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Lysosomes in Healthy Neurons and in Neurons with Juvenile Batten Disease

Researchers at Baylor College of Medicine, Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital and King’s College London have discovered a treatment that improves the neurological symptoms in a mouse model of juvenile Batten disease. This discovery brings hope to patients and families affected by the disease that a treatment might be available in the future. The study appears in Nature Communications.

“Patients with juvenile Batten disease are born healthy and reach the expected developmental milestones of the first 4 to 6 years of age,” said senior author Dr. Marco Sardiello, assistant professor of molecular and human genetics at Baylor. “Then, these children progressively regress their developmental achievements; they gradually lose their vision and develop intellectual and motor disabilities, changes in behavior and speech difficulties. Most people with this condition live into their 20s or 30s. This inherited, rare disease has no cure or treatment other than palliative care.”

“As we started this project, patients and families affected by this condition visited us in the laboratory,” said first author Dr. Michela Palmieri, who was a postdoctoral fellow in the Sardiello lab during this project and currently is at the San Raffaele Scientific Institute in Milan, Italy. “We were deeply affected by our interactions with the patients and their families and this further motivated us to pursue this research with the hope that maybe one day it will lead to a treatment that will improve the lives of people affected by this condition.”

Juvenile Batten disease, a problem with cellular waste management

Like a large dynamic city, a cell carries out many activities that generate waste. Waste needs to be disposed of properly in order for the city to continue its activities without interruption. If waste management fails, waste progressively accumulates and eventually leads to interruption and paralysis of the activities of the city. Something similar happens in cells when cellular waste is not discarded.

The lysosomes are the structures in charge of clearing the waste produced by the cell’s regular functions. Lysosomes are sacs inside all cells containing enzymes that degrade cellular waste into its constituent components, which the cell can recycle or discard. When lysosomes fail and cellular waste accumulates, disease follows. Although all types of cells can be affected by defects in lysosomal waste processing and cellular waste accumulation, brain cells – neurons – are particularly susceptible.

“In juvenile Batten disease, one of nearly 50 human lysosomal storage disorders, the function of brain cells is progressively affected by the accumulation of cellular waste,” Sardiello said. “This accumulation leads to perturbation of many cellular processes, cell death and progressive regression of motor, physical and intellectual abilities.”

A novel approach to finding a treatment

“A few years back we discovered a protein in cells called TFEB, a master transcription factor that stimulates the cell to produce more lysosomes and degrade cellular waste more effectively,” said Sardiello. “So we thought about counteracting the accumulation of cellular waste in Batten disease by acting on TFEB.”

“We and others had found that enhancing the activity of TFEB genetically can help counter the accumulation of cellular waste in different diseases,” Sardiello said. “What was missing was a way to activate TFEB with a drug that in the future could be put in a pill to treat the condition. We focused on investigating how to activate TFEB pharmacologically.”

“We discovered that TFEB is under the control of another molecule called Akt, which is a kinase, a protein that can modify other proteins,” said Palmieri. “Akt has been studied in detail. There are drugs available that can modulate the activity of Akt.”

The researchers discovered that Akt modifies TFEB by adding a chemical group, a phosphate, to it. This chemical modification inactivates TFEB.

“We wanted to inhibit Akt to keep TFEB more active,” said Palmieri. “We discovered that the sugar trehalose is able to do this job.”

Testing a treatment for juvenile Batten disease in a mouse model of the condition

The scientists tested the effect of trehalose in a mouse model of juvenile Batten disease.

“We dissolved trehalose in drinking water and gave it to mice that model juvenile Batten disease,” said Sardiello. “Then, over time we examined the mice’s brain cells under the microscope. We found that the continuous administration of trehalose inhibits Akt and activates TFEB in the brains of the mice. More active TFEB meant more lysosomes in the brain and increased lysosomal activity, followed by decreased accumulation of the storage material and reduced tissue inflammation, which is one of the main features of this disease in people, and reduced neurodegeneration. These changes resulted in the mice living significantly longer. This is a good start toward finding a treatment for people with this disease.”

“We are very excited that these findings put research a step closer to understanding the mechanisms that underlie human lysosomal storage diseases,” said Palmieri. “We hope that our research will help us design treatments to counteract this and other human diseases with a pathological storage component, such as Alzheimer’s, Huntington’s and Parkinson’s diseases, and hopefully ameliorate the symptoms or reduce the progression of the disease for those affected.”

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Scientists Engineer Gene Pathway to Grow Brain Organoids with Surface Folding

One of the most significant ways in which the human brain is unique is the size and structure of the cerebral cortex. But what drives the growth of the human cortex, likely the foundation for our unique intellectual abilities?

In research published in the journal Cell Stem Cell—in a study entitled, Induction of expansion and folding in human cerebral organoids—researchers at Whitehead Institute provide insight into a specific gene pathway that appears to regulate the growth, structure, and organization of the human cortex. They also demonstrate that 3D human cerebral organoids—miniature, lab-grown versions of specific brain structures—can be effective in modeling the molecular, cellular, and anatomical processes of human brain development. And they suggest a new path for identifying the cells affected by Zika virus.

“We found that increased proliferation of neural progenitor cells (NPs) induces expansion of cortical tissue and cortical folding in human cerebral organoids,” says Yun Li, a lead author of study and post-doctoral researcher at Whitehead Institute. “Further, we determined that deleting the PTEN gene allows increased growth factor signaling in the cell, unleashing its growth potential, and stimulating proliferation.”

These findings lend support to the notion that an increase in the proliferative potential of NPs contributes to the expansion of the human cerebral neocortex, and the emergence of surface folding.

With normal NPs, the human organoid developed into relatively small cell clusters with smooth surface appearance, displaying some features of very early development of a human cortex. However, deleting PTEN allowed the progenitor population to continue expanding and delayed their differentiation into specific kinds of neurons—both key features of the developing human cortex. “Because the PTEN mutant NPs experienced more rounds of division and retained their progenitor state for an extended period, the organoids grew significantly larger and had substantially folded cortical tissue,” explains Julien Muffat, also a lead author and post-doctoral researcher at Whitehead Institute.

In contrast, they found that while PTEN deletion in mouse cells does create a somewhat larger than normal organoid, it does not lead to significant NP expansion or to folding. “Previous studies have suggested that abnormal variation in PTEN expression may play an important role in driving brain development conditions leading to syndromes such as Autism Spectrum Disorders,” says Rudolf Jaenisch, Founding Member of Whitehead Institute and senior author of the study. “Our findings suggest that the PTEN pathway is also an important mechanism for controlling brain-structure differences observed between species.”

The Whitehead investigators chose to focus on the PTEN gene because it had previously been shown to have some function in cortical development and to have a role in regulating progenitor cells of various lineages. Notably PTEN loss-of-function mutations have been associated with human macrocephaly.

In this study, deletion of the PTEN gene increased activation of the PI3K-AKT pathway and thereby enhanced AKT activity in the human NPs comprising the 3D human cerebral organoids; it promoted cell cycle re-entry and transiently delayed neuronal differentiation, resulting in a marked expansion of the radial glia and intermediate progenitor population. Validating the molecular mechanism at work with PTEN, the investigators used pharmacological AKT inhibitors to reverse the effect of the PTEN deletion. They also found that they could regulate the degree of expansion and folding by tuning the strength of AKT signaling—with reduced signaling resulting in smaller and smooth organoids, and increased signaling producing larger and more folded organoids.

