Rett-Syndrome

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“On February 9th, 2015, Zeina was taken from my family and I. Zeina was 18 months when she was diagnosed with a severe postnatal neurological disorder known as Rett Syndrome that only affects girls. Rett syndrome varies in degrees and has very unique and distinct qualities. Due to her diagnosis, Zeina has regressed over the years. Year by year, I had to watch her lose her ability to walk, grasp objects with her hands, eat on her own, and stand-up straight. As she was losing her physical abilities, she did not gain any mental abilities such as the ability to make sense of the world through thinking, logic, and reasoning. She did not develop language or ways to communicate. Zeina needed round-the-clock care and my 2 sisters, mother, and I provided her with that. Our father left us which made it harder, but we would do anything for Zeina. Due to her syndrome, she also developed scoliosis, which was severely impacting her health. Her hips, spine, and neck were constantly in excruciating pain. They became shifted and unaligned with her body. Through it all though, she kept a smile on her face. 
We cannot bring Zeina back, but we can help other girls suffering with Rett Syndrome. This disorder has the potential to be reversed, but lacks the funding. I am not sure we will even make a hundred dollars from this, but every penny helps. If you cannot donate money, it is understandable, but spreading the message is just as valuable. Together, we can help cure Rett.”
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One of my best friends lost the most important person in the world to her a few days ago. Instead of wallowing in her grief like I probably would have done had I been in her situation, she wants to help others who may suffer from Rett Syndrome. If you can donate, please do so. If you cannot donate, please reblog this and spread the word. Thank you. x

  


http://www.gofundme.com/helpzeina

JUST THE FAQs: 3D Stem Cell-Based Model for Brain Research

Researchers at University of California, San Diego School of Medicine and Skaggs School of Pharmacy and Pharmaceutical Sciences have created a 3D, stem cell-based system for studying and manipulating brain development in the lab. This installment of JUST THE FAQs breaks down the technique, which was recently published by the Proceedings of the National Academy of Sciences.

Why do we need this 3D model?

For about a decade now, researchers have been using a special kind of stem cell known as an induced pluripotent stem cell (iPSC) to model and study human brain cells. iPSCs are made from any adult cell, such as a skin cell. Researchers add a molecular cocktail to the skin cells that reprograms them into iPSCs, cells that now have the capacity to become almost any kind of cell. By adding a specific combination of growth factors and other molecules, researchers can then coax iPSCs into becoming a self-renewing population of almost any cell type they are interested in studying. Studies using iPSCs can also be very personalized, since the final cell type preserves the genomic makeup of the original skin sample donor.

By turning iPSCs into neural progenitor cells—precursors to neurons—this system allows researchers to study how neurons develop, using cells from both healthy people and people with autism, Alzheimer’s disease or other neurological disorders. But these studies have had one major limitation: they are for the most part done using cells growing flat in a dish, whereas in reality the brain is a 3D organ made up of many different cell types.

“Research in the neurodevelopment field is stuck in 2D, while we’re trying to study 3D phenomena,” says Adah Almutairi, PhD, associate professor and director of the Center for Excellence in Nanomedicine in the Skaggs School of Pharmacy at UC San Diego. “This is mainly due to the lack of simple and user-friendly 3D tools for tissue culture.”

Almutairi, a polymer chemist, led the study with stem cell biologist Alysson Muotri, PhD, associate professor of pediatrics and cellular and molecular medicine at UC San Diego School of Medicine, and Adam Engler, PhD, associate professor of bioengineering in the UC San Diego Jacobs School of Engineering.

How did the researchers make this 3D model?

To overcome the limitations of 2D systems, in this study Almutairi, Muotri and their teams layered hydrogels to create a 3D model for neural progenitor cells derived from iPSCs. In short, they mixed up a recipe of small-molecular density modifiers and prepolymer-containing cell suspensions, then gently layered the mixture with a syringe. Then the researchers applied UV irradiation until they had hydrogels with their desired stiffness and pore size. This 3D structure recreates cell-to-cell interactions, the researchers say, producing a tissue-like architecture and more realistic physiological responses than conventional 2D cultures.

