MSCs: what’s in a name?

Whether they are "stem" or "stromal", from adult tissues or from umbilical cord blood, MSCs are being used for a lot of clinical trials. Read more

Mopping up immune troublemakers after transplant

Memory CD8+ T cells play an important role in kidney transplant rejection, and they resist drugs that would otherwise improve Read more

Tracking a frameshift through the ribosome

Ribosomal frameshifting, visualized through X-ray Read more

Fragile X Syndrome

Fragile X: preclinical portfolio for PI3k drug strategy

Research in mice shows that a pharmacological strategy can alleviate multiple behavioral and cellular deficiencies in a mouse model of fragile X syndrome (FXS), the most common inherited form of intellectual disability and a major single-gene cause of autism spectrum disorders.

The results were published online last week by Neuropsychopharmacology, and were presented at the NFXF International Fragile X Conference in Cincinnati.

When the compound GSK6A was given to mice lacking the Fmr1 gene, an established animal model of fragile X syndrome, it relieved symptomatic behaviors, such as impaired social interactions and inflexible decision making, which can be displayed by humans with fragile X syndrome.

The findings indicate that treatment with GSK6A or a similar compound could be a viable strategy for addressing cognitive and behavioral problems in fragile X syndrome; this would need to be tested directly in clinical trials. GSK6A inhibits one particular form of a cellular signaling enzyme: the p110β form of PI3 (phosphoinositide-3) kinase. A closely related p110β inhibitor is already in clinical trials for cancer.

Video from the iBook “Basic Science Breakthroughs: Fragile X Syndrome”. Narration by Emory genetics chair Stephen Warren, whose team identified the gene responsible for fragile X.

“Our results suggest that p110β inhibitors can be repurposed for fragile X syndrome, and they have implications for other subtypes of autism spectrum disorders that are characterized by similar alterations of this pathway,” says Gary Bassell, PhD, professor and chair of cell biology at Emory University School of Medicine.

“Right now, no proven efficient treatments are available for fragile X syndrome that are targeted to the disease mechanism,” says Christina Gross, PhD, from Cincinnati Children’s. “We think that p110β is an appropriate target because it is directly regulated by FMRP, and it is overactivated in both mouse models and patient cell lines.”

The paper represents a collaboration between three laboratories: two at Emory led by Bassell and Shannon Gourley, PhD, and one at Cincinnati Children’s, led by Gross. Gourley is based at Yerkes National Primate Research Center; see this earlier item on her collaboration with Bassell here.

While the researchers are discussing clinical trials of p110β inhibitors in fragile X syndrome, they say that long-term studies in animals are needed to ensure that undesirable side effects do not appear. More here.

With respect to clinical trials, the fragile X community has been disappointed before. Based on encouraging studies in mouse models, drugs targeting mGluR5 glutamate receptors were tested in adolescents and adults. mGluR5 drugs did not show clear benefits; recent re-evaluation suggests the choice of outcome measures, the ages of study participants and drug tolerance may have played a role.

Warren played a major role in developing the mGluR5 approach and Emory investigators were part of those studies. More recently, clinical trials for one of the mGluR5 medications were revived in younger children and Emory is a participating site. Also, see this 2016 discussion in Spectrum with Elizabeth Berry-Kravis on the fragile X mouse model; Bassell, Gross and Gourley have made some inroads on the limitations Berry-Kravis describes.

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Toe in the water for Emory cryo-EM structures

Congratulations to Christine Dunham and colleagues in the Department of Biochemistry for their first cryo-electron microscopy paper, recently published in the journal Structure.

The paper solves the structure of a bacterial ribosome bound to a messenger RNA containing a loop that regulates translation. This process is important for the study of several neurological diseases such as fragile X syndrome, for example.

Christine Dunham, PhD

Dunham writes: “We are focusing on establishing this in bacteria to understand frameshifting and protein folding as a consequence of codon preference. We will then build up our knowledge to potentially study eukaryotic translational control.”

The paper neatly links up with two Nobel Prizes: the 2017 Chemistry prize for cryo-electron microscopy and the 2009 Chemistry prize for ribosome structure, awarded in part to Dunham’s mentor Venki Ramakrishnan. Also, see this 2015 feature from Nature’s Ewen Callaway outlining how cryo-EM is a must have for structural biologists wanting to probe large molecules that are difficult to crystallize.