Finally, the researchers utilized the 3D human cerebral organoid system to show that infection with Zika virus impairs cortical growth and folding. In the organoids, Zika infection at the onset of surface folding (day 19 of development) led to widespread apoptosis; and, ten days later, it had severely hampered organoid growth and surface folding. Zika infection of 4-week-old organoids, showed that PTEN mutant organoids were much more susceptible to infection than normal control organoids; notably, they showed increased apoptosis and decreased proliferation of progenitor cells.

“Although not an original goal of our study, we have demonstrated that 3D human cortical organoids can be very effective for Zika modeling—better enabling researchers to observe how human brain tissue reacts to the infection and to test potential treatments,” Li says.

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Researchers Find Potential Therapy For Brain Swelling During Concussion

Biomedical engineering researchers pre-treated cells that swell after traumatic injury with an existing, FDA-approved drug.

A team of biomedical engineering researchers at the University of Arkansas have identified a cause of fluid swelling of the brain, or cellular edema, that occurs during a concussion.

The researchers discovered that pre-treating the cells with an existing, FDA-approved drug used for epilepsy and altitude sickness reduces the expression of a specific protein that causes swelling.

Their findings were published in a recent issue of Nature’s Scientific Reports.

“Our study found that mild traumatic brain injury resulted in increased expression of a protein called aquaporin-4, which caused a massive cellular influx of fluid, leading to increased astrocyte cell volume and injury,” said Kartik Balachandran, assistant professor of biomedical engineering. “We then worked with a drug called Acetazolamide. Our results showed that Acetazolamide minimized cell swelling and injury, suggesting a therapeutic role for this drug in reducing the detrimental effects of concussions.”

In addition to Balachandran, who led the study, the research was conducted by Nasya Sturdivant, biomedical-engineering doctoral candidate; Jeffrey Wolchok, assistant professor of biomedical engineering; and partners at the FDA’s National Center for Toxicological Research in Jefferson, Arkansas.

Mild traumatic brain injury, also known as a concussion, is a devastating condition that is commonly experienced in car accidents, full-contact sports and battlefield injuries. One of the main factors that leads to the high death rate in patients who experience mild traumatic brain injury is the swelling or edema of astrocytes, the most abundant cell type in the brain.

The researchers engineered a benchtop bioreactor to examine astrocyte cells. This device helped them see that mild traumatic brain injury led to an increased expression of aquaporin-4, the protein that causes a large cellular influx of fluid, which in turn leads to increased astrocyte cell volume.

“This study demonstrates the collaborative neuro-engineering efforts that are contributing to both diagnostic and therapeutic methods for addressing traumatic brain injury,” said Raj Rao, professor and chair of the Department of Biomedical Engineering at the University of Arkansas.

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New Study Finds Cardiac PET/CT Imaging Effective In Detecting Calcium Blockages, Assessing Heart Attack Risk

Many people who experience chest pain but don’t have a heart attack breathe a big sigh of relief when a stress test comes back negative for blockages in their blood vessels.

But a new study by cardiac researchers at the Intermountain Medical Center Heart Institute in Salt Lake City found they may not be off the hook after all.

Researchers studied 658 men and women between the ages of 57 and 77 who passed a stress test for blocked arteries and who were later found to have calcium in their arteries after being screened by imaging technology that measured their total coronary artery calcification.

They found that five percent of patients who passed their stress test and later tested high for calcium in their arteries — 31 of 658 patients — went on to have an adverse cardiac event within one year. Such events included death, heart attack and stroke.
Researchers say there is something more doctors can do to assess a patient’s risk of future heart attack: check the calcium — a sign of plaque buildup — in a patient’s arteries.

“We now have the ability to better measure coronary artery calcification,” says Viet Le, MPAS, PA-C, lead author of the Intermountain Medical Center Heart Institute study, who will deliver results at the American Heart Association Scientific Session in New Orleans on Nov 14, at 10:45 am, CST.

“People say, ‘I’m good. They gave me a stress test,’” said Le. “But it doesn’t tell the whole story. The story it tells is that on that day your engine — your heart — passed the test. Some of these people die within a year from a heart attack.”
Cardiac experts have known for years that calcium left by plaque is a good marker of heart disease, but there was not good imaging technology to measure it without exposing the patient to too much radiation, Le said. That changed about five years ago.
PET/CT, an advanced nuclear imaging technology that combines positron emission tomography (PET) and computed tomography (CT) in one machine, allows physicians doing a chemical stress test to also measure coronary artery calcification.

Calcification cannot be reversed, but the plaque that causes it can be reduced or stabilized with proper medication, diet and exercise.

Researchers found that 33 patients in the study, or five percent, had no or mild calcification, and they had no cardiac events. But there was a significant correlation between the amount of calcium and the occurrence of cardiac events in the remainder of the patients.

Twelve of 309 (3.88 percent) patients with moderate calcification had a cardiac event within a year, 10 of 190 (5.26 percent) with severe calcification had a cardiac event within a year, and nine of 126 (7.14 percent) with very severe calcification had a cardiac event within a year. In total, 16.28 percent of calcified patients in the study had a heart event.

The results confirmed for Le the value of assessing calcification in patients suspected of having clogged arteries.

“Right now, it’s a neglected tool that should better be utilized,” he said.

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Temple Attains $20 Million Award For Materials, Brain Injury Research

In one of the largest cooperative agreements for research in Temple University history, an interdisciplinary team of faculty is participating in a $20 million, two-year agreement with other universities and the U.S. Army Research Laboratory, or ARL.

Temple will be working with the ARL to perform research in three major areas: understanding and improving the performance of materials through the use of computational modeling; understanding the mechanisms and thresholds of traumatic brain injury by reviewing clinical, behavioral and biochemical changes related to traumatic brain injuries and concussions; and exploring new ways to improve protection against ballistics impacts.

“This pioneering research by some our most highly regarded faculty supports the protection of soldiers and also has potential for broader applications,” said Temple University President Richard M. Englert. “Temple’s research enterprise is clearly on the rise, and this is a tremendous example of what our expertise can do to improve lives.”

Other higher education collaborators include the University of Southern California, University of Southern Mississippi and the University of North Texas.

“ARL is creating a transformative global science and technology ecosystem by linking government, academia and business to share the best and brightest people, ideas and facilities in forward-reaching research areas of strategic importance to the Army,” said Philip Perconti, ARL acting director.

Under the leadership of Vice President for Research Michele M. Masucci, Temple’s research team features: College of Science and Technology Dean and Laura H. Carnell Professor of Science Michael L. Klein; Laura H. Carnell Professor of Physics and Chemistry John Perdew; Associate Professor of Neuroscience and Neurovirology T. Dianne Langford of Temple’s Lewis Katz School of Medicine; and Associate Professor of Kinesiology Ryan Tierney in the College of Public Health. Langford and Tierney’s project team includes additional Temple faculty from medicine, engineering, science and technology, and public health, as well as a representative from Temple Athletics.

“This award evidences that by working together across schools, colleges and universities, Temple’s faculty is able to provide national leadership in the design, development and measurement of advanced materials to protect army personnel as well as athletes,” Masucci said. “Through improving our knowledge of the protective effects of such materials by conducting clinical studies of their use, we hope to dramatically improve the safety of individuals at risk for traumatic brain injury.”