The researchers found that all iPSC-derived neural progenitor cells grown in this new 3D hydrogel model differentiated faster than they do in traditional 2D cultures. In other words, they more quickly specialized from stem cells to precursor cells to neurons—a difference that may have a significant effect on many studies.

How might this 3D model be used to advance research?

In their pilot study of the 3D hydrogel model, the Almutairi and Muotri teams compared migration and maturation of normal iPSC-derived neural progenitor cells to the same cells with a mutation in one particular gene, MeCP2. Defects in this gene are known to cause a rare neurodevelopmental disorder called Rett syndrome. They also tested neural progenitor cells derived from children with Rett Syndrome.

As previous studies have found, the cells with defective MeCP2 had reduced neurite outgrowth and fewer synapses as compared to the cells with normal MeCP2. In the 3D system, the MeCP2-defective cells were also limited in their abilities to migrate—an observation not previously made in 2D studies.

Almutairi and Muotri hope many others in the scientific community will use their 3D hydrogel model to ask any number of research questions about brain development and function and how they are influenced by genetic defects and environmental factors.

“Our method makes it simple enough for any biologist to construct 3D tissue mimics to study developmental diseases, such as autism,” Almutairi says.

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October is Rett Syndrome Awareness month!
It’s also Awareness month for a lot of other great causes, but Rett Syndrome is something you most likely haven’t heard of. It’s a rare neurogical condition which effects almost exclusively girls. The girls typically develop normally until around 6-18 months when they begin to ‘regress’, losing any skills they have gained. It’s often described as 'the symptoms of autism, cerebral palsy, Parkinson’s, anxiety and epilepsy all in one little girl.’
Girls with the condition cannot talk, though research shows they are capable of understanding much more than they can express. Only around half can walk. Almost all have no functional hand use, often experiencing repeated uncontrollable hand movements. Other symptoms include seizures, breathing difficulties, scoliosis and digestive issues. Girls are often very sociable, but find it almost impossible to commmunicate.
Currently there are virtually no treatments. But, research has shown that Rett Syndrome can be reversed in mice, there is no brain damage! Right now, research is continuing with the hopes of developing treatments and even bringing this reversal to humans.
I’ve been looking into Rett as a project for school and as part of that I interviewed the mother of a local girl with the condition. It was really amazing to hear about everything her daughter had to deal with on a daily basis, and how they have all adapted and remain hopeful and patient. But what shocked me most was that the woman said there was very little professional, never mind public, awareness of the disorder! This delays diagnosis for many girls and without awareness, there is little funding for research. If the public aren’t interested, then money doesn’t get raised and grants rarely get given.
We could see this be the first curable neurological disorder, and give these girls their freedom.

Please spread the word. To find out more, visit the websites of Reverse Rett or RSRT. There’s also a wonderful video here describing 'A Father’s Words’ on Rett. 

New Drug Target May Lead to Novel Treatment for Severe Autism

Penn State University scientists have discovered a novel drug target and have rescued functional deficits in human nerve cells derived from patients with Rett Syndrome, a severe form of autism-spectrum disorder. The research, led by Gong Chen, professor of biology and the Verne M. Willaman Chair in Life Sciences at Penn State, could lead to a new treatment for Rett Syndrome and other forms of autism-spectrum disorders.

The research will appear in PNAS.

Mouse Version of an Autism Spectrum Disorder Improves When Diet Includes a Synthetic Oil

When young mice with the rodent equivalent of a rare autism spectrum disorder (ASD), called Rett syndrome, were fed a diet supplemented with the synthetic oil triheptanoin, they lived longer than mice on regular diets. Importantly, their physical and behavioral symptoms were also less severe after being on the diet, according to results of new research from The Johns Hopkins University.

(Image caption: Mitochondria (arrows) in muscle cells from mice with Rett syndrome improved in appearance after the mice were given triheptanoin oil. Top: Muscle from mice given regular food. Bottom: Muscle from mice given food supplemented with triheptanoin. Left: Healthy mice. Right: Mice with a genetic mutation that mimics Rett syndrome.)

