Feb 13 2014

Alex’s Lemonade Stand Foundation Grant Supports CHOP Childhood Cancer Research Project

Alex's Lemonade StandOne in every 691 babies in the U.S. is born with Down syndrome, according to the National Down Syndrome Society, and have a predisposition for a certain kind of cancer. A Children’s Hospital hematologist, Stella T. Chou, MD, will receive $100,000 over the course of one year to fund her research on how an extra chromosome 21 and mutations in a transcription factor gene called GATA1 affect blood development, creating a predisposition to leukemia in children with Down syndrome.

A new Springboard Grant awarded by Alex’s Lemonade Stand Foundation will jumpstart the project, which fell short of funding due to sequester cuts within the National Institutes of Health.

For fiscal year 2013, the sequestration required NIH to cut 5 percent or $1.55 billion of its budget. In response to the budget reduction, Alex’s Lemonade Stand Foundation stepped in to advance new projects with high impact potential, such as Dr. Chou’s investigation.

“With less than 5 percent of the federal government’s total funding for cancer research each year being dedicated to childhood cancers, Alex’s Lemonade Stand Foundation is dedicated to keeping promising research alive,” stated Jay Scott, co-executive director of the foundation, in a Dec. 19 press release announcing the award. “Through the Springboard Grant, we work to sustain the research of these promising investigators while they reapply for large-scale funding, ultimately resulting in better treatments and cures for all childhood cancers.”

Dr. Chou’s research project aims to “provide new insights into blood cell production, generate new experimental tools for the biomedical community, and elucidate new strategies to study inherited blood diseases.”

Children with Down syndrome are predisposed to “a unique constellation of blood diseases,” Dr. Chou said. These include an increase in total red blood cell mass and a decrease in the number of platelets. In addition, about 10 percent of neonates with Down syndrome are born with preleukemia known as transient myeloproliferative disorder (TMD), which spontaneously resolves in most cases. However, 20 percent of patients with TMD subsequently develop acute megakaryoblastic leukemia (AMKL) by age 5, which responds well to chemotherapy but is associated with significant treatment-related toxicity.

In order to figure out how TMD and AMKL occur, Dr. Chou’s research team will trace the formation and development of blood cells from their early beginnings during embryogenesis and then define how they go awry. They will focus on how two potential culprits — mutations in GATA1 and genes on chromosome 21 (HSA21) — act separately and together to modulate hematopoiesis.

The investigators will use a novel approach that involves the creation and manipulation of patient-derived induced pluripotent stem cells (iPSCs) for the study of genetic disease. iPSCs are a renewable human cell source that can recapitulate the multiple stages of blood formation. They are an alternative to human samples, which are difficult to obtain in sufficient quantities for scientific investigation.

Cancer is the leading cause of death by disease among U.S. children between infancy and age 14, according to the National Cancer Institute. Approximately 11,600 new cases of pediatric cancer are expected to be diagnosed in children ages 0 to 14 years in 2013. Alex’s Lemonade Stand Foundation has raised more than $65 million toward finding a cure for all children with cancer, funding more than 350 pediatric cancer research projects nationally.

Permanent link to this article: http://www.research.chop.edu/blog/alexs-lemonade-stand-foundation-grant-supports-chop-childhood-cancer-research-project/

Feb 11 2014

Neurologist Receives Award to Study Cell-Based Epilepsy Treatment

160248924The Children’s Hospital of Philadelphia’s Ethan Goldberg, MD, PhD, recently received an award from the epilepsy advocacy organization Citizens United for Research in Epilepsy (CURE) to study using transplanted cells to treat epilepsy. Dr. Goldberg was one of three researchers to receive a “Taking Flight” award, a one-year grant of up to $100,000 designed to “promote the careers of young investigators and support them as they develop an independent research focus,” according to CURE.

A brain disorder marked by seizures of varying intensity and type, epilepsy affects approximately 2 million Americans. And per the CDC, roughly 10 percent of the U.S. population — around 31 million people — will experience a seizure during their lifetime. Seizures associated with epilepsy range from short absence seizures to generalized tonic clonic, or grand mal, seizures. These whole body seizures involve loss of consciousness, incontinence, and potentially violent convulsions.

