080210xf's Blog

L'X fragile sera vaincu | Fragile X will be conquered

Archive for July, 2010

Scientists flash videos of brain development in fragile X

SFARI, Virginia Hughes

Scientists have devised a technique to watch, in real time, the dynamic ebb and flow of brain connections in young mouse models of fragile X syndrome. The findings appeared in June in the Journal of Neuroscience1.

Postmortem tissue from people with the syndrome2 and static images of the brains of young mouse models3 have both shown that fragile X brains look much less mature than do the brains of control animals. For example, they have abnormally long and dense dendritic spines — the slender neuronal projections that receive electrical messages from other cells and that are heavily pruned during development.

The new work shows, however, that dendrites in the fragile X brain appear more normal than those studies suggested.

“This is a big deal,” notes Anis Contractor, assistant professor of physiology at Northwestern University, who was not involved in the study. “It contradicts the dogma in the field that in all parts of the cortex [in fragile X] there’s this immature, delayed development.”


Boston’s Autism Mini-Cluster: New Drugs and Diagnostics Target Mysterious Brain Disorders

Ryan McBride |

One day in my high school Spanish class, a kid who I was told had autism started hitting himself on the head repeatedly until our teacher sent him to the nurse. Looking back, I wonder whether he understood how abnormal his behavior was. But 17 years later, I’m encouraged by the growing cluster of outfits in the Boston area that are developing a host of new treatments and medical tests for people like my former classmate.

Autism spectrum disorders—which are brain disorders that make socializing difficult, among other symptoms—are a growing health concern in the United States. And it’s viewed as a huge potential market for drugs and diagnostics. There are an estimated one in 110 children in the country who have autism spectrum disorders, according to the U.S. Centers for Disease Control and Prevention. To date, there are neither approved drugs nor any easy ways to diagnose autism. Yet there have been discoveries at MIT and other research centers in the Boston area in recent years that have given people hope of improved treatments for autism—and reasons for investors to pump capital into startups focused on advancing these treatments.

“What we’re hoping to do is step into a complete void out there in terms of proven medical treatments for the condition,” says George Evans, the chairman and chief executive of Beverly, MA-based Cellceutix, which is seeking capital to advance its experimental compound for autism.

In the Boston area, which is rich with renowned academic centers and biotech companies, there are clusters of companies in almost every kind of disease: cancer, autoimmune diseases, cardiovascular conditions, and on and on. However, there appear to be a particularly high proportion of recent entrants in the area’s budding autism cluster, which tells me that I probably would have had trouble compiling much of a list of such firms back, say, in the early 1990s.


Cellceutix a “Dark Horse” leader in Autism Research (as in article by Allan Jackson)

Allan Jackson wrote an article on Stockhouse that compares industry leaders in the area of autism research. It’s a race to break into this billion-dollar industry. Cellceutix is a world-leader, but still relatively unknown. Nice to see someone else recognizes the potential of Cellceutix.

Mr. Jackson’s article:

Dark horse candidate developing a novel compound

Biotech is one of the most lucrative of all industries. The success of a single drug has the potential to generate billions of dollars annually.

Understand that there does indeed exist an altruistic motive, the primary intention of developing compounds to provide new treatments for unmet needs for the good of the species. Yet the profit motive remains–business is still business and revenue generating potential certainly has its place in providing perspective among the panoply of therapeutic avenues that could be pursued.

Investors in biotechnology generally follow a couple methods in selecting for a company with tremendous upside. One of the primary strategies is identifying a company involved in white-hot, bleeding edge area of research. A second method is to identify a niche company with an orphan or completely novel drug that, if successful, is protected from competition for several years. Success in either one of these areas will greatly increase the likelihood of a larger financial windfall for all involved.

Considering the first of these investment methods brings us to one of the hottest frontiers in neuro-biotechnology: autism. With a 10-17% annual growth rate, Autism Spectrum Disorder is the single fastest growing developmental disease in the world today. About 1% of the United States population, ages 3 to 17, is afflicted with autism spectrum disorder and more children will be diagnosed with autism this year than with AIDS, diabetes & cancer combined. Even with these stunning facts, there is NO drug available on the market today that addresses the core issues of autism. There are many drugs designed to allay autistic symptoms, e.g., Ritalin. But none that address the core issues of the autistic brain. Presently, there is one drug approved by the FDA for such use, the antipsychotic, Risperidone, produced by Johnson & Johnson (NYSE: JNJ, Stock Forum) and approved for use in infantile autism. Risperidone has not been without its critics, though, as many question the use of the antipsychotic medication. With President Obama recently earmarking $1 billion for studies extending through 2018, biotechnology companies have realized both the great financial and humanitarian benefits that can result with the successful development of a compound for autism and have begun a push to develop therapeutic compounds.