The research effort, which aims to create a new class of materials for use in personal protective equipment and decrease brain injuries, will leverage Temple’s Center for Computational Design of Functional Layered Materials and the Temple Materials Institute to develop and test new materials, as well as the university’s clinical, research and educational expertise in monitoring and understanding the consequences of head injuries.

“The project will also develop technologies that can be commercialized and brought to market, broadening the benefits of the program to society at large,” said Stephen Nappi, Temple’s associate vice president for technology commercialization and business development.

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Restoring The Sense Of Touch In Amputees Using Natural Signals Of The Nervous System

Scientists at the University of Chicago and Case Western Reserve University have found a way to produce realistic sensations of touch in two human amputees by directly stimulating the nervous system.

The study, published Oct. 26 in Science Translational Medicine (STM), confirms earlier research on how the nervous system encodes the intensity, or magnitude, of sensations. It is the second of two groundbreaking publications this month by University of Chicago neuroscientist Sliman Bensmaia, PhD, using neuroprosthetic devices to recreate the sense of touch for amputee or quadriplegic patients with a “biomimetic” approach that approximates the natural, intact nervous system.

On Oct. 13, in a separate publication from STM, Bensmaia and a team led by Robert Gaunt, PhD, from the University of Pittsburgh, announced that for the first time, a paralyzed human patient was able to experience the sense of touch through a robotic arm that he controls with his brain. In that study, researchers interfaced directly with the patient’s brain, through an electrode array implanted in the areas of the brain responsible for hand movements and for touch, which allowed the man to both move the robotic arm and feel objects through it.

The new study takes a similar approach in amputees, working with two male subjects who each lost an arm after traumatic injuries. In this case, both subjects were implanted with neural interfaces, devices embedded with electrodes that were attached to the median, ulnar and radial nerves of the arm. Those are the same nerves that would carry signals from the hand were it still intact.

“If you want to create a dexterous hand for use in an amputee or a quadriplegic patient, you need to not only be able to move it, but have sensory feedback from it,” said Bensmaia, who is an associate professor of organismal biology and anatomy at the University of Chicago. “To do this, we first need to look at how the intact hand and the intact nervous system encodes this information, and then, to the extent that we can, try to mimic that in a neuroprosthesis.”

Recreating different sensations of intensity

The latest research is a joint effort by Bensmaia and Dustin Tyler, PhD, the Kent H. Smith Professor of Biomedical Engineering at Case Western Reserve University, who works with a large team trying to make bionic hands clinically viable. Tyler’s team, led by doctoral student Emily Graczyk, systematically tested the subjects’ ability to distinguish the magnitude of the sensations evoked when their nerves were stimulated through the interface. They varied aspects of the signals, such as frequency and intensity of each electrical pulse. The goal was to understand if there was a systematic way to manipulate the sensory magnitude.

Earlier research from Bensmaia’s lab predicted how the nervous system discerns intensity of touch, for example, how hard an object is pressing against the skin. That work suggested that the number of times certain nerve fibers fire in response to a given stimulus, known as the population spike rate, determines the perceived intensity of a given stimulus.

Results from the new study verify this hypothesis: A single feature of electrical stimulation—dubbed the activation charge rate—was found to determine the strength of the sensation. By changing the activation charge rate, the team could change sensory magnitude in a highly predictable way. The team then showed that the activation charge rate was also closely related to the evoked population spike rate.

Building neuroprosthetics that approximate the natural nervous system

While the new study furthers the development of neural interfaces for neuroprosthetics, artificial touch will only be as good as the devices providing input. In a separate paper published earlier this year in IEEE Transactions on Haptics, Bensmaia and his team tested the sensory abilities of a robotic fingertip equipped with touch sensors.

Using the same behavioral techniques that are used to test human sensory abilities, Bensmaia’s team, led by Benoit Delhaye and Erik Schluter, tested the finger’s ability to distinguish different touch locations, different pressure levels, the direction and speed of surfaces moving across it and the identity of textures scanned across it. The robotic finger (with the help of machine learning algorithms) proved to be almost as good as a human at most of these sensory tasks. By combining such high-quality input with the algorithms and data Bensmaia and Tyler produced in the other study, researchers can begin building neuroprosthetics that approximate natural sensations of touch.

Without realistic, natural-feeling sensations, neuroprosthetics will never come close to achieving the dexterity of our native hands. To illustrate the importance of touch, Bensmaia referred to a piano. Playing the piano requires a delicate touch, and an accomplished pianist knows how softly or forcefully to strike the keys based on sensory signals from the fingertips. Without these signals, the sounds the piano would make would not be very musical.

“The idea is that if we can reproduce those signals exactly, the amputee won’t have to think about it, he can just interact with objects naturally and automatically. Results from this study constitute a first step towards conveying finely graded information about contact pressure,” Bensmaia said.

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Neighborhoods Important Factor In Risk Of Stroke For All Races

A higher neighborhood advantage, or socioeconomic status, of where a person lives contributes to a lower risk of having a stroke no matter the person’s race, according to findings published in the Oct. 14 online issue of Neurology®, the medical journal of the American Academy of Neurology.

The report from the University of Alabama at Birmingham REasons for Geographic And Racial Differences in Stroke study shows this effect is the same for black and white adults, both men and women.

“More blacks than whites in the United States have strokes and die from strokes,” saidVirginia Howard, Ph.D., lead author of the study and professor in the UAB School of Public Health Department of Epidemiology. “More people who live in the Southeastern area known as the stroke belt have stroke and die from stroke compared to those who live in the rest of the United States.”

This study showed that residents in more disadvantaged neighborhoods had greater stroke risk than those who lived in more advantaged neighborhoods. The neighborhood index is composed of six factors, including a higher value of housing units and higher proportion of residents employed in professional occupations. A higher score in all of these categories leads to a higher advantaged neighborhood.

The observation was true even after adjustment for age, race, sex and region of the country. But after adjustment for other stroke risk factors, there was no association between the level of the neighborhood advantage and stroke risk, suggesting that those living in more disadvantaged neighborhoods are more likely to develop risk factors including hypertension, diabetes and smoking. Because of being more likely to develop these risk factors, they are at higher risk of stroke.

“These results are consistent with other evidence showing that factors associated with living in more disadvantaged neighborhoods contribute to stroke risk. However, it is difficult to separate the influence of neighborhood characteristics from characteristics of the individuals living in the neighborhood,” Howard said. “Many social and behavioral risk factors, such as smoking and physical inactivity, are more prevalent in the less advantaged neighborhoods. Greater attention needs to be paid to risk factor management strategies in disadvantaged neighborhoods in order to make a difference in preventing stroke on an individual level.”

The current study looked at measures of the neighborhood advantage where people live to determine whether these factors contributed to future stroke risk. Data came from the REGARDS study, a national random sample of the general population with more people selected from the stroke belt and about half black, half white.

The study involved 24,875 people with an average age of 65 who had not had a stroke at the start of the study. The participants were divided into four neighborhood groups, ranging from lowest level of advantage to the highest. The participants were followed for an average of seven and a half years. During that time, 929 people had a stroke.

This study has advantages over other studies in that it includes individuals of low, middle, upper-middle and high individual wealth across 1,833 urban and rural counties in the United States, and a large number of both blacks and whites. Other stroke risk factors were measured prior to the stroke.

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New Hope For Recovery Of Hand Movement For Stroke Patients

Stroke patients are starting a trial of a new electronic device to recover movement and control of their hand.

