging is the No. 1 risk factor for the disorder, and there’s no stopping that. Most researchers believe the disease is caused by one of two proteins, one called tau, the other beta-amyloid. As we age, most scientists say, these proteins either disrupt signaling between neurons or simply kill them.
Now, a new UCLA study suggests a third possible cause: iron accumulation. Dr. George Bartzokis, a professor of psychiatry at the Semel Institute for Neuroscience and Human Behavior at UCLA and senior author of the study, and his colleagues looked at two areas of the brain in patients with Alzheimer’s. They compared the hippocampus, which is known to be damaged early in the disease, and the thalamus, an area that is generally not affected until the late stages. Using sophisticated brain-imaging techniques, they found that iron is increased in the hippocampus and is associated with tissue damage in that area. But increased iron was not found in the thalamus. The research appears in the August edition of the Journal of Alzheimer’s Disease. While most Alzheimer’s researchers focus on the buildup of tau or beta-amyloid that results in the signature plaques associated with the disease, Bartzokis has long argued that the breakdown begins much further “upstream.” The destruction of myelin, the fatty tissue that coats nerve fibers in the brain, he says, disrupts communication between neurons and promotes the buildup of the plaques. These amyloid plaques in turn destroy more and more myelin, disrupting brain signaling and leading to cell death and the classic clinical signs of Alzheimer’s. Myelin is produced by cells called oligodendrocytes. These cells, along with myelin, have the highest levels of iron of any cells in the brain, Bartzokis says, and circumstantial evidence has long supported the possibility that brain iron levels might be a risk factor for age-related diseases like Alzheimer’s. Although iron is essential for cell function, too much of it can promote oxidative damage, to which the brain is especially vulnerable. In the current study, Bartzokis and his colleagues tested their hypothesis that elevated tissue iron caused the tissue breakdown associated with Alzheimer’s disease. They targeted the vulnerable hippocampus, a key area of the brain involved in the formation of memories, and compared it to the thalamus, which is relatively spared by Alzheimer’s until the very late stages of disease. The researchers used an MRI technique that can measure the amount of brain iron in ferritin, a protein that stores iron, in 31 patients with Alzheimer’s and 68 healthy control subjects. In the presence of diseases like Alzheimer’s, as the structure of cells breaks down, the amount of water increases in the brain, which can mask the detection of iron, according to Bartzokis. “It is difficult to measure iron in tissue when the tissue is already damaged,” he said. “But the MRI technology we used in this study allowed us to determine that the increase in iron is occurring together with the tissue damage. We found that the amount of iron is increased in the hippocampus and is associated with tissue damage in patients with Alzheimer’s but not in the healthy older individuals ? or in the thalamus. So the results suggest that iron accumulation may indeed contribute to the cause of Alzheimer’s disease.” But it’s not all bad news from this study, Bartzokis noted. “The accumulation of iron in the brain may be influenced by modifying environmental factors, such as how much red meat and iron dietary supplements we consume and, in women, having hysterectomies before menopause,” he said. In addition, he noted, medications that chelate and remove iron from tissue are being developed by several pharmaceutical companies as treatments for the disorder. This MRI technology may allow doctors to determine who is most in need of such treatments. ### Other authors of the study included Erika Raven, Po Lu, Todd Tishler and Panthea Heydari. Funding was provided by National Institutes of Health grants MH 0266029, AG027342 and T32 NS041231 and by the RCS Alzheimer’s Foundation. The UCLA Department of Psychiatry and Biobehavioral Sciences is the home within the David Geffen School of Medicine at UCLA for faculty who are experts in the origins and treatment of disorders of complex human behavior. The department is part of the Semel Institute for Neuroscience and Human Behavior at UCLA, a world-leading interdisciplinary research and education institute devoted to the understanding of complex human behavior and the causes and consequences of neuropsychiatric disorders. Contact: Mark Wheeler |
| Ingredient in turmeric spice when combined with anti-nausea drug kills cancer cells Posted: 19 Aug 2013 09:00 PM PDT In a laboratory, preclinical study recently published by the journal Organic & Biomolecular Chemistry, Virginia Commonwealth University Massey Cancer Center researchers combined structural features from anti-nausea drug thalidomide with common kitchen spice turmeric to create hybrid molecules that effectively kill multiple myeloma cells.