Researchers involved in the study think that triheptanoin improved the functioning of mitochondria, energy factories common to all cells. Since mitochondrial defects are seen in other ASDs, the researchers say, the experimental results offer hope that the oil could help not just people with Rett syndrome, but also patients with other, more common ASDs.

A description of the research was published on Oct. 9 in the journal PLOS ONE.

ASDs affect an estimated one in 68 children under 8 years of age in the United States. Rett syndrome is a rare ASD caused by mutations in the MECP2 gene, which codes for methyl-CpG-binding-protein 2 (MeCP2). Rett syndrome includes autismlike signs, such as difficulty communicating, socializing and relating to others. Other hallmarks are seizures, decreased muscle tone, repetitive involuntary movements, and gastrointestinal and breathing problems. These other signs are also seen in some patients with other ASDs, suggesting underlying similarities in their causes. While the causes of most ASDs are unknown and thought to be complex, Rett syndrome is unique — and could be a source of insight for the others — because it is caused by an error in a single gene.

The research team used mice lacking the MeCP2 protein, which left them with severe Rett syndrome. In examining those mice, what stood out, according to Gabriele Ronnett, M.D., Ph.D., who led the research project at the Johns Hopkins University School of Medicine, was that they weighed the same as healthy mice but had large fat deposits accompanied by lower amounts of nonfat tissue, such as muscle. This suggested that calories were not being used to support normal tissue function but instead were being stored as fat.

This possibility led Ronnett and her research team to consider the role of mitochondria, which transform the building blocks of nutrients into a high-energy molecule, ATP. This molecule drives processes such as the building of muscle and the growth of nerve cells. Mitochondria use a series of biochemical reactions, collectively called the TCA cycle, to make this transformation possible. According to Susan Aja, Ph.D., a research associate and lead member of the research team, “If the components of the TCA cycle are low, nutrient building blocks are not processed well to create ATP. They are instead stored as fat.”

Ronnett suspected, she says, that some of Rett syndrome’s neurological symptoms could stem from metabolic deficiencies caused by faulty mitochondria and reduced energy for brain cells. “Rett syndrome becomes apparent in humans 6 to 18 months old, when the energy needs of the brain are particularly high, because a lot of new neural connections are being made,” says Ronnett. “If the mitochondria are already defective, stressed or damaged, the increased demand would be too much for them.”

Previous small clinical trials in people with a different metabolic disorder suggested that dietary intervention with triheptanoin could help. Triheptanoin is odorless, tasteless and a little thinner than olive oil. It is easily processed to produce one of the components of the TCA cycle.

When Rett syndrome mice were weaned at 4 weeks of age, they were fed a diet in which 30 percent of their calories came from triheptanoin, mixed in with their normal pelleted food. Though far from a cure, the results of the triheptanoin treatment were impressive, the researchers say. Treated mice had healthier mitochondria, improved motor function, increased social interest in other mice and lived four weeks — or 30 percent — longer than mice who did not receive the oil. The team also found that the diet normalized their body fat, glucose and fat metabolism.

“You can think of the mitochondria of the Rett syndrome model mice as damaged buckets with holes in them that allow TCA cycle components to leak out,” says Aja. “We haven’t figured out how to plug the holes, but we can keep the buckets full by providing triheptanoin to replenish the TCA cycle.”

“It is still too early to assume that this oil will work in humans with ASDs, but these results give us hope,” says Ronnett. “It’s exciting to think that we might be able to improve many ASDs without having to identify each and every contributing gene.”

According to Aja, additional mouse studies are needed to learn if female mice respond to the treatment, to perform a wider range of physiology and behavior tests, and, importantly, to assess the effects of triheptanoin treatment on the brain, which is considered the main driver of many Rett symptoms. The team would also like to provide triheptanoin at earlier ages, perhaps via the mothers’ milk, to mimic developmental ages at which most children are diagnosed with Rett syndrome.

Triheptanoin is currently made for research purposes only and is not available as a medicine or dietary supplement for humans.

Another FC story: a truly blind facilitator

This one from a mother and daughter I know. They both have Rett syndrome, the mother mild and the daughter severe. The mother was just diagnosed as having autism and a severe intellectual disability growing up, until she learned to write, and later speak. Her daughter will probably never speak but does type using FC.