Construction now underway in the Biochemistry Connector will allow installation of microscopes (worth $6 million) necessary for Dunham and others to do cryo-EM here at Emory, although she advises that it will be several months until they are photo-op ready. For the Structure paper, Dunham collaborated with George Skiniotis at University of Michigan; he recently moved to Stanford. Read more

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Insight into brain + learning via ‘friend of fragile X’ gene

We can learn a lot about somebody from the friends they hang out with. This applies to people and also to genes and proteins. Emory scientists have been investigating a gene that we will call — spoiler alert — “Friend of fragile X.”

Fragile X syndrome is the most common inherited form of intellectual disability, studied by research teams around the world with drug discovery and clinical trials in mind. It is caused by a disruption of the gene FMR1.

In an independent form of inherited intellectual disability found in a small number of Iranian families, a gene called ZC3H14 is mutated. Two papers from Ken Moberg, PhD, associate professor of cell biology, Anita Corbett, PhD, professor of biology and colleagues show that FMR1 and ZC3H14 are, in effect, friends.

The findings provide new insight into the function of FMR1 as well as ZC3H14; the evidence comes from experiments performed in fruit flies and mice. The most recent paper is in the journal Cell Reports (open access), published this week.

The scientists found that the proteins encoded by FMR1 and ZC3H14 stick together in cells and they hang out in the same places. The two proteins have related functions: they both regulate messenger RNA in neurons, which explains their importance for learning and memory.

The fragile X protein (FMRP) was known to control protein production in response to signals arriving in neurons, but the Cell Reports paper shows that FMRP is also regulating the length of  “tails” attached to messenger RNAs – something scientists did not realize, even after years of studying FMRP and fragile X, Moberg says.

To be sure, FMRP interacts with many proteins and appears to be a critical gatekeeper. Emory geneticist Peng Jin, who has conducted his share of research on this topic, says that “FMRP must be very social and has a lot of friends.” More here.

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Fragile X regulation is a finely tuned machine

A PNAS paper published Monday demonstrates the kinds of insights that can be gleaned from a large scale sequencing project examining the fragile X gene.

Most children (boys, usually) who have fragile X syndrome have a particular mutation. An expanded “triplet repeat” stretch of DNA, which is outside the protein-coding region of the gene, puts the entire gene to sleep.

At Emory, geneticist Steve Warren, cell biologist Gary Bassell and colleagues have been identifying less common changes in the fragile X gene by looking in boys who are developmentally delayed, but don’t have the triplet repeat expansion. The first author of the paper is former postdoc Joshua Suhl, now at Booz Allen Hamilton in Massachusetts.

The authors describe two half-brothers who have the same genetic variant, which changes how production of the FMRP protein is regulated. These examples show that the fragile X gene is so central to how neurons function that several kinds of genetic glitches in it can make this finely tuned machine break down.

“This is a hot area and not much is known about it,” Warren says. Read more

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Fragile X syndrome: building a case for a treatment strategy

New research in mice strengthens a potential strategy for treating fragile X syndrome, the most common inherited form of intellectual disability and a major single-gene cause of autism spectrum disorder.

The results, published April 23 in Cell Reports, suggest that a drug strategy targeting a form of the enzyme PI3 (phosphoinositide-3) kinase could improve learning and behavioral flexibility in people with fragile X syndrome. The PI3 kinase strategy represents an alternative to one based on drugs targeting mGluR5 glutamate receptors, which have had difficulty showing benefits in clinical trials.

Research led by Emory scientists Gary Bassell, PhD and Christina Gross, PhD had previously found that the p110β form of PI3 kinase is overactivated in the brain in a mouse fragile X model, and in blood cells from human patients with fragile X syndrome.

Now they have shown that dialing back PI3 kinase overactivation by using genetic tools can alleviate some of the cognitive deficits and behavioral alterations observed in the mouse model. Drugs that target the p110β form of PI3 kinase are already in clinical trials for cancer.

“Further progress in this direction could lead to a clinical trial in fragile X,” says Bassell, who is chair of Cell Biology at Emory University School of Medicine. “The next step is to test whether this type of drug can be effective in the mouse model and in human patient cells.” Read more

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Regrouping on fragile X drug strategies

Fragile X syndrome has many fascinating aspects:

* the complex inheritance pattern

* its status as the most common inherited form of intellectual disability and a major single-gene cause of autism spectrum disorder (ASD)

*the importance of the RNA-binding protein FMRP as a regulator of synaptic plasticity in neurons

*the potential applicability of drugs developed for fragile X for other forms of ASD

Readers interested in neurodevelopment disorders may want to check out this Nature Reviews Drug Discovery piece, which chews over some setbacks in clinical research on fragile X. Emory researchers have a strong connection with the drug strategies used in the recent clinical trials, but have also been working on alternative approaches. Read more

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Point mutation in fragile X gene reveals separable functions in brain

A new paper in PNAS from geneticist Steve Warren and colleagues illustrates the complexity of the protein disrupted in fragile X syndrome. It touches on how proposed drug therapies that address one aspect of fragile X syndrome may not be able to compensate for all of them. [For a human side of this story, read/listen to this recent NPR piece from Jon Hamilton.]