Neuroscientists at Newcastle University have developed the device, the size of a mobile phone, which delivers a series of small electrical shocks followed by an audible click to strengthen brain and spinal connections.

The experts believe this could revolutionise treatment for patients, providing a wearable solution to the effects of stroke.

Following successful work in primates and healthy human subjects, the Newcastle University team are now working with colleagues at the prestigious Institute of Neurosciences, Kolkata, India, to start the clinical trial. Involving 150 stroke patients, the aim of the study is to see whether it leads to improved hand and arm control.

Stuart Baker, Professor of Movement Neuroscience at Newcastle University who has led the work said: “We were astonished to find that a small electric shock and the sound of a click had the potential to change the brain’s connections. However, our previous research in primates changed our thinking about how we could activate these pathways, leading to our study in humans.”

Recovering hand control

Publishing today in the Journal of Neuroscience, the team report on the development of the miniaturised device and its success in healthy patients at strengthening connections in the reticulospinal tract, one of the signal pathways between the brain and spinal cord.

This is important for patients as when people have a stroke they often lose the major pathway found in all mammals connecting the brain to spinal cord. The team’s previous work in primates showed that after a stroke they can adapt and use a different, more primitive pathway, the reticulospinal tract, to recover.

However, their recovery tends to be imbalanced with more connections made to flexors, the muscles that close the hand, than extensors, those that open the hand. This imbalance is also seen in stroke patients as typically, even after a period of recuperation, they find that they still have weakness of the extensor muscles preventing them opening their fist which leads to the distinctive curled hand.

Partial paralysis of the arms, typically on just one side, is common after stroke, and can affect someone’s ability to wash, dress or feed themselves. Only about 15% of stroke patients spontaneously recover the use of their hand and arm, with many people left facing the rest of their lives with a severe level of disability.

Senior author of the paper, Professor Baker added: “We have developed a miniaturised device which delivers an audible click followed by a weak electric shock to the arm muscle to strengthen the brain’s connections. This means the stroke patients in the trial are wearing an earpiece and a pad on the arm, each linked by wires to the device so that the click and shock can be continually delivered to them.

“We think that if they wear this for 4 hours a day we will be able to see a permanent improvement in their extensor muscle connections which will help them gain control on their hand.”

Improving connections

The techniques to strengthen brain connections using paired stimuli are well documented, but until now this has needed bulky equipment, with a mains electric supply.

The research published today is a proof of concept in human subjects and comes directly out of the team’s work on primates. In the paper they report how they pair a click in a headphone with an electric shock to a muscle to induce the changes in connections either strengthening or weakening reflexes depending on the sequence selected. They demonstrated that wearing the portable electronic device for seven hours strengthened the signal pathway in more than half of the subjects (15 out of 25).

Professor Stuart Baker added: “We would never have thought of using audible clicks unless we had the recordings from primates to show us that this might work. Furthermore, it is our earlier work in primates which shows that the connections we are changing are definitely involved in stroke recovery.”

The work has been funded through a Milstein Award from the Medical Research Council and the Wellcome Trust.

The clinical trial is just starting at the Institute of Neurosciences, Kolkata, India. The country has a higher rate of stroke than Western countries which can affect people at a younger age meaning there is a large number of patients. The Institute has strong collaborative links with Newcastle University enabling a carefully controlled clinical trial with results expected at the end of this year.

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Brain Cancer And Leukemia: New Molecular Mechanisms Decoded

Brain cancer and leukemia are two potentially fatal diseases that affect thousands of Canadians each year. But a joint study conducted by researchers Frederick Antoine Mallette, of the Maisonneuve-Rosemont Hospital Research Centre and the University of Montreal, and Marc-Étienne Huot, of Laval University, and published in the prestigious scientific journal Nature Communications has uncovered new molecular causes of brain cancer and leukemia.

We already knew the existence of a mutation phenomenon involving certain metabolic enzymes called isocitrate dehydrogenases 1 and 2 (IDH1/2) in various forms of brain cancer, including gliomas and glioblastomas, and in acute myeloid leukemia. Although the mutated forms of IDH1/2 appear to contribute to cancer formation, until now we had only limited understanding of the ways in which these metabolic defects caused cancer. Research conducted by Mélissa Carbonneau, a master’s student in Professor Mallette’s laboratory, has helped to better understand the effect of IDH1/2 mutations in cancer by demonstrating their role in activating the pathways involved in cell proliferation and survival.

“With the identification of the molecular modes of action that contribute to cancer in patients carrying IDH1/2 mutations, it is now possible to consider personalized treatment to potentially improve therapeutic response,” said Dr. Mallette.
Some statistics

It is estimated that in 2015, 3,000 Canadians were diagnosed with brain and spinal cord cancer, and 6,200 Canadians were diagnosed with leukemia.

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Visual Cortex Plays Role In Plasticity Of Eye Movement Reflex

By peering into the eyes of mice and tracking their ocular movements, researchers made an unexpected discovery: the visual cortex – a region of the brain known to process sensory information – plays a key role in promoting the plasticity of innate, spontaneous eye movements. The study, published in Nature, was led by researchers at the University of California, San Diego (UCSD) and the University of California, San Francisco (UCSF) and funded by the National Eye Institute (NEI), part of the National Institutes of Health.

“This study elegantly shows how analysis of eye movement sheds more light on brain plasticity– an ability that is at the core of the brain’s capacity to adapt and function. More specifically, it shows how the visual cortex continues to surprise and to awe,” said Houmam Araj, Ph.D., a program director at the NEI.

Without our being aware of it, our eyes are in constant motion. As we rotate our heads and as the world around us moves, two ocular reflexes kick in to offset this movement and stabilize images projected onto our retinas, the light-sensitive tissue at the back of our eyes. The optokinetic reflex causes eyes to drift horizontally from side-to-side— for example, as we watch the scenery through a window of a moving train. The vestibulo-ocular reflex adjusts our eye position to offset head movements. Both reflexes are crucial to survival. These mechanisms allow us to see traffic while driving down a bumpy road, or a hawk in flight to see a mouse scurrying for cover.

The two reflexes occur automatically as a result of signals from the brainstem, an evolutionarily older part of the brain. These reflexes also are precisely coordinated in relation to each other. When one of the two reflexes is impaired by age or alcohol, for example, the other compensates. This orchestration requires adaptive plasticity, said the study’s lead investigator, Massimo Scanziani, Ph.D., who at the time of the study was professor of neurobiology at UCSD before moving to UCSF. Scanziani collaborated with the study’s first author, Bao-hua Liu, Ph.D., a post-doc at UCSD and Andrew Huberman, Ph.D., now associate professor at Stanford University.

Scanziani and his colleagues sought to understand the origins of this adaptive plasticity by studying the eye movements in mice before and after disabling their vestibular ocular reflex. In their mouse model, disabling the vestibulo-ocular reflex increases the optokinetic reflex. They measure the increase by holding the mouse’s head still and then presenting the mouse with visual stimuli in the form of black and white horizontal stripes that rotate around the mouse. A camera records the animal’s eye movements. More forceful eye movements indicate an increase in optokinetic reflex activity.

To test the visual cortex’s role in the plasticity of these reflexes, the researchers applied a technique called optogenetics, which uses light to turn target cells on or off. The researchers targeted inhibitory neurons in the visual cortex to turn them “on,” thus silencing that region of the brain. Silencing the visual cortex led to a significant reduction in the activity of the optokinetic reflex, suggesting that it is the visual cortex that is involved in mediating the plasticity between the optokinetic and the vestibulo-ocular reflexes.