They have used a lot of ingenious ways of proving that her daughter is really the one doing the typing. But one of them involved having a blind facilitator. As in, the facilitator himself was literally blind and could not see the letter board. They set everything up like usual, to show to a skeptical teacher. Then without telling the facilitator, they flipped the letter board upside down.

The daughter of course continued to type perfectly accurate responses. The facilitator was very confused and somewhat agitated about the whole thing, and kept asking “are you sure you meant to hit that letter?” But she firmly continued to type on her upside down letter board, and the facilitator clearly had no idea she was typing anything other than gibberish. He was able to give her hand the support it needed to type without having to see the letters, because it was her hand he was focused on.

After that incident, the teacher no longer doubted that the daughter was doing her own work. I’ve never doubted it either. Her daughter is highly sensing and has an entire way of communicating that doesn’t involve speech or typing at all. The content of her typing matches the person she comes across as on a sensing level. Hard to explain.

I wish she and her mother would write a book together because they have both done so many interesting things. But too much of their time is taken up by survival. The daughter has severe health issues and many times has had a projected lifespan of months. So working on a book would not be her priority. But I wanted to add this to my #fc tag for those interested in stories about FC, both done right and done horribly wrong, and my thoughts on the matter. I can’t consolidate all those ideas into one post so I keep them all in one tag for those who have expressed an interest in my experiences and opinions.

*jumps into your moving vehicle*

but what about when those of us with disabilities grow up? Our processing disorders, ADHD/ADD, etc don’t end when childhood does. Where’s the community centers for adults with Autism(ASD) or Downs or IDD or Rett? Where are our resources for our families and adulting?

these   ~*inspirational*~  ~*brave*~  children grow up to be adults

and we still need help

Stem Cell-derived “Mini-brains” Reveal Potential Drug Treatment for Rare Disorder

Using “mini-brains” built with induced pluripotent stem cells derived from patients with a rare, but devastating, neurological disorder, researchers at University of California, San Diego School of Medicine say they have identified a drug candidate that appears to “rescue” dysfunctional cells by suppressing a critical genetic alteration.

Their findings are published in the September 8 online issue of Molecular Psychiatry.

The neurological disorder is called MECP2 duplication syndrome. First described in 2005, it is caused by duplication of genetic material in a specific region of the X chromosome that encompasses MECP2 and adjacent genes. The disorder displays a wide variety of symptoms, among them low muscle tone, developmental delays, recurrent respiratory infections, speech abnormalities, seizures, autistic behaviors and potentially severe intellectual disability.  

It is heritable, but can also occur randomly. MECP2 duplication syndrome occurs almost exclusively in males. A similar disorder known as Rett (RTT) Syndrome, which involves MECP2 gene deletions, primarily affects females. Current treatment is largely symptomatic, involving therapies, drugs and surgeries that address specific issues.

As in previous, ground-breaking research with Rett Syndrome patients, senior author Alysson Muotri, PhD, associate professor in the UC San Diego departments of Pediatrics and Cellular and Molecular Medicine, and colleagues took skin cells from MECP2 duplication patients, converted them into induced pluripotent stem cells (iPSC), then programmed the stem cells to become neurons that recapitulate the disorder more robustly than existing mouse models.

Muotri said analyses of the iPSC-derived neurons revealed novel molecular and cellular phenotypes, including an over-synchronization of the neuronal networks. Interestingly, these phenotypes go in a direction opposite of what scientists had previously reported for Rett syndrome, suggesting that the correct gene dosage is important for homeostasis in human neurons. More importantly, said Muotri, the finding with human neurons helped direct the next stage, a drug screening, which uncovered a drug candidate – a histone deacetylase inhibitor that reversed all the MECP2 alterations in the mutant neurons, with no harm to control neurons.

“This work is encouraging for several reasons,” said Muotri. “First, this compound had never before been considered a therapeutic alternative for neurological disorders. Second, the speed in which we were able to do this. With mouse models, this work would likely have taken years and results would not necessarily be useful for humans.”