Fragile X syndrome is the most common single-gene disorder responsible for intellectual disability. Most patients with fragile X syndrome inherit it because a repetitive stretch of DNA, which is outside the protein-coding portion of the fragile X gene, is larger than usual. The expanded number of CGG repeats silences the entire gene.

However, simple point mutations affecting the fragile X protein are possible in humans as well. In the PNAS paper, Warren’s team describes what happens with a particularly revealing mutation, which allowed researchers to dissect fragile X protein’s multifaceted functions. Read more

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Socialization relative strength in fragile X longitudinal study

A study published in Pediatrics this week tracks “adaptive behavior” as children and adolescents with fragile X syndrome are growing up. This is the largest longitudinal study to date in fragile X, which is the leading inherited cause of intellectual disability and the leading single-gene risk factor for autism spectrum disorder.

Adaptive behavior covers a range of everyday social and practical skills, including communication, socialization, and completing tasks of daily living such as getting dressed. In this study, socialization emerged as a relative strength in boys with fragile X, in that it did not decline as much as the other two domains of adaptive behavior measured: communication and daily living skills.

The lead author of the paper is Cheryl Klaiman, formerly of the Stanford University Center for Interdisciplinary Brain Sciences, now senior psychologist at Marcus Autism Center.

The “socialization as relative strength in fragile X” findings meshes with a growing awareness in the autism field, summarized nicely here by Jessica Wright at the Simons Foundation Autism Research Initiative, that fragile X syndrome symptoms are often distinct from those in autism spectrum disorder.

One key distinction between the disorders, for example, is in social interactions. Children with autism and those with fragile X syndrome both shy away from social contact, have trouble making friends and avert their gaze when people look at them.

But children with fragile X syndrome often sneak a peek when the other person turns his back, researchers say. Children with autism, in contrast, seem mostly uninterested in social interactions.

“Children with fragile X syndrome all have very severe social anxiety that plays a big role in the perception that they have autism,” says Stephen Warren, professor of human genetics at Emory University School of Medicine in Atlanta. “They are actually interested in their environment; they are just very shy and anxious about it.”

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Fragile X clinical trials: this is not the end

A clinical trial testing a therapy for children with fragile X syndrome is closing down, after the sponsoring company announced that the drug, called arbaclofen, was not meeting its goals.

Readers of Emory Health magazine may remember Samuel McKinnon, an arbaclofen study participant who was featured in a 2012 article and video (below).

“We were surprised,” Samuel’s mother Wendy told us Monday. “But we knew going in that there were no guarantees.”

She reports that Samuel has made significant progress in the last couple of years. He likes playing and talking with the family’s new puppy, Biscuit. Samuel’s language skills have Ray Ban outlet blossomed and he will be headed to second grade this fall. But it’s hard to say whether that’s mainly because of the experimental drug or because Samuel has been continuing to grow and work hard in school and in therapy, she says.

A sizable fraction of patients in the study appeared to benefit from the drug, just not the majority of them, says Emory genetics chair Steve Warren.

Read more

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Links between autism and epilepsy

An article in the April 2011 issue of Nature Medicine highlights the mechanistic overlap between autism and epilepsy.

By studying how rare genetic conditions known to coincide with both epilepsy and autism—such as Rett syndrome, fragile X syndrome and tuberous sclerosis—unfold at an early age, neuroscientists are finding that both disorders may alter some of the same neural receptors, signaling molecules and proteins involved in the development of brain cell synapses.

Gary Bassell, PhD

Emory cell biologist Gary Bassell and his colleagues have been taking exactly this approach. Recently they published a paper in Journal of Neuroscience, showing that the protein missing in fragile X syndrome, FMRP, regulates expression of an ion channel linked to epilepsy. This could provide a partial explanation for the link between fragile X syndrome and epilepsy.

The Nature Medicine article also mentions a drug strategy, targeting the mTOR pathway, which Bassell’s group has been exploring with fragile X syndrome.

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