Sciencedaily published three abstracts today that summarize new findings in autism, bipolar disorder and schizophrenia. We are moving forward, no question about that, but when will we have a real breakthrough? It becomes more and more clear that autism, bipolar disorder or schizophrenia have physical and genetic causes. Charting Autism's Neural Circuitry: Deleting Single Gene Results in Autism-Like Behavior and Immunosuppressant Drug Prevents Symptoms http://www.sciencedaily.com/releases/2012/07/120702210303.htm ScienceDaily (July 2, 2012) — Deleting a single gene in the cerebellum of mice can cause key autistic-like symptoms, researchers have found. They also discovered that rapamycin, a commonly used immunosuppressant drug, prevented these symptoms. The deleted gene is associated with Tuberous Sclerosis Complex (TSC), a rare genetic condition. Since nearly 50 percent of all people with TSC develop autism, the researchers believe their findings will help us better understand the condition's development. "We are trying to find out if there are specific circuits in the brain that lead to autism-spectrum disorders in people with TSC," said Mustafa Sahin, Harvard Medical School associate professor of neurology at Boston Children's Hospital and senior author on the paper. "And knowing that deleting the genes associated with TSC in the cerebellum leads to autistic symptoms is a vital step in figuring out that circuitry." This is the first time researchers have identified a molecular component for the cerebellum's role in autism. "What is so remarkable is that loss of this gene in a particular cell type in the cerebellum was sufficient to cause the autistic-like behaviors," said Peter Tsai, HMS instructor of neurology and the first author of this particular study. These findings were published online July 1 in Nature. TSC is a genetic disease caused by mutations in either one of two genes, TSC1 and TSC2. Patients develop benign tumors in various organs in the body, including the brain, kidneys and heart, and often suffer from seizures, delayed development and behavioral problems. Researchers have known that there was a link between TSC genes and autism, and have even identified the cerebellum as the key area where autism and related conditions develop. In both cases, deleting this gene caused the three main signs of autistic-like behaviors: Abnormal social interactions. The mice spent less time with each other and more with inanimate objects, compared to controls. Repetitive behaviors. The mice spent extended amounts of time pursuing one activity or with one particular object far more than normal. Abnormal communication. Ultrasonic vocalizations, the communication technique among rodents, were highly distressed. The researchers also tested learning. "These mice were able to learn new things normally," said Tsai, "but they had trouble with 'reversal learning,' or re-learning what they had learned when their environment changed." Tsai and colleagues tested this by training the mice to swim a particular path in which a platform where they could rest was set up on one side of the pool. When the researchers moved the platform to the other side of the pool, the mice had greater difficulty than the control mice re-learning to swim to the other side. "These changes in behavior indicate that the TSC1 gene in Purkinje cells, and by extension, the cerebellum, are a part of the circuitry for autism disorders," emphasized Sahin. The researchers also found that the drug rapamycin averted the effects of the deleted gene. Administering the drug to the mice during development prevented the formation of autistic-like behaviors. Currently, Sahin is the sponsor-principal investigator for an ongoing Phase II clinical trial to test the efficacy of everolimus, a compound in the same family as rapamycin, in improving neurocognition in children with TSC. The trial will be open for enrollment until December 2013. "Our next step will be to see how the abnormalities in Purkinje cells affect autism-like development. We don't know how generalizable our current findings are, but understanding mechanisms beyond TSC genes might be useful to autism," said Tsai. This study was supported by the National Institutes of Health (R01 NS58956), the John Merck Scholars Fund, Autism Speaks, Nancy Lurie Marks Family Foundation, Children's Hospital Boston Translational Research Program, the Children's Hospital Boston Mental Retardation and Developmental Disabilities Research Center (P30 HD18655). Sahin serves as a consultant and site primary investigator for Novartis. --- Success Reported in Treating Autism Spectrum Disorder in Mice http://www.sciencedaily.com/releases/2012/07/120702192512.htm ScienceDaily (July 2, 2012) — Using a mouse model of autism, researchers at the University of Cincinnati (UC) and Cincinnati Children's Hospital Medical Center have successfully treated an autism spectrum disorder characterized by severe cognitive impairment. The research team, led by Joe Clark, PhD, a professor of neurology at UC, reports its findings online July 2, 2012, in the Journal of Clinical Investigation, a publication of the American Society for Clinical Investigation. The disorder, creatine transporter deficiency (CTD) is caused by a mutation in the creatine transporter protein that results