While its cause is sometimes unknown, epilepsy can be brought on by an injury or a medical condition, such as a brain tumor or infection. Though there is no cure for epilepsy, about 70 percent of those who have the disease can have their seizures controlled with medication, according to the National Institute of Neurological Disorders and Stroke. But for many, epilepsy is a lifelong condition.

CURE was founded by parents of children with epilepsy to “spearhead the search for a cure” by raising money to support epilepsy research. Dr. Goldberg’s project is an investigation of using “specific, defined subtypes of cortical interneuron precursors to treat epilepsy and its comorbidities in an experimental model of acquired chronic temporal lobe epilepsy.” Dr. Goldberg has been working with Children’s Hospital’s Stewart A. Anderson, MD, Associate Professor and Research Director of Child Psychiatry at CHOP, as well Jennifer Tyson, a graduate student in Dr. Anderson’s laboratory.

With this investigation, the researchers hope to discover novel treatments for forms of epilepsy that are resistant to standard medication.

“A large component of our epilepsy practice here at CHOP is the care of patients with severe, medically intractable epilepsy, either acquired epilepsy secondary to brain injury or due to a genetic cause,” said Dr. Goldberg. “Cell-based therapies offer hope of a future cure for our patients who are in greatest need, although significant additional basic science research is required to realize this potential. This generous grant from CURE will greatly assist in getting this project off the ground and pushing it forward.”

The Children’s Hospital of Philadelphia has a robust epilepsy treatment and research program. Part of Children’s Hospital’s Division of Neurology, the Pediatric Regional Epilepsy Program’s multidisciplinary team of clinicians, nurse practitioners, and researchers works with families to design personalized treatment plans that best control epilepsy with as few side effect as possible.

To learn more about the Pediatric Regional Epilepsy Program, see the Hospital’s website.

Permanent link to this article: http://www.research.chop.edu/blog/neurologist-receives-award-study-cell-based-epilepsy-treatment/

Feb 06 2014

Collaborations Set to Advance the Healthcare of Children

IMG_5455Along with its research partners Drexel University and Hebrew University of Jerusalem, The Children’s Hospital of Philadelphia Research Institute recently hosted a collaborative research symposium that gave researchers from all three institutions the chance to connect and share ideas.

The Advancing Healthcare for Children symposium, held Jan. 27-29 brought together investigators for presentations, discussions, and networking events.

Announced in November, the research agreement between Children’s Hospital, Drexel University, and Hebrew University will focus on pediatric translational research and moving investigations from the bench to the bedside. One of the goals of the symposium was to form collaborative “Dream Teams” of investigators who would unite to craft innovative solutions to challenges.

Saying in his opening remarks that “we must dare to cross disciplinary and national boundaries” to meet unmet medical needs, John A. Fry, president of Drexel University, noted “our job is to take bold steps” and break through barriers.

IMG_5428The symposium also featured a visit from Philadelphia Mayor Michael Nutter. The research agreement between Children’s Hospital, Drexel University, and Hebrew University came about in part due to a trade mission Mayor Nutter led to Israel in November 2013. CHOP and Drexel’s “partnership with Hebrew University will allow all three parties to share research and ultimately improve children’s healthcare,” said Mayor Nutter when the agreement was signed.

And on the opening day of the symposium, after proudly noting that Children’s Hospital was “the best children’s hospital in the U.S.,” Mayor Nutter said that he could think of no better place to celebrate such a “tremendous collaboration.”

The symposium featured sessions on everything from the nervous system to orphan diseases to pediatric cancers and drug discovery. In addition to several plenary sessions, concurrent breakout sessions on topics such as nervous system disorders, nanomedicine, gene therapy, and autoimmunity promoted dialogue and collegiality between experts.