Muotri said the findings further underscore the potential of stem cell-based models as an efficient method for screening potential drug libraries for the ability to rescue human neuronal phenotypes in a dish. He said his research team would be concluding its preclinical studies in preparation for moving into clinical trials as soon as possible.

Pictured: Neuronal stem cells in red. Image courtesy of Gerry Shaw/Wikimedia Commons.

(Image caption: Callosal projection neurons (green) in the cerebral cortex. Credit: Jessica MacDonald and Jeffrey Macklis)

New drug target for Rett syndrome

Harvard Stem Cell Institute (HSCI) researchers have identified a faulty signaling pathway that, when corrected, in mice ameliorates the symptoms of Rett syndrome, a devastating neurological condition. The findings could lead to the discovery of compounds or drugs that may benefit children affected by the disease, says neurobiologist Jeffrey Macklis, Max and Anne Wien Professor of Life Sciences in the Department of Stem Cell and Regenerative Biology, and Center for Brain Science, at Harvard University, who directed the work.

The research was recently published in Nature Communications. Noriyuki Kishi and Jessica MacDonald, both recent postdoctoral fellows in the Macklis laboratory, are co-first authors.

Rett syndrome is a relatively common neurodevelopmental disorder, the second most common cause of intellectual disability in girls after Down’s syndrome; it is associated with a dysfunctional gene on the X chromosome. Boys with Rett syndrome are rare, because male fetuses who carry the mutations on their one X chromosome usually have prenatally lethal forms of the disease. Girls with Rett syndrome appear to develop relatively normally for the first six to eighteen months of life, but then regress; they tend to lose their ability for speech and the purposeful use of their hands, withdraw from social situations, and wring their hands.

Austrian physician Andreas Rett first described the disorder in 1966, but it wasn’t until 1999 that Huda Zoghbi and her lab at Baylor College of Medicine identified mutations in the gene MECP2 as the root cause of Rett syndrome. MECP2, however, turns a very large number of genes on and off throughout the entire body, so it has been a longstanding puzzle why girls and rare boys with Rett syndrome have this very specific and reproducible developmental cognitive brain disorder.

“My view was that MECP2 mutation in Rett syndrome disrupts so many genes and their protein products that we weren’t going to find a single gene that we could fix to help girls with Rett,” said Macklis, a member of HSCI’s Executive Committee, former Program Head of HSCI’s Nervous System Diseases Program, and an Allen Distinguished Investigator of the Paul G. Allen Family Foundation. “But if we found a disrupted, improperly regulated signaling pathway that was ‘drug-able,’ that affected enough of the girls’ pathology, we might be able to make them dramatically functionally better with already available therapeutics– and that might make a real difference in their lives and their families’ lives.”

Instead of concentrating on the MECP2 gene, Macklis’ group focused on neurons he knew were “abnormal and implicated in Rett syndrome and autism spectrum disorders,” and in 2004, Macklis’ lab was the first to describe abnormal development in this type of neurons responsible for communicating signals between the two hemispheres of the brain. These neurons, called inter-hemispheric callosal projection neurons (CPN), have shorter, less developed dendrites, or “receiving antennas” in mice with the Rett gene mutations, and in individuals with Rett syndrome.

Building on their 2004 findings, the researchers were able to fluorescently label CPN in mice with or without the Rett mutation, purify them from other types of neurons, and look at the levels at which many thousands of genes were active, and thus how much of the proteins coded for by those genes was made.

They found one gene for IRAK1, which Macklis’ group identified to be regulated by MECP2 and is a well-known part of the NF-kB signaling pathway, was making about three times more protein than normal. They modified IRAK1 levels both in mice with Rett mutations and in mouse neurons in culture dishes. When they reduced the activity of its gene Irak1 by roughly half, and consequently the amount of IRAK1 protein made, the neurons and their dendrites developed substantially better, indistinguishable by several assays from normal. Further, mice with reduced levels of IRAK1 had significantly fewer symptoms, better function, and much longer lifespan. They had much improved health, well beyond only these neurons.