Next, the researchers sought to learn more about how the visual cortex modulates the reflexes. It has long been observed that a collection of neural projections from the visual cortex extends to cells of the brainstem that regulate innate motor behaviors. The scientists lesioned these projections and again observed a decrease in the optokinetic reflex. Such findings suggest that the neural projections are the anatomical structures by which the visual cortex adjusts the plasticity of the optokinetic reflex, Scanziani said.

The findings shed new light on the role of the mammalian cortex in orchestrating eye movement, according to Scanziani. “Most of our reflexes are encoded in the brainstem, but from an evolutionary standpoint, the ability for one’s cortex to modify these reflexes expands one’s behavioral repertoire as the circumstances require,” he said. “If you’ve ever noticed how people in an audience tend to cough after a solo musical performance ends, you’ve seen this ability to modify reflexes in action. It’s an ability that appears to have been an attribute important for survival. After all when you’re hiding from a tiger, it would be the very worst moment to cough.”

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Dysfunction In Neuronal Transport Mechanism Linked To Alzheimer’s Disease

Researchers at University of California San Diego School of Medicine have confirmed that mutation-caused dysfunction in a process cells use to transport molecules within the cell plays a previously suspected but underappreciated role in promoting the heritable form of Alzheimer’s disease (AD), but also one that might be remedied with existing therapeutic enzyme inhibitors.

The findings published in the October 11 online issue of Cell Reports.

“Our results further illuminate the complex processes involved in the degradation and decline of neurons, which is, of course, the essential characteristic and cause of AD,” said the study’s senior author Larry Goldstein, PhD, Distinguished Professor in the Departments of Neuroscience and Cellular and Molecular Medicine at UC San Diego School of Medicine and director of both the UC San Diego Stem Cell Program and Sanford Stem Cell Clinical Center at UC San Diego Health. “But beyond that, they point to a new target and therapy for a condition that currently has no proven treatment or cure.”

Alzheimer’s disease is a neurodegenerative disorder characterized by progressive memory loss and cognitive dysfunction. It affects more than 30 million people worldwide, including an estimated 5.4 million Americans. One in 10 persons over the age of 65 has AD; one in three over the age of 85. There are currently no treatments proven to cure or reduce the progression of AD.

Genetically, AD is divided into two groups: the much more common sporadic (sAD) form of the disease in which the underlying primary cause is not known and the rarer familial (fAD) form, produced by inherited genetic mutations. In both forms, the brains of AD patients feature accumulations of protein plaques and neurofibrillary tangles that lead to neuronal impairment and eventual cell death.

The prevailing “amyloid cascade hypothesis” posits that these plaques and tangles are comprised, respectively, of amyloid precursor protein (APP) fragments and tau proteins that fuel cellular stress, neurotoxicity, loss of function and cell death. There has been some evidence, however, of another disease-driver: defects in endocytic trafficking — the process by which cells package large, external molecules into vesicles or membrane-bound sacs for transport into the cell for a variety of reasons or uses.

But previous research focused on non-neuronal cells and did not examine the effects of normal expression levels of AD-related proteins, leaving it unclear to what degree decreased endocytosis and other molecular movement within cells played a causative role.

Goldstein and colleagues analyzed neurons created from induced pluripotent stem cells in which they generated PS1 and APP mutations characteristic of fAD using the emerging genome editing technologies CRISPR and TALEN. In this “disease-in-a-dish” approach, they found that the mutated neurons displayed altered distribution and trafficking of APP and internalized lipoproteins (proteins that combine with or transport fat and other lipids in blood plasma). Specifically, there were elevated levels of APP in the soma or cell body while levels were reduced in the neuronal axons.

In previous work, Goldstein’s team had demonstrated that PS1 and APP mutations impaired the activity of specific cellular enzymes. In the latest work, they found that treating mutated fAD neurons with a beta-secretase inhibitor rescued both endocytosis and transcytosis (molecule movement within a cell) functions.

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Brain Cell ‘Executioner’ Identified

Despite their different triggers, the same molecular chain of events appears to be responsible for brain cell death from strokes, injuries and even such neurodegenerative diseases as Alzheimer’s. Now, researchers at Johns Hopkins say they have pinpointed the protein at the end of that chain of events, one that delivers the fatal strike by carving up a cell’s DNA. The find, they say, potentially opens up a new avenue for the development of drugs to prevent, stop or weaken the process.

A report on the research appears in the Oct. 7 issue of the journal Science.

The new experiments, conducted in laboratory-grown cells, build on earlier work by research partners Ted Dawson, M.D., Ph.D., now director of the Institute for Cell Engineering at the Johns Hopkins University School of Medicine, and Valina Dawson, Ph.D., professor of neurology. Their research groups found that despite their very different causes and symptoms, injury, stroke, Alzheimer’s disease, Parkinson’s disease and the rare, fatal genetic disorder Huntington’s disease have a shared mechanism of a distinct form of “programmed” brain cell death they named parthanatos after the personification of death in Greek mythology and PARP, an enzyme involved in the process.

“I can’t overemphasize what an important form of cell death it is; it plays a role in almost all forms of cellular injury,” Ted Dawson says. His and Valina Dawson’s research groups have spent years delineating each of the links in the parthanatos chain of events and the roles of the proteins involved.

The current study, they say, has completed the chain. From previous studies, the researchers knew that when a protein called mitochondrial apoptosis-inducing factor, or AIF, leaves its usual place in the energy-producing mitochondria of the cell and moves to the nucleus, it sparks the carving up of the genome housed in the nucleus and leads to cell death.

But AIF itself, they say, can’t cut DNA. So then-postdoctoral fellow Yingfei Wang, Ph.D., now an assistant professor at the University of Texas Southwestern Medical Center, used a protein chip to screen thousands of human proteins to find those that interacted most strongly with AIF. Working with the 160 candidates she uncovered, she then used custom molecules called small interfering RNAs to stop each of those proteins’ manufacture, one by one, in lab-grown human cells to see if doing so would prevent cell death.

One of the 160 proteins, known as macrophage migration inhibitory factor (MIF), was a winner. “We found that AIF binds to MIF and carries it into the nucleus, where MIF chops up DNA,” Ted Dawson says. “We think that’s the final execution step in parthanatos.”

The group reports that in work to be published, it also identified a few chemical compounds that block MIF’s action in the lab-grown cells, protecting them from parthanatos. Dawson says they plan to test these in animals, and modify them to maximize their safety and effectiveness.

He cautions that while parthanatos is known to cause cell death in many brain conditions, MIF’s ability to chop up DNA has so far only been definitively linked with stroke — when the MIF gene was disabled in mice, the damage caused by a stroke was dramatically reduced. “We’re interested in finding out whether MIF is also involved in Parkinson’s, Alzheimer’s and other neurodegenerative diseases,” he says. If so, and if an inhibitor of MIF proves successful in testing, it could have implications for treating many conditions, he says.

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Iowa State University Scientists Identify New Lead In Search For Parkinson’s Cure

AMES, Iowa – Recently published research from Iowa State University may hint at a new treatment for Parkinson’s disease.

In a paper published in the academic journal Nature Communications, ISU scientists identified a protein called Prokineticin-2 (PK2) that may protect brain cells and is expressed with greater frequency in the early stages of Parkinson’s disease.