Thalidomide was first introduced in the 1950s as an anti-nausea medication to help control morning sickness, but was later taken off the shelves in 1962 because it was found to cause birth defects. In the late 1990′s the drug was re-introduced as a stand-alone or combination treatment for multiple myeloma. Turmeric, an ancient spice grown in India and other tropical regions of Asia, has a long history of use in herbal remedies and has recently been studied as a means to prevent and treat cancer, arthritis and Alzheimer’s disease. According to the American Cancer Society, laboratory studies have shown that curcumin, an active ingredient in turmeric, interferes with several important molecular pathways and inhibits the formation of cancer-causing enzymes in rodents. “Although thalidomide disturbs the microenvironment of tumor cells in bone marrow, it disintegrates in the body. Curcumin, also active against cancers, is limited by its poor water solubility. But the combination of thalidomide and curcumin in the hybrid molecules enhances both the cytotoxicity and solubility,” says the study’s lead researcher Shijun Zhang, assistant professor in the Department of Medicinal Chemistry at the VCU School of Pharmacy. Compared to mixing multiple drugs, creating hybrid molecules can provide certain advantages. “Enhanced potency, reduced risk of developing drug resistance, improved pharmacokinetic properties, reduced cost and improved patient compliance are just a few of those advantages,” says another of the study’s researchers Steven Grant, M.D., Shirley Carter Olsson and Sture Gordon Olsson Chair in Oncology Research, associate director for translational research, program co-leader of Developmental Therapeutics and Cancer Cell Signaling research member at VCU Massey Cancer Center. The hybrid molecules of turmeric and thalidomide created more than 15 compounds, each with a different effect. Scientists found that compounds 5 and 7 exhibited superior cell toxicity compared to curcumin alone or the combination of curcumin and thalidomide. Furthermore, the compounds were found to induce significant multiple myeloma cell death. “Overall, the combination of the spice and the drug was significantly more potent than either individually, suggesting that this hybrid strategy in drug design could lead to novel compounds with improved biological activities,” added Grant. “The results also strongly encourage further optimization of compounds 5 and 7 to develop more potent agents as treatment options for multiple myeloma.” ### Zhang and Grant collaborated on this study with Kai Liu from the Department of Medicinal Chemistry at the VCU School of Pharmacy; Jeremy Chojnacki, from the VCU Department of Medicinal Chemistry; Datong Zhang, from the School of Chemistry and Pharmaceutical Engineering at Shandong Polytechnic University in Jinan, Shandong; and Yuhong Du and Haian Fu, from the Department of Pharmacology and Emory Chemical Biology Discovery Center at Emory University in Atlanta, Georgia. The full manuscript of this study is available at: http://pubs.rsc.org/en/content/articlepdf/2013/ob/c3ob40595h. News directors: Broadcast access to VCU Massey Cancer Center experts is available through VideoLink ReadyCam. ReadyCam transmits video and audio via fiber optics through a system that is routed to your newsroom. To schedule a live or taped interview, contact Alaina Farrish, (804) 628-4578. About VCU Massey Cancer Center VCU Massey Cancer Center is one of only 67 National Cancer Institute-designated institutions in the country that leads and shapes America’s cancer research efforts. Working with all kinds of cancers, the Center conducts basic, translational and clinical cancer research, provides state-of-the-art treatments and clinical trials, and promotes cancer prevention and education. Since 1974, Massey has served as an internationally recognized center of excellence. It has one of the largest offerings of clinical trials in Virginia and serves patients in Richmond and in four satellite locations. Its 1,000 researchers, clinicians and staff members are dedicated to improving the quality of human life by developing and delivering effective means to prevent, control and ultimately to cure cancer. Visit Massey online at http://www.massey.vcu.edu or call 877-4-MASSEY for more information. About VCU and the VCU Medical Center Virginia Commonwealth University is a major, urban public research university with national and international rankings in sponsored research. Located in downtown Richmond, VCU enrolls more than 31,000 students in 222 degree and certificate programs in the arts, sciences and humanities. Sixty-six of the programs are unique in Virginia, many of them crossing the disciplines of VCU’s 13 schools and one college. MCV Hospitals and the health sciences schools of Virginia Commonwealth University compose the VCU Medical Center, one of the nation’s leading academic medical centers. For more, see http://www.vcu.edu. Contact: Alaina Farrish |
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