Now, Macklis said, the researchers have started looking into potential compounds and drugs that are already available and that might partially correct this pathway, and what dosages and timing might ultimately ameliorate the affects of Rett syndrome.

An X-linked Autism Spectrum Disorder

Rett syndrome is a postnatal neurodevelopmental disorder defined as an X-linked autism spectrum disorder. Put simply, it affects the development of the nervous system after birth. The underlying genetic defects have been associated with the X-chromosome, and it is a disorder which comes under the Autism Spectrum of disorders.

Rett syndrome principally affects women. Approximately 1 in 10,000 women are affected by this disorder. Despite being a genetic, developmental disorder, the symptoms for Rett Syndrome do not usually present until about 6 months following birth. What seems to be occurring is that impairment in the development of the nervous system is having a deleterious effect on learning. The symptoms are characterised by:

  • Normal development during gestation and for the first few months following birth, followed by a phase of developmental regression
  • Deceleration of head growth
  • Breathing disturbances during (but not limited to) waking
  • Loss of acquired skills in manual dexterity and hand movements resulting in repeated hand movements such as clapping, hand squeezing, wringing, and rubbing
  • Evidence of social withdrawal
  • Loss of learned vocabulary

Classical Rett syndrome exhibits most of the aforementioned symptoms and is usually the severe form. Variant Rett syndrome exhibits fewer of the described symptoms, so may appear to be more ‘mild’. In Variant Rett syndrome, there is improvement in the social withdrawal and communication symptoms into the mid to late teens. Disturbances in movement persist, however. There is also the risk of Rett syndrome patients undergoing scoliosis. Scoliosis is extreme curvature and twisting in the structure of the spine, showing some impairment in skeletal development also.

X-ray of scoliosis in a teenager, picture from The Lancet p.1533 vol.317 (2008)

Rett syndrome has been linked to a mutation in the X chromosome. In particular, this mutation occurs within the MECP2 gene. This gene codes for a protein involved in regulating the activity of some other genes by switching off their function. The mutations responsible for Rett Syndrome appear to inactivate the MECP2 gene, thus impairing gene silencing. Ordinarily, different genes are expressed during different stages of development. In Rett syndrome, genes from an earlier developmental stage which should be turned off to allow for a shift in genetic profile, remain switched on thus confusing the developmental progress. This disrupts the pattern of genetic expression, and has knock on effects on later development.

Rett Syndrome is part of the Autism spectrum disorders due to the social withdrawal which makes up part of the syndrome. Social skills rely on aspects of learning, and learning appears to be affected in Rett syndrome, as is evident from the loss of learned (acquired) skills. Learning is a process which involves modifications of the existing wiring of the brain, as well as forming new connections between neurons. This can be seen as a developmental process as neurons must produce new proteins and modify their structure and function. The impairments to cognitive and social function which occurs due to Rett Syndrome may be attributed to the effects of the mutations on learning and general development.

In studies comparing the size and weight of brains from average girls with those of Rett Syndrome sufferers, scientists found a reduction in weight of the brain of between 14-34% demonstrating a deficit in brain development. Regions which were affected the greatest were the cerebral cortex, midbrain and basal ganglia. Consistent with the symptoms, the cerebral cortex is principally associated with higher cognitive function and learning. The midbrain is part of the brain stem, and is involved in regulating basic processes such as respiratory rhythm and heart rate. The basal ganglia have some involvement in learning, as well as being the coordinators of limb movement.

A simple diagram of brain anatomy. I put this here because it shows the locations of the brainstem, cortex and the basal ganglia. The basal ganglia are a set of structures which include the structure highlighted in the diagram (which is the thalamus) are actually difficult to show a diagram of the brain such as this, as they’re actually buried within each hemisphere, and this picture only shows a section down the centre of the brain ( a sagittal section).

There are neuronal circuits in the brain stem which regulate breathing, outside of conscious influence. Impairment in the development of these circuits disrupts the function they’re supposed to carry out and this can have a knock on effect on how the brain coordinates breathing. The breathing difficulties appear to be most pronounced during waking hours, but do occur at night - albeit to a lesser extent. This has been attributed to the different neurochemical states the brain occupies during sleeping and waking. What this means is that some populations of neurons which use different neurotransmitters as their means of communication with each other, are implemented during sleep.  Activating a different system of neurons which is less affected by the underlying pathology of Rett syndrome may produce less negative effects on breathing. There may be impairment in the connections from arousal centres which feed into the breathing circuits to match their function with the organisms current state of arousal (sleep/wakefulness).