Rescuing Fruit Flies from Alzheimer’s Disease: Penn Researchers Reverse Cognitive Decline in Flies With Alzheimer’s Gene Mutation


Investigators have found that fruit fly (Drosophila melanogaster) males — in which the activity of an Alzheimer’s disease protein is reduced by 50 percent — show impairments in learning and memory as they age. What’s more, the researchers were able to prevent the age-related deficits by treating the flies with drugs such as lithium, or by genetic manipulations that reduced nerve-cell signaling.

The research team — Thomas A. Jongens, Ph.D., associate professor of Genetics at the University of Pennsylvania School of Medicine; Sean M. J. McBride M.D, Ph.D. and Thomas McDonald M.D., at the Albert Einstein College of Medicine; and Catherine Choi M.D., Ph.D. at Drexel University College of Medicine — worked with the familial form of Alzheimer’s disease (FAD), an aggressive form of the disease that is caused by mutations in one of the two copies of the presenilin (PS) or amyloid precursor protein (APP) genes. Studies in animal models have previously shown that the FAD-linked PS mutations lead to less presenilin (psn) protein activity.

Their findings are published in this week’s issue of the Journal of Neuroscience.

“The results from our study suggest a new route to explore for the treatment of familial Alzheimer’s disease and possibly the more common sporadic forms of Alzheimer’s disease,” notes Jongens. “They also reveal that proper presenilin activity levels are required to maintain normal cognitive capabilities during aging.” Learning and Memory Tests in Flies Fruit flies can hardly take a pen-and-pencil test to assess age-related memory decline. Instead, the team relied on the ability to train fruit fly males to learn and remember courtship behavior.

During courtship the male fly performs an instinctive set of behaviors to both determine if the female is receptive and to entice her to mate. The courtship activity that a male displays toward a female is affected by several factors, including the type of pheromones produced by the female, as well as her response to his courtship attempts. If the female is not receptive she releases less attractive pheromones and more aggressively discourages the male to court her. Under these conditions, the male will quickly learn to not court her as well as other females and will remember this for several hours.

The researchers found that with age, the presenilin mutant — the Alzheimer’s fruit fly model — lost the ability to learn and remember and that this age-onset cognitive deficit could be prevented by treating the flies with drugs, or by genetic manipulations that reduce metabotropic glutamate receptor (mGluR) signaling. MGluR is located on the surface of neurons, including in the hippocampus — a major memory and learning center in the brain.

In addition, treatment of older flies with these same drugs reversed the age-dependent deficits.

“A clear advantage of the drugs used in this study is that one, lithium, is currently FDA approved for other indications and the other class of drugs, the mGluR antagonists, are currently in clinical trials in humans for the treatment of Fragile X syndrome,” comments Choi .

“We demonstrate that these treatments, even when begun after the onset of cognitive impairment, can reverse memory deficits,” says McBride. “This indicates that there is a window of time during which memory is impaired, but the cellular function can still be rescued with proper treatment, again allowing for the ability to form proper memory. This is a critical finding since in humans Alzheimer’s is diagnosed only clinically after the onset of cognitive impairment. So, this finding may indicate that even at the point of early memory impairment, the disease may be reversible.”

Relation to Fragile X Syndrome

In attempts to identify related pathways affected by a reduction in presenilin activity, the team performed genetic tests with genes known to affect cognition. They found that the presenilin mutation genetically interacts with the Fragile X mutation in fruit flies. Fragile X is the most common genetically inherited form of cognitive impairment in humans and a known cause of autism that affects about 1 in 4,000 individuals worldwide.

“We were shocked that the two genes work in what appears to be the same pathway,” says Jongens. The outward characteristics of the Fragile X fly model are loss of courtship activity and memory. In earlier studies, the same research team had found that lithium and mGluR antagonists also restored normal courting behavior and memory in Fragile X flies. This is what led Jongens and his colleagues to test lithium and mGluR antagonists on the FAD-mutated fruit flies.

Eight years ago, studies outside of Penn using a mouse model proposed that Fragile X patients have a tendency to have weakened synaptic connections (sites used for neuron to neuron communication) more readily than the general population. This weakening is due to increased activity in the mGluR. In turn, this increased activity compromises neurotransmission for memory-associated functions.