For example, during the session “Transformative Approaches to Diseases and Disorders of Childhood,” Director of CHOP Research Philip R Johnson, MD, said that defining the future of pediatric medicine “is a tall challenge.” But in Dr. Johnson’s talk, he challenged researchers to consider the interplay of genomics and microbiomes, as they considered ways to advance pediatric care.

IMG_5362Over the course of the symposium, investigators from all three organizations presented. Researchers from Children’s Hospital included Robert J. Levy, MD, Stewart Anderson, MD, Hakon Hakonarson, MD, PhD, and Marni Falk, MD. Drexel University’s representatives included Kenny Simansky, PhD, Amir Toib, MD, and Sriram Balasubramanian, PhD, while a number of Hebrew University investigators attended, including Rami Yaka, PhD, Eylon Yavin, PhD, and Galia Blum, PhD.

On the final day of the symposium, participants were given the opportunity to meet with meeting participants privately for one-on-one discussions. These meetings allowed investigators to follow up on presentations and discussions, and served as the first step in the development of new collaborations.

“The symposium really exceeded our expectations,” said CHOP Research’s Deputy Scientific Director Tom Curran, PhD, FRS, who led the organization of the symposium. “It set the tone for us to work together, transcending traditional boundaries, and forming unique collaborations with the common theme of improving the health and welfare of children.”

The investigators will continue their discussions in the coming weeks and work to develop and hone various “Dream Teams” to tackle pediatric diseases.

To learn more about the Advancing Healthcare for Children symposium, see the symposium’s website.

Permanent link to this article: http://www.research.chop.edu/blog/collaborations-set-advance-healthcare-children/

Feb 04 2014

Center for Injury Research and Prevention Launches Child Safety Blog for Parents

Winston, FlauraA series of blog posts on driving safety for teens grabbed the attention of editors at the Philadelphia Inquirer’s online news source Philly.com and gave researchers at CHOP’s Center for Injury Research and Prevention (CIRP) a new opportunity to highlight their work and provide valuable information to Philadelphia families. Flaura Koplin Winston, MD, PhD (@safetyMD on Twitter), CIRP scientific director and a frequent contributor to the Center’s Research in Action blog, was invited in November 2013 to become a monthly guest contributor for the Healthy Kids blog, produced by Philly.com.

Launched a year ago, the Research in Action blog celebrated its 100th blog post on Jan. 14. More than 20 authors from CIRP and guest bloggers have penned posts for it, presenting diverse perspectives on injury and violence prevention and treatment. The Research in Action blog following base has grown to more than 250 blog subscribers and has had a combined 21,000+ page views.

For the Healthy Kids blog, Dr. Winston covers topics of her choosing and draws from recent research findings or other important evidence-based information appropriate for parents. As a practicing pediatrician at the CHOP Karabots Primary Care Center, Dr. Winston has extensive experience talking with children and teens, parents, and grandparents about sensitive and complicated medical issues. She brings this experience to her blog posts, translating scientific findings, psychological concepts, and engineering principles into practical tips to help parents prevent child and adolescent injury and violence, as well as what to do when a child is injured.

“It is intellectually interesting to find new research results, but the satisfaction comes when we translate our research into usable information to help parents keep their children safe,” said Dr. Winston, who is also a professor of Pediatrics at the University of Pennsylvania Perelman School of Medicine. “The Healthy Kids Blog is a perfect vehicle for our Center’s ‘research-action-impact’ model.”

The feedback from readers so far has been positive. They have been visiting the CIRP family of websites to download tools and to learn more about the topics covered in the blog posts.

Recognizing that motor vehicle crashes are the leading cause of teen death, Dr. Winston’s latest Healthy Kids blog post gave tips to “pave the way for a smooth road” for teens with attention deficit hyperactivity disorder (ADHD) who are learning to drive.

“The symptoms of ADHD — difficulty with attention, challenges with emotion regulation, disorganization and impulsivity — heighten a teen’s risk for unsafe driving behaviors and crashes,” Dr. Winston wrote in the Jan. 2 blog post, which also appeared in the print version of the Sunday Philadelphia Inquirer.