in deficient energy metabolism in the brain. Linked to the X chromosome, CTD affects boys most severely; women are carriers and pass it on to their sons. The brains of boys with CTD do not function normally, resulting in severe speech deficits, developmental delay, seizures and profound mental retardation. CTD is estimated to currently affect about 50,000 boys in the United States and is the second-most common cause of X-linked mental retardation after Fragile X syndrome. Following CTD's discovery at UC in 2000, researchers at UC and Cincinnati Children's led by Clark discovered a method to treat it with cyclocreatine -- also known as CincY, and pronounced cinci-why -- a creatine analogue originally developed as an adjunct to cancer treatment. They then treated genetically engineered mice as an animal model of the human disease. "CincY successfully entered the brain and reversed the mental retardation-like symptoms in the mice, with benefits seen in nine weeks of treatment," says Clark, adding that no harmful effects to the mice were observed in the study. "Treated mice exhibited a profound improvement in cognitive abilities, including recognition of novel objects, spatial learning and memory." As a repurposed drug (originally developed for another therapy), CincY has already been through part of the U.S. Food and Drug Administration (FDA) approval process. It is taken orally as a pill or powder. UC's Office of Entrepreneurial Affairs and Technology Commercialization has reached agreement with Lumos Pharma, a privately held Austin, Texas, startup company based on UC technology, to develop and commercialize CincY. Lumos Pharma was created with technology licensed from UC's Office of Entrepreneurial Affairs and Technology Commercialization. Its CEO is Rick Hawkins, a 30-year biotech industry veteran. Jon Saxe is its chairman. "It has taken many years to get here and I am happy that our efforts have led to this translational effort to make a therapy available to those afflicted with CTD," says Clark. "We look forward with commitment and hope to the day when those patients will benefit from our work." The collaboration gained momentum when Lumos Pharma submitted a proposal based on Clark's technology to the National Institutes of Health and was selected as a drug development project partner by the National Center for Advancing Translational Sciences' Therapeutics for Rare and Neglected Diseases (TRND) program. Under TRND's collaborative operational model, project partners form joint project teams with TRND and receive in-kind support from TRND drug development scientists, laboratory and contract resources. Lumos Pharma plans to initiate a TRND-supported preclinical development plan, with TRND support continuing through the filing of an Investigational New Drug (IND) application with the FDA prior to beginning a clinical trial. Such a trial would be about three years away, Clark says. In addition to Clark, study team members are Yuko Kurosawa, PhD; Ton de Grauw, MD, PhD; Diana Lindquist, PhD; Victor Blanco, PhD; Gail Pyne-Geithman, DPhil; Takiko Daikoku, PhD; James Chambers, PhD; and Stephen Benoit, PhD. The research by Clark's team was supported by funding from the National Institutes of Health. The study authors report no conflicts of interest. --- Autism, Schizophrenia and Bipolar Disorder May Share Common Underlying Factors, Family Histories Suggest http://www.sciencedaily.com/releases/2012/07/120702210216.htm ScienceDaily (July 2, 2012) — New research led by Patrick F. Sullivan, MD, FRANZCP, a medical geneticist at the University of North Carolina School of Medicine, points to an increased risk of autism spectrum disorders (ASDs) among individuals whose parents or siblings have been diagnosed with schizophrenia or bipolar disorder. The findings were based on a case-control study using population registers in Sweden and Israel, and the degree to which these three disorders share a basis in causation "has important implications for clinicians, researchers and those affected by the disorders," according to a report of the research published online July 2, 2012 in the Archives of General Psychiatry. "The results were very consistent in large samples from several different countries and lead us to believe that autism and schizophrenia are more similar than we had thought," said Dr. Sullivan, professor in the department of genetics and director of psychiatric genomics at UNC. Sullivan and colleagues found that the presence of schizophrenia in parents was associated with an almost three times increased risk for ASD in groups from both Stockholm and all of Sweden. Schizophrenia in a sibling also was associated with roughly two and a half times the risk for autism in the Swedish national group and a 12 times greater risk in a sample of Israeli military conscripts. The authors speculate that the latter finding from Israel resulted from individuals with earlier onset schizophrenia, "which has a higher sibling recurrence." Bipolar disorder showed a similar pattern of association but of a lesser magnitude, study results indicate. "Our findings suggest that ASD, schizophrenia and bipolar disorder share etiologic risk factors," the authors state. "We suggest that future research could usefully attempt to discern risk factors common to these disorders."