Einav Keet

A study led by investigators from Shinshu University in Nagano, Japan, has made a key discovery about the mechanism that causes microcephaly with pontine and cerebellar hypoplasia (MICPCH), a rare genetic disorder affecting brain development.

One of 2 CASK-related intellectual disabilities, 

 is a rare condition, with only 53 cases in females and 7 cases in males to date described in literature. Symptoms of the disorder include an unusually small head at birth that does not grow at the same rate as the body, severe intellectual disability, underdevelopment in the brain’s cerebellum and pons, seizures, sleep disturbances, vision and hearing loss, and decreased muscle tone. MICPCH is caused by mutations in the gene providing instructions for making a protein called calcium/calmodulin-dependent serine protein kinase (CASK), and the CASK gene is located on the X chromosome. The protein is mostly found in neurons and helps control the expression of genes that are important to brain development.

, investigators overcame obstacles to studying CASK-deficiency in mice by using X-chromosome inactivation in female mice, shutting off the CASK gene without killing the mice. They then examined the synaptic functions of CASK-knockout neurons in acute brain slices of heterozygous female mice, and examined CASK-knockdown neurons in acute brain slices generated by in utero electroporation.

“Unlike most of the genetic disorders in which all of the cells in the body have same mutant genotype, our disease model possesses normal and morbid cells in the body as a result of X-chromosome inactivation,” explained study author Katsuhiko Tabuchi, MD, PhD, in an interview with 

. The study examined the role of CASK in maintaining the balance of the excitatory neurons and inhibitory neurons in the brain that work to increase and decrease brain activity, and how mutations in the gene and an imbalance in this mechanism lead to neurological disorders.

“In our study, we found an increase in the excitatory synaptic function and decrease in the inhibitory synaptic function only in CASK mutant neurons, but not in wild-type neurons in the same brain,” added Tabuchi.

The study team found that the imbalance is caused by a decrease in concentration of a specific receptor on the membrane that receives signals from other neurons, and increasing the concentration restored balance. The findings, said Tabuchi, may have important implications for other mental disorders such as autism or epilepsy.

“Although the number of patients of MICPCH syndrome is not that many, I believe the basic idea in our study would be applicable, at least, to the other x-linked female neurodevelopmental disorders, such as Rett syndrome, of which pathophysiology is affected by x-chromosome inactivation,” he explained.

Tabuchi said the findings may help with research on the epilepsy drug diazepam, an enhancer of inhibitory synaptic transmission. “It may be harmful if it affects normal cells in the patients with those disorders,” he said. “Our model mice can provide the answer by testing those drugs. For the next step of our work, we aim to study how skewness of the distribution of 2 different genotype of cells affects the symptoms of disorders. We also want to study whether normal and mutant neurons constitute neural circuit separately or cooperatively.”

Deficiency of calcium/calmodulin-dependent serine protein kinase disrupts the excitatory-inhibitory balance of synapses by down-regulating GluN2B

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Research into a rare neurological disorder may help researchers working on more common diseases including autism and epilepsy.

Insights on Rare MICPCH Syndrome Could Help with Autism, Epilepsy

A new study details the work of a research team from the Université Laval in Québec City, Canada, on a new therapeutic approach for amyotrophic lateral sclerosis (ALS).

ALS is a rare neurological condition that mainly involves the nerve cells, or neurons, responsible for controlling voluntary muscle movement. Cases of ALS progress rapidly and as motor neurons degenerate and die, they stop sending messages to muscles, which then gradually weaken and atrophy. Early symptoms include muscle twitching and weakness in the arms, hands, legs, and swallowing muscles, and later progress into difficulties moving, swallowing, and speaking.

Patients with ALS typically die of respiratory failure within 3 to 5 years of onset, though about 10% of ALS patients go on to live for 10 or more years. There are 2 new cases of ALS each year per 100,000 people, and worldwide, ALS affects white males ages 60 years and older more than any other group.