“It’s important for families to recognize that teens with ADHD can exhibit a wide range of symptoms — varying both in severity and in type — that can negatively impact driving behaviors. Each teen driver is unique, and those with ADHD may require even more individualized plans and attention.  For example, if a teen with ADHD receives medication to treat symptoms, care should be taken to ensure that that medication coverage includes times later in the day when teens might be driving,” Dr. Winston added.

“At CHOP we often say — right advice and treatment for the right patient and family in the right context.  This is true of driving assessment and management. It is less important whether a teen has ADHD (or any other condition) than it is to understand how they function with this condition,” Dr. Winston explained. “Our role, in research and in practice, is to create solutions and situations that recognize and value the unique needs of teens and their families. ‘Can they drive?’ is not the right question. We should instead be asking, ‘Under what conditions can they drive, and how do we allow them to achieve safe, independent mobility and self-reliance?’”

While researchers have much to learn about ADHD and driving performance, there is a growing recognition of its importance and the need for more research regarding assessments and interventions.

“We hope that our research will add to the evidence base so that we can ensure that teens can achieve their goals for life and do so safely,” Dr. Winston said. “We are currently looking for funding to support this work.”

Click here for information on ways to support CIRP research and help us save the lives of children teens.

Click here to subscribe to the Research in Action blog.

Permanent link to this article: http://www.research.chop.edu/blog/center-injury-research-prevention-launches-child-safety-blog-parents/

Jan 30 2014

CHOP Researcher Sets Goals as New ISTSS President

Kassam-Adams NancyRGBReaching out across the globe to advance traumatic stress research and practice is a top goal that CHOP’s Nancy Kassam-Adams, PhD plans to accomplish as the new president of the International Society for Traumatic Stress Studies (ISTSS).

Traumatic stress occurs in significant numbers of children and parents after unintentional injuries such as concussions, interpersonal violence, and other difficult medical events, according to CHOP’s Center for Injury Research and Prevention (CIRP).

Founded 29 years ago, ISTSS is an international, interdisciplinary professional organization that includes researchers, psychiatrists, psychologists, social workers, nurses, and others with an interest in the study and treatment of traumatic stress. Dr. Kassam-Adams, associate director for behavioral research at the CIRP, has been an ISTSS member for more than 20 years.

“It has been incredibly valuable to me as a forum in which I hear about the latest work in the traumatic stress field from around the world and get to know other researchers, as well as clinicians who are working in this area,” Dr. Kassam-Adams said.

In her one-year term as ISTSS president, Dr. Kassam-Adams is working to advance the Society’s strategic goals by fostering mutual scientific exchange and engaging ISTSS’ broad international membership. She is excited about fostering a lively professional community online and in ISTSS meetings around the world. ISTSS recently hosted a conference in Norway, and in the next few months will be in Singapore, China, and Chile, among other places.

“I find the international and multidisciplinary nature of the society most exciting and stimulating,” Dr. Kassam-Adams said. “Many of the research collaborations I have developed, with colleagues in the U.S. and in several other countries, have grown from relationships that began via ISTSS.”

ISTSS Past President Karestan C. Koenen, PhD, described Dr. Kassam-Adams as having a “rare combination of passion, intelligence, and kindness. She will be successful because she will motivate ISTSS members through her passion to improve the lives of traumatized children, employ ISTSS resources intelligently, and listen to our members and make sure their views are represented.”

Dr. Koenen, associate professor and director of the Psychiatric-neurological Epidemiology cluster in the Department of Epidemiology at Columbia University’s Mailman School of Public Health, added that Dr. Kassam-Adams’ willingness to take risks will help make the ISTSS a better organization. For example, she is instituting a Spanish track at the ISTSS Annual Meeting in November that will enable ISTSS to expand its reach to new attendees and allow greater interchange among researchers and clinicians in the U.S., Latin America, and Spain. The theme for the 2014 ISTSS Annual Meeting relates to trauma in childhood and its impact for children, adults, and communities.