“The neurons use PK2 to cope with stress. It’s an in-built protective mechanism,” said Anumantha Kanthasamy, a Clarence Hartley Covault Distinguished Professor in veterinary medicine, the Eugene and Linda Lloyd Endowed Chair of Neurotoxicology, and chair of biomedical sciences at Iowa State. Kanthasamy, one of the paper’s lead authors, has been working to understand the complex mechanisms of Parkinson’s and searching for a cure for the past two decades.

Prokineticin-2 stimulates the neurons to produce more mitochondria, the part of the cell that produces energy. The resulting improved energy production helps neurons withstand the ravages of the disease, which is a neurological disorder that results in insufficient levels of dopamine in the brain.

Parkinson’s disease is a progressive disorder that takes years to develop. A better understanding of Prokineticin-2 could turn up a means of slowing development of the disease or lead to new therapies, Kanthasamy said. For instance, there may be ways to stimulate more production of the protein or protein analogs to bind with its receptors on neurons, he said.

The research team took a multidisciplinary and integrated approach to studying Parkinson’s disease. The study was funded by a grant from the National Institutes of Health to Kanthasamy and Arthi Kanthasamy, a professor of biomedical sciences and Anumantha’s spouse. Six graduate students in Kanthasamy’s lab also contributed to the study, including co-first authors Richard Gordon and Matthew Neal, as well as researchers at other institutions.

The scientists studied cultured brain cells, a rodent model and post-mortem human brains to track changes brought on by Parkinson’s disease, and they confirmed a high expression of Prokineticin-2 in each facet of the study.

It was this team effort that resulted in a comprehensive finding, Arthi Kanthasamy noted.

The discovery prompted the research team to investigate more thoroughly.

“Of the thousands and thousands of factors we tracked in our experiments, why was this protein expressed so highly?” Arthi Kanthasamy said.

Finding the answer to that question poses a challenge that will take time to overcome, but the potential appears to be significant, she said.

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Closing In On Biomarkers For Suicidal Behavior

An enzyme called ACMSD—part of a chain of biochemical reactions called the kynurenine pathway, activated by inflammation—could become an important target for new drugs aimed at preventing suicide.

The enzyme shows reduced activity in people who have tried to kill themselves, according to astudy published online Aug. 2, 2016, in Translational Psychiatry. And downstream effects of the sluggish enzyme—namely, abnormal levels of two acids in the body—could potentially be measured in blood tests to help identify patients at high risk, say the researchers.

The study was conducted with Swedish patients but involved collaborators in three other countries, including in the U.S. at VA’s Rocky Mountain Mental Illness Research, Education, and Clinical Center (MIRECC) for Suicide Prevention in Denver, and at the Van Andel Research Institute in Michigan.

“We now want to find out if these changes are only seen in individuals with suicidal thoughts or if patients with severe depression also exhibit this. We also want to develop drugs that might activate the enzyme ACMSD and thus restore balance between quinolinic and picolinic acid,” said Dr. Sophie Erhardt of the Karolinska Institutet in Stockholm, one of the leaders of the study.

Senior author on the study was Dr. Lena Brundin at Van Andel. Representing VA was Dr. Teodor Postolache, a clinical and research psychiatrist with VA’s Rocky Mountain MIRECC for Suicide Prevention. Postolache is also an investigator with VA’s MIRECC in Baltimore, and a professor at the University of Maryland School of Medicine.

The immune system and mental health

An increasing body of evidence in recent years has implicated the immune system—particularly inflammation—as a possible contributing factor in both depression and suicidal behavior. Inflammation is one way the body responds to stress. But the link is complex, and researchers are still far from grasping exactly how the pieces fit together, and whether the findings can be used clinically to advance suicide prevention.

The new study, conducted in several phases, involved more than 300 Swedish patients and other volunteers. The researchers took samples of blood and cerebrospinal fluid from those who had attempted suicide, immediately after the suicidal episode and at intervals thereafter, and compared them with samples from healthy controls.

In the suicidal patients, the ratio between picolinic and quinolinic acid was out of whack—too little of the former, too much of the latter. Picolinic acid is protective, whereas quinolinic acid is toxic to the brain and nervous system.

The changes were most pronounced in the cerebrospinal fluid, the clear liquid that cushions the brain and spinal cord. The abnormal levels persisted at least two years in repeated tests of the fluid. The changes also showed up in blood tests, albeit less markedly. But blood tests are much easier to perform than spinal taps, so they could represent a more practical clinical option.

Gene tests confirm results

The researchers knew from past studies that ACSMD modulates the levels of the two acids. They confirmed the link in the current study though a genetic analysis. They found that a particular variant of the ACSMD gene was more prevalent in suicide attempters, and was associated with increased quinolinic acid.

Targeting ACSMD with a drug to boost its activity could, in theory, normalize the ratio between the two acids it affects, say the researchers.

But the study wasn’t designed to show a direct causal relationship between ACSMD activity and suicide risk. So it’s not clear that raising ACSMD activity and restoring the picolinic-quinolinic ratio would actually curb suicidal behavior.

The next step in exploring that, say the researchers, would be lab tests with an animal model of depression. Lab animals that exhibit traits typical of depression, such as lack of interest in normal activities, as well as traits such as impulsivity, are commonly studied by scientists looking at suicidal behavior.

Combating inflammation over long term may be best

Further research may also shed light on issues of timing. To the extent that inflammation does drive suicidal behavior, it could be a problem that is years in the making, and that demands long-range strategies.

Dr. John Krystal, a psychiatry researcher with VA and Yale School of Medicine, is the editor of the journal Biological Psychiatry. He was quoted in response to a study in the journal last year that showed increased levels of inflammation-causing immune chemicals called cytokines in suicidal patients:

“Inflammation affects every organ in the body,” noted Krystal. “It is increasingly evident that we need to take a long-term perspective on the effects of inflammation on the brain. The path to preventing suicide may be to intervene early in long-term processes that increase the risk for suicide, rather than to focus solely on the elusive short-term predictors of suicide.”

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New Clinical Trial Will Test Cancer Drug As Alzheimer’S Treatment

The Alzheimer’s Drug Discovery Foundation (ADDF) announces a $2.1 million grant awarded to R. Scott Turner, MD, PhD, of Georgetown University Medical Center to conduct a phase II clinical trial of low-dose nilotinib (marketed as Tasigna® for use as a cancer therapy) in patients with Alzheimer’s disease.

Nilotinib is an FDA-approved drug for the treatment of adult chronic myeloid leukemia. In preclinical studies conducted by Georgetown researchers, nilotinib reduced cognitive impairment by targeting two of the underlying causes of Alzheimer’s—neuroinflammation and misfolded proteins. Nilotinib triggers a process (called autophagy) that removes the toxic proteins tau and beta-amyloid from the brain before they accumulate into plaques and tangles.

Dr. Turner, co-medical director of Georgetown University Medical Center’s Translational Neurotherapeutics Program (TNP) and director of the Georgetown Memory Disorders Program, says, “By stimulating the brain’s normal autophagic process, which clears out these misfolded proteins in cells, we hope to prevent or slow the progression of Alzheimer’s. In fact, nilotinib may be a first—a broad-spectrum anti-neurodegenerative drug that targets all misfolded protein aggregates that accumulate in the brain of Alzheimer’s patients. By targeting both amyloid and tau, this study may point the way to a new strategy in Alzheimer’s disease treatment.”