There is currently no cure for ALS or any treatment that halts or reverse the progression of the disease, though research continues into 

potential new therapies, such as trazodone

 investigators detail research on an antibody they developed to target the TDP-43 protein—which the team had previously found is overexpressed in the spinal cords of people with ALS&mdash;in the brains of mice with ALS. The development of TDP-43 aggregates in nerve cells leads to an exaggerated inflammatory response that increases neurons’ vulnerability.

The investigators produced the TDP-43-targeting antibodies by inserting genetic material encoding the antibody into viruses, and for 2 months gave them to mice that had developed TDP-43 aggregates. The mice receiving the antibodies showed significant improvements in their cognitive and motor performance.

®, principal investigator Jean-Pierre Julien, PhD, described the team’s findings. “The mice were analyzed for pathological changes. The treatment ameliorated pathological defects including the preservation of neuromuscular junctions. So, in principle and providing that antibodies are present in the appropriate motor neurons, there should be amelioration of deficits,” said Julien. “However, we did not monitor respiratory function in the mice and phrenic motor neurons following the treatment in the mice.”

The investigative team is currently working on a way to create the antibodies that doesn’t use viruses. “The alternative to viral-mediated transfer of small single chain antibody is to use full length antibodies against TDP-43,” explained Julien. “We have preliminary data, unpublished yet, suggesting that antibodies can penetrate motor neurons when injected chronically intrathecally in mice. Work is in progress in my lab to test this approach in a mouse model of ALS. Intrathecal administration of antibodies with a mini-pump would be a suitable approach for ALS patients.”

If full length antibodies injected intrathecally succeeds in mitigating TDP-43 pathology, said Julien, the next step will be to humanize the antibody and to test it in model systems. “If all does well, it will take about 3 years before initial testing in human ALS patients.”

Viral-mediated delivery of antibody targeting TAR DNA—binding protein 43 mitigates associated neuropathology

Investigators have found that mice with ALS given the novel treatment showed significant improvements in their cognitive and motor performance.

Experimental ALS Therapy Uses Antibodies to Target TDP-43 protein

A new study details a discovery by investigators in Texas and China, which sheds light on what makes 

 so hard to stop and offers new insight into how to halt its progression.

 are malignant Grade IV tumors made up of abnormal astrocytic cells. With this aggressive and lethal brain cancer, tumors readily spread into nearby brain tissue, and at times, to the opposite side of the brain.

While there is no cure for glioblastoma, investigators at the University of Texas MD Anderson Cancer Center are working on the Glioblastoma Moon Shot program, which is part of an ambitious plan to accelerate the termination of 13 types of cancer.

More specifically, a team of investigators from the University of Texas MD Anderson Cancer Center and the Beijing Institute for Brain Disorders examined the functional role of fibrinogen-like protein 2 (FGL2)—a membrane-bound or secreted protein expressed by macrophages, T cells, and tumor cells that have coagulation activity or immune-suppressive functions&mdash;in glioblastoma. 

According to the new study, prior research has found that FGL2 promotes mammary tumor progression and is a key hub of tumor-mediated immune suppression in glioblastoma multiforme. However, its functional role at the molecular and cellular levels has been mostly unknown.

In the current study, investigators found that high expression of FGL2 in glioblastoma allows the protein to control a specialized group of CD103 dendritic cells, which are necessary for the activation of tumor-killing T cells. In addition, investigators discovered that these dendritic cells can only activate T cells by making their way to the tumor microenvironment in the central nervous center.

By using a FGL2 neutralization, or “knockout” therapy on tumor cells, investigators found they could achieve FGL2 “knockout” and eliminate tumor progression in mice with intact immune systems. In an interview with 

®, study co-lead Shulin Li, PhD, explained that the research team is testing other types of Fgl2 neutralization therapy, with promising results. “We have a Fgl2 neutralization cell therapy ready for clinical trials whenever clinicians are ready,” said Li.