These results led to the “The mGluR Theory of Fragile X,” first proposed by Dr. Mark Bear at MIT and his coauthors. This theory proposed that the underlying cause of the cognitive impairment and many of the other symptoms associated with Fragile X Syndrome were due to enhanced metabotropic glutamate receptor signaling.

Jongens, McBride, and colleagues tested if mGluR overactivity might be at the root of many of phenotypes associated with their fly Fragile X model. In 2005, the team reported that treatment of fragile X flies with drugs such as lithium or mGluR antagonists restored normal courtship behavior and memory in their mutant flies and rescued some neuronal structural defects, as well. The group used lithium because it is known to have activities analogous to blocking mGluR-receptor activity, and it is already an FDA-approved drug used to treat other ailments in humans such as bipolar disorder.

A Potential Link to Calcium

Back in the Alzheimer’s fly model, the team surmised that if they could rescue mutated flies with lithium or mGluR antagonists, that pathways downstream of mGluR might also be useful targets for rescuing age-related cognitive impairments. One pathway they investigated was the regulation of the inositol trisphosphate receptor (InsP3R), which releases calcium from internal stores into the cytoplasm of the cell.

They focused on this pathway because previous studies have found elevated calcium levels in the cells of Alzheimer’s patients and more recently Dr. Kevin Foskett and his colleagues, also at Penn, had found that FAD mutations of presenilin make InsP3R more responsive to the signal that stimulates it to release calcium in the cytoplasm. (In normal situations, presenilin functions to cleave several transmembrane proteins, including the APP protein, which can produce the A-peptide found in the plaques of Alzheimer’s patients.)

Jongens, McBride and their colleagues found that genetic reduction of the InsP3R pathway also prevented the age-related loss of learning and memory in the FAD fly model.

“The release of calcium from internal cellular stores during the cellular encoding of memory seems to be finely tuned so that either too much or too little calcium release could impair memory formation,” notes McBride.

“Our next steps will involve validating results in a relevant mouse model of FAD or AD, as well as exploring the underlying basis for this new found connection between Fragile X Syndrome and Alzheimer’s disease,” says Jongens. “It is intriguing that the drugs being developed for the treatment of Fragile X might also be useful in the treatment of another disease affecting cognition, namely Alzheimer’s disease.”


Abnormal brain growth seen in children with fragile X

SFARI, Virginia Hughes

Brains of children with fragile X syndrome go through an abnormal trajectory of development in the first few years of life, according to the first study to track how the disease unfolds in the brain. The findings were published in May in the Proceedings of the National Academy of Sciences1.

Fragile X syndrome — a genetic disease that causes mental retardation and often autism — results from the complete loss of fragile X mental retardation protein, or FMRP, which is important for many brain processes. By comparing children with the syndrome and healthy controls, the new findings present a picture of when and where FMRP is expressed during early development.

“This is beautiful work,” says April Benasich, director of the Infancy Studies Laboratory at Rutgers University, who was not involved in the study. “The ability to link individual differences in the structure of the brain to some genetic precursor is extremely powerful.”

Previous imaging studies of adults and young children with fragile X syndrome have consistently shown that they have an enlarged caudate, which is important for learning and memory, compared with healthy controls and with children who have general developmental delay2. Those with the syndrome also tend to have an abnormally small cerebellar vermis, which helps maintain balance and in sensing one’s own movement3.


NCBS breakthrough: soothing the frayed nerves of Fragile X

Geoff Hyde, NCBS News

A team of neuroscientists, led by Prof. Sumantra Chattarji at the National Centre for Biological Sciences, Bangalore has identified  previously unrecognised synaptic defects in an area of the brain that is involved in the debilitating emotional symptoms of Fragile X Syndrome (FXS), the leading genetic cause of autism and mental retardation. The study is of potential therapeutic significance because it also shows that even a relatively brief pharmacological treatment is capable of correcting some of these defects in mice that were genetically engineered to model FXS. The work, done together with collaborators at New York University, will be reported in the online early edition of the Proceedings of the National Academy of Sciences the week of June 7-11.

Individuals with FXS, which is caused by a mutation in a gene on the X chromosome, suffer from a wide range of problems, such as learning disabilities, attention deficit, seizures, anxiety and mood instability, probably involving several regions of the brain. Currently there is no effective treatment for FXS and other types of autism, but helpful clues about potential drug therapy were provided by previous work that found defects in neurotransmission in the hippocampus, a region important for learning and long-term memory. These defects involve abnormal chemical signaling across the synapse – the junction between neighbouring nerves. Prof. Chattarji’s group focuses on the amygdala, a small, almond-shaped area long known as the brain’s emotional hub.