The preclinical research was conducted by Charbel Moussa, MD, PhD, scientific and clinical research director for Georgetown’s TNP, who explains, “Nilotinib seems to activate the cell’s garbage disposal machine, reduce plaques and tangles and reverse cognitive decline in animal models of Alzheimer’s disease. We hope that this trial will clarify the effects of nilotinib in Alzheimer’s patients.” Moussa will be a co-investigator on the Alzheimer’s trial.

The trial is expected to start this year and will include 42 patients, with half randomized to receive an escalating dose of nilotinib, while the other half receives a placebo. The primary objectives of the study will be to test the drug’s safety and tolerability and to measure whether nilotinib reduces inflammation and the presence of beta-amyloid and tau in spinal fluid. Dr. Turner and his colleagues in the Georgetown Memory Disorders Program will also perform cognitive and functional abilities tests.

Dr. Howard Fillit, Founding Executive Director and Chief Science Officer of the ADDF, says: “The ADDF is proud to support a clinical trial that holds such promise for Alzheimer’s patients. This funding is part of our wider initiative to use the knowledge gained from cancer research to advance effective treatments for Alzheimer’s.”

The ADDF’s initiative “Learning from Cancer to Advance Treatments for Neurodegenerative Diseases” launched in 2015 with a conference held in partnership with the New York Academy of Sciences. Its goal is both to develop new therapies and test existing cancer therapies for their potential in treating Alzheimer’s disease. In addition to the nilotinib trial at Georgetown, this initiative includes funding for drug development projects at Oryzon Genomics, Rodin Therapeutics, and Yuma Therapeutics.

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Georgetown Receives FDA Clearance To Conduct Clinical Trial With Nilotinib In Alzheimer’s Disease

Georgetown University Medical Center (GUMC) today announces the U.S. Food and Drug Administration has completed its review of an investigational new drug application (IND) for the use of nilotinib in a phase II clinical trial for patients with mild to moderate Alzheimer’s disease.

The FDA also informed GUMC investigators that the study can proceed. The clinical trial is expected to begin this year at Georgetown University Medical Center with its clinical partner, MedStar Georgetown University Hospital.

The clinical trial is a phase II, randomized, double blinded, placebo-controlled study to evaluate the impact of low doses of nilotinib (sold as Tasigna®) on biomarkers and clinical outcomes in people with mild to moderate Alzheimer’s disease.

The rationale for using nilotinib is based on research conducted at Georgetown and involves clearing the brain of accumulated beta-amyloid (Abeta) plaques and Tau tangles. Both biomarkers are hallmarks of Alzheimer’s disease. Nilotinib appears to penetrate the blood-brain barrier and turn on the “garbage disposal” machinery inside neurons (a process known as autophagy) to clear Tau and Abeta and other toxic proteins.

“In a 2015 small study at Georgetown, patients with Parkinson’s and dementia with Lewy bodies were given nilotinib. As my colleagues reported, all who completed the study had a reversal in disease progression, observed both clinically and in key biomarkers — the same biomarkers seen in Alzheimer’s ,” explains Scott Turner, MD, PhD, co-medical director of Georgetown University Medical Center’s Translational Neurotherapeutics Program and director of the Georgetown Memory Disorders Program, who will lead the Alzheimer’s study. “But even before the Parkinson’s study, research in the laboratory strongly supported studying this drug in people with Alzheimer’s. The promising results of the Parkinson’s study gives an even stronger rationale.”

Charbel Moussa, MD, PhD, conducted the preclinical research that led to the discovery of nilotinib for the treatment of neurodegenerative diseases.

“When used in higher doses for chronic myelogenous leukemia (CML), nilotinib forces cancer cells into autophagy or cell death. The dose used in CML treatment is significantly higher than what we will use in our Alzheimer’s study,” says Moussa, scientific and clinical research director for the Georgetown Translational Neurotherapeutics Program. “When used in smaller doses once a day, as in this study, nilotinib turns on autophagy for about four to eight hours — long enough to clean out the cells without causing cell death. Toxic proteins that build up again will be cleared when the drug is given again the next day.”

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Tumor Paint Brings Light To Toddler’s Brain Tumor

In December of last year, Laura Coffman began to notice that something wasn’t quite right with her 2-year-old son, Hunter. He was leaning to one side and seemed to lose his balance easily. When he became lethargic and started vomiting a few days later on Dec. 28, she knew it was time to see the pediatrician.

After all standard tests came back normal, they were sent to Seattle Children’s for further testing and to find an answer. Unfortunately, it was far worse than anything Coffman could have imagined.

“What I thought was probably just Hunter being a wobbly toddler with a virus turned out to be a brain tumor,” said Coffman. “I will never forget that day. It was the most traumatic six hours of our lives.”

Tumor Paint sheds some light

Hunter was immediately scheduled for surgery to remove the brain tumor that was the size of a golf ball. In preparing for the operation, Coffman and her husband, Atom, were also presented with the opportunity to enroll Hunter in Seattle Children’s Phase 1 trial of BLZ-100 Tumor Paint. Since tumor cells can be difficult to distinguish from healthy cells, the drug aims to improve surgical outcomes by acting as a molecular flashlight that allows surgeons to visibly distinguish a tumor from normal brain tissue.

“We didn’t see how it could hurt and we wanted them to use every tool at their disposal so we enrolled him in the trial,” said Coffman.

Dec. 30 was the day of Hunter’s surgery. Another day the Coffman’s will never forget.

“As a parent you know that your child may never be the same after brain surgery – they may not be able to see, walk or speak,” Coffman said. “It’s the risk you have to take to save their life. But we trusted our surgeon, Dr. Amy Lee, with everything we had.”

Prior to surgery, BLZ-100 Tumor Paint was administered by intravenous injection. In the operating room, the tumor glows green when viewed under a laser light and imaged with a near-infrared camera system.

BLZ-100 Tumor Paint was invented by a team led by Dr. Jim Olson, pediatric neuro-oncologist at Seattle Children’s and Fred Hutch and co-founder of Blaze Bioscience: The Tumor Paint Company. While this Phase 1 trial is focused on examining the safety of the drug and how well it targets tumor tissue, the hope is that it will eventually help guide skilled surgeons to prevent the removal of healthy tissue that can lead to serious long-term side effects.

“Cure is not just about successful treatment of a tumor, but successful treatment of a child,” said Dr. Sarah Leary, principal investigator for the trial and Hunter’s oncologist at Seattle Children’s. “Much of cancer treatment for children is a trade-off where curative therapy comes with serious long-term side effects. By lighting the way for expert surgeons, we’re hopeful that BLZ-100 Tumor Paint could help improve the quality of life for children by reducing treatment-related damage to the healthy brain.”

Hunter’s surgery went well and the majority of his tumor was removed. One small piece on his brain stem was intentionally left because removal may have led to serious neurological injury.

After surgery, it was not long until Hunter was back to his young self.

“We were incredibly lucky to have such an amazing surgeon and we were thrilled that he was able to bounce back so quickly,” said Coffman. “He was able to walk, run and put words together only weeks after the operation.”

A terrifying diagnosis, the journey to remission

Once the tumor was removed, the Coffman’s faced their next hurdle as pathology determined that Hunter had a form of aggressive cancer called medulloblastoma. His next phase of treatment quickly began as he underwent seven months of chemotherapy and radiation to target the remaining tumor, as well smaller lesions in his brain and spine.