Along with these findings, the investigators analyzed human glioblastoma from The Cancer Genome Atlas and found that lower levels of FGL2 protein expression coupled with other factors was associated with longer survival of glioblastoma patients.

“GBM is a deadly disease because of its aggressive growth, invasion of surrounding tissues, and poor immunogenicity. Here we show that knockout of FGL2 in tumor cells induces adaptive immune responses, resulting in 100% tumor suppression in GL261, DBT, and LLC brain tumor model systems,” the study’s authors wrote. “These unexpected results suggest that FGL2 in tumor cells could serve as a potential therapeutic target for treating brain tumors and preventing tumor relapse. Supporting this conclusion, our previously published data showed that blocking FGL2 prolonged survival.”

About 15% of all primary brain tumors are 

. The median survival time for adults with glioblastoma can range from 11 to 31 months depending on the type of tumor, and tumor growth can be slowed by radiation and chemotherapy following surgery

FGL2 promotes tumor progression in the CNS by suppressing CD103

Investigators working on Glioblastoma Moon Shot program have made a key discovery on glioblastoma progression, identifying a key target to help stop it.

Targeting an Immune Regulating Protein May Help Halt Glioblastoma Progression

Investigators conducting studies on genomic sequencing in healthy newborns and adults say they have found genetic results revealing far more variants associated with diseases than previously anticipated, along with previously unrecognized, but related, clinical features of genetic conditions.

 (NIH) compiles information on more than 1200 health conditions with a genetic basis. A 

 or mutation can be inherited from a parent or acquired during the course of a person’s life. A genetic variation can make a gene function improperly and may influence the risk of developing certain disorders. Some individuals with a genetic predisposition to disease may go on to develop disease while others with the same variant will never get the disease.

Investigators from Brigham and Women’s Hospital and Boston Children’s Hospital working on the 

 Projects. In these 2 randomized clinical trials, the study team has worked to analyze the genomes of infants and adults for approximately 5000 disease-associated genes to identify monogenic disease risk variants—mutations associated with diseases thought to be caused by variants in a single gene. These monogenic diseases include rare diseases such as hereditary cancer syndromes, hereditary cardiac syndromes, and metabolic disorders that can have life-threatening complications.

In research presented at the recent 2018 American Society for Human Genetics meeting, BabySeq and MedSeq investigators say they have found that searching for unanticipated genetic results in newborns and adults can reveal far more variants associated with diseases than previously thought. In addition, they can detect previously unrecognized, but related, clinical features of genetic conditions. 

These findings come following the team’s genome or exome sequencing on a total of 269 individuals. They found unanticipated risk variants in 16 of 110 adults (14.5%) and in 18 of 159 infants (11.3%). Upon further examination on these study participants, the investigators discovered clinical features suggestive of a previously unrecognized genetic condition in 4 of the adult cases and 4 of the newborn cases, including 3 cases with highly effective interventions.

“These results are unexpected and exciting, suggesting that if we examine enough well-established, disease-associated genes, we will unearth monogenic risk variants in more than 10 percent of purportedly healthy individuals,” the projects’ principal investigator Robert Green, MD, MPH, said in a recent statement. “And, if on the basis of these genetic clues, we carefully examine those individuals, we find that a quarter of them have previously unrecognized features of underlying disease—something that we might never have realized had we not performed genetic sequencing.”

Additional presentations made by the team at the recent meeting included The Impact of Newborn Genomic Sequencing on Families: Findings from the BabySeq Project and Analysis of Actionable Adult-Onset Disease Risk Findings in Newborn Genomic Sequencing. The BabySeq Project is funded by a 5-year $25 million grant from the National Institute of Child Health and Human Development and the National Human Genome Research Institute. MedSeq is also funded by the NIH.

New research suggests that more healthy people than previously thought have genetic variants associated with disease.

Einav Keet

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