Rett syndrome is still a poorly understood disorder, and the science behind how it affects breathing still has some way to go. So far, our understanding tells us this much, but this complex disorder demonstrates the complex array of functions genes carry out, and how a large part of our seemingly fluid mind is at the mercy of basic genetics.

Rett Syndrome Hope

Discovery of a faulty connection between genes in mice with Rett syndrome has brought the possibility of effective therapies a step closer for this rare but devastating disorder in humans. The faulty link is believed to cause a gene called Irak1 to over-produce a protein, stunting the growth of brain cells called callosal projection neurons (CPNs) – pictured, stained green, in a section of a mouse cerebral cortex. When scientists reduced the activity of Irak1 in mice with Rett syndrome, levels of the protein fell back to normal, the CPNs developed properly and the mice had fewer symptoms. In humans, Rett syndrome often causes severe disability and loss of speech in girls from an early age. It’s rare in boys because male foetuses don’t often survive to birth.

Written by Mick Warwicker

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rettgive.org
A Cure for Irini | RettGive
My sweet daughter, IRINI, was diagnosed with Rett Syndrome in February 2015 at the age of 3 years old. In the year+ since the diagnosis...

Ηey guys. A cousin of mine has been diagnosed with Rett syndrome and they are trying to find a cure for it which does not currently exist. If you could be kind enough to donate even the smallest amount of money for the research I would be forever grateful. If you can’t donate, please reblog this so that other people can find it and maybe donate themselves. Thank you in advance.

p.s. All the information you could possibly get about the syndrome is in the link.

Stem Cell Derived ‘Mini Brains’ Reveal Potential Drug Treatment for Rare Disease

Using “mini-brains” built with induced pluripotent stem cells derived from patients with a rare, but devastating, neurological disorder, researchers at University of California, San Diego School of Medicine say they have identified a drug candidate that appears to “rescue” dysfunctional cells by suppressing a critical genetic alteration.

The research is in Molecular Psychiatry. (full access paywall)

Research: “Altered neuronal network and rescue in a human MECP2 duplication model” by S Nageshappa, C Carromeu, C A Trujillo, P Mesci, I Espuny-Camacho, E Pasciuto, P Vanderhaeghen, C M Verfaillie, S Raitano, A Kumar, C M B Carvalho, C Bagni, M B Ramocki, B H S Araujo, L B Torres, J R Lupski, H Van Esch and A R Muotri in Molecular Psychiatry doi:10.1038/mp.2015.128

Image: Analyses of the iPSC-derived neurons revealed novel molecular and cellular phenotypes, including an over-synchronization of the neuronal networks. Image is for illustrative purposes only and the original caption reads “Nerve cells, an example of a cell type after differentiation”. Credit: Nissim Benvenisty, Russo E/PLOS Biology.

First Pre-Clinical Gene Therapy Study to Reverse Rett Symptoms

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.

I’m gonna be honest people, communicating with a person who’s only “voice” is an eyebrow raise meaning “yes,” is incredibly frustrating

it can also bring some of the most fun, hilarious, exhilarating conversations you will ever have

because when you finally arrive at that thought they wanted to share, that hidden “yes” that holds so much relief for the nonverbal person, it may as well be “YES, THANK GOD, FINALLY,” you realize that while most conversations are free, some are hard-won, which, no matter what the topic, makes them unbelievably precious

justgiving.com
Eleanor Moore is fundraising for RETT UK

Okay y'all know Tyler is doing his fundraiser for the Trevor project Right now and it inspired my older sister to do something that means alot to us . We have a sister with a rare condition called rett Syndrome and her goal is £400. So far she’s raised £120 . At the end of the campaign in 4 week her and her boyfriend will be running a half marathon together and it would mean the world to me if you donated . Even a pound makes a difference