“I remember how terrifying that diagnosis was to hear, but Dr. Leary was so optimistic and immediately reassured us when she said ‘this is a cancer that we’ve cured many times,’” said Coffman. “And that’s exactly what they did.”

In August, four weeks after Hunter ended treatment, MRI scans confirmed he was in remission.

“The news was phenomenal – all of his cancer was gone,” she said. “You can’t ask for anything more.”

Today, Hunter is thriving.

“You’d never even know he had cancer or brain surgery,” she said. “His hair is growing back, he’s swimming, impressing us with his speaking skills and having playdates with friends.”

When reflecting on their decision to participate in the trial, Coffman is glad they had the opportunity to experience something that could be a game changer for future kids like Hunter.

“Brain surgery is not something you ever want to think about your child going through, but if that dreadful day ever comes, you definitely want a tool like Tumor Paint that could help guide the surgeon in making potentially life-altering decisions,” said Coffman.

What’s next for BLZ-100 Tumor Paint in children

Since the trial began in June 2015, Seattle Children’s has performed 15 brain surgeries with BLZ-100 Tumor Paint. To date, none of the patients have had any negative side effects and Leary and her team are working to determine the best dose. The drug also appears to be doing what it was designed to do – make tumor tissue glow.

“We have been excited to see that BLZ-100 Tumor Paint is binding to many different types of brain tumors in children and so far has not resulted in any side effects,” said Leary. “We are optimistic that in the future it could be an incredible tool when placed in the expert hands of a neurosurgeon that could lead to improved patient outcomes.”

Dr. Amy Lee, the lead neurosurgeon in the trial and Hunter’s surgeon, adds, “We believe BLZ-100 Tumor Paint holds tremendous potential and eventually could be a valuable aid for surgeons in differentiating tumor from healthy tissue, particularly when there are areas of question.”

Leary said their goal is that this Phase 1 trial at Seattle Children’s, which has the largest pediatric Brain Tumor Program and the most pediatric neurosurgeons in the Northwest, will be followed by other studies that lead BLZ-100 Tumor Paint to become a part of standard care for brain tumor surgery. The next step will be to determine the effectiveness of the drug, which will involve a larger collaborative study that will involve 15 of the leading pediatric brain tumor centers across the country.

“In the future, I hope we’ll look back and wonder how these surgeries were ever done without the lights on,” said Leary.

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Optimal Management For NSCLC Patients With Brain Metastases

A Yale Cancer Center team completed a multi-institutional analysis of treatment options for patients with newly diagnosed EGFR-mutant non-small cell lung cancer (NSCLC) with brain metastases to determine the best option for treatment. Stereotactic radiosurgery, in combination with targeted therapy using EGFR tyrosine kinase inhibitors, resulted in the longest survival and best outcomes for patients. The findings were presented September 26 at the American Society for Therapeutic Radiology and Oncology (ASTRO) meeting in Boston.

This study analyzed three current options by reviewing outcomes of 351 patients from six institutions with EGFR-mutant NSCLC who were treated with either stereotactic radiosurgery in conjunction with targeted therapy (100), whole brain radiotherapy in conjunction with targeted therapy (120), or targeted therapy alone followed by stereotactic radiosurgery or whole brain radiotherapy if salvage was required (131).

The multi-institutional analysis demonstrated that the use of targeted therapy alone with deferral of radiotherapy resulted in inferior overall survival. Stereotactic radiosurgery in conjunction with targeted therapy resulted in the longest overall survival for patients.

“Patients with advanced NSCLC that has newly spread to their brain have many treatment options today,” said Veronica Chiang, MD, senior author on the study and an Associate Professor of Neurosurgery and of Therapeutic Radiology at Yale School of Medicine. “Physicians need to feel confident that we know the best option and this study helps us to identify that. A randomized trial will be our next step.”

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Medulloblastoma Patients Should Receive Both Chemotherapy And Radiation Post-Surgery

In a recent study, a Yale Cancer Center team revealed that the addition of chemotherapy to postoperative treatment for adults with medulloblastoma improves survival. The benefit of chemotherapy, in addition to craniospinal radiation, was seen in adult patients with medulloblastoma (MB), including those with localized disease who received high-dose radiation treatment following surgery. The findings were presented September 26 at the American Society for Therapeutic Radiology (ASTRO) meeting in Boston.

Medulloblastoma is the most common brain tumor in children, but is relatively rare in adults. Chemotherapy use in adult MB is largely based on pediatric outcomes, and its effectiveness has been unclear.

This study used the National Cancer Data Base to identify 751 patients diagnosed with MB over the age of 18 who underwent surgical resection for MB and post-surgical radiation. Of the 751 patients, 520 (69.2%) received chemotherapy and radiation therapy and 231 (30.8%) received only radiation therapy. Estimated overall survival at five years was 14.5% higher for patients who received chemotherapy and radiation compared to patients who received radiation alone (86.1% versus 71.6%).

“Our analysis is the first to clearly demonstrate the improved survival that chemotherapy adds post-surgery for adult patients with medulloblastoma,” said Benjamin H. Kann, MD, first author on the study and a Resident in the Department of Therapeutic Radiology at Yale School of Medicine. “We can now confidently support the addition of chemotherapy to radiation therapy for our patients who can tolerate both treatments.”

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Genetic ‘Switch’ Identified As Potential Target For Alzheimer’S Disease

A team at the MRC Clinical Sciences Centre (CSC), based at Imperial College London, has found an important part of the machinery that switches on a gene known to protect against Alzheimer’s Disease.

Working in collaboration with scientists at the Hong Kong University (HKU) and the Erasmus University in Rotterdam, CSC associate professor Richard Festenstein explored the steps by which this Neuroglobin gene is gradually switched on, or up-regulated.

Neuroglobin has previously been shown to protect against Alzheimer’s disease in mice in which it makes the protective Neuroglobin. It is thought that the gene might play a protective role early in the disease in patients, but appears to be down-regulated as the disease progresses. It may therefore prove useful in developing new ways to try to prevent or treat this common cause of dementia, for which there is currently no cure.

Professor Festenstein and Dr Tan-Un from HKU, with help from Professor Sjaak Phillipsen at the Erasmus University, examined how the Neuroglobin gene ‘folds up’ in the cell using a technique called chromosome conformation capture. In results published today in the journal Nucleic Acids Research, they showed that a particular region of DNA, outside the coding region of the Neuroglobin gene itself, loops round to make contact with the start of the gene.

They tested the ability of this newly-identified DNA region to switch on the Neuroglobin gene using two approaches. First, they linked the DNA region directly to another so-called ‘reporter’ gene, and demonstrated simply that it does indeed act as an up-regulator. Second, they used the new ‘Crispr’ technique of gene editing to completely remove this section of DNA from the cell, and showed that the Neuroglobin gene was no longer switched on.

Together, the results gave the team confidence that this newly-identified DNA region is indeed a powerful switching mechanism of the Neuroglobin gene.

As Neuroglobin is thought to be protective in Alzheimer’s, it may be possible in the future to use this ‘switch’ in developing new treatments, such as gene therapy. Such therapeutic approaches require a compact ‘chunk’ of DNA to be most efficient. Importantly, the team pinpointed the position of the new regulatory region, and found that it is some distance away from the Neuroglobin gene itself. It may now be possible to remove the less relevant sections of DNA in between the Neuroglobin gene and its regulator to create an efficient therapeutic gene therapy unit. It may be that this target may prove useful not only in Alzheimer’s but also in other neurodegenerative diseases.