CHOP research over the past several decades has been at the forefront of understanding the impact of pediatric medical events (illness and injury) for children and their families through the lens of traumatic stress. This includes the work of Anne Kazak, PhD, Flaura Winston, MD, PhD, Lamia Barakat, PhD, Meghan Marsac, PhD, and many others.

“Our research at CHOP has shown that the traumatic stress framework holds up empirically, and that it also makes sense to families,” Dr. Kassam-Adams said. “We recognize children’s and families’ competence and strengths as they face really challenging and sometimes traumatic experiences.”

Dr. Kassam-Adams has completed several large prospective studies of traumatic stress in children and youth in medical settings. With colleagues at CHOP, she developed innovative web-based tools for parents that promote secondary prevention of traumatic stress in ill or injured children.

“I see my involvement and leadership roles in ISTSS as mutually beneficial for ongoing CHOP research in this area, helping to tie us in with the larger field of traumatic stress and promoting mutual exchange of ideas with colleagues around the world who are doing very interesting work in related areas,” Dr. Kassam-Adams said.

Dr. Kassam-Adams also co-directs the Center for Pediatric Traumatic Stress, an intervention development center that is part of the National Child Traumatic Stress Network. She served on the American Psychological Association’s 2008 Presidential Task Force on Child Trauma.

Permanent link to this article: http://www.research.chop.edu/blog/chop-researcher-sets-goals-new-istss-president/

Jan 28 2014

Treating the Chicken with the Egg

S3.2The term “stem cell,” stammzellen, was first used in 1868 by the German biologist Ernst Haeckel to describe the original, unicellular progenitor from which Dr. Haekel supposed all multicellular plant and animal life might have descended. The question, Dr. Haeckel asked, was where that progenitor — the original stem cell — came from in the first place. The chicken or the egg?

Since then, just what defines a stem cell has undergone a few changes. The evolutionary sense of Dr. Haeckel’s term has been dropped, but the sense of stem cells being precursor cells, able to become specialized through the process known as differentiation, remains. Because of their ability to become many types of cells and to renew themselves, stem cells hold enormous promise in understanding and treating a variety of diseases.

What’s more, researchers have identified several different types of stem cells. These include what is perhaps the most popularly known type of stem cell, embryonic stem cells (ESCs), which as their name suggests are derived from embryos. Most often, these come from embryos that have been fertilized through in vitro fertilization and then donated for research purposes.

Another type of stem cell, somatic stem cells, are rare, undifferentiated cells found among other differentiated cells. Also called adult stem cells, there are several types of somatic stem cells: hematopoietic stem cells can differentiate into every type of blood cell, while mesenchymal stem cells can become fat, cartilage, and bone cells.

But in the past decade, researchers have detailed another type of stem cell: induced pluripotent stem cells, or iPSCs. Differentiated adult cells that have been “reprogrammed” and forced to express genes, these cells are capable of developing into many or even all cell types. During fiscal 2013, The Children’s Hospital of Philadelphia’s Mitchell J. Weiss, MD, PhD, published two studies of using iPSCs to study the rare congenital blood disorder Diamond Blackfan Anemia and the childhood cancer juvenile myelomonocytic leukemia.

In the anemia study, Dr. Weiss and his colleagues — including investigators Monica Bessler, MD, PhD, and Philip J. Mason, PhD — removed fibroblasts from Diamond Blackfan Anemia patients and reprogrammed the cells into iPSCs. As those iPSCs were stimulated to form blood tissues, like the patient’s original mutated cells they were deficient in producing red blood cells. However, when the researchers corrected the genetic defect that causes the disorder, the iPSCs developed into red blood cells in normal quantities.

“The technology for generating these cells has been moving very quickly,” said Dr. Weiss. “These investigations can allow us to better understand at a molecular level how blood cells go wrong in individual patients — and to test and generate innovative treatments for the patients’ diseases,” he added.

And in April of 2012, Paul J. Gadue, PhD, published a study detailing a brand new type of stem cell, which the investigators call endodermal progenitor (EP) cells. Produced from ESCs and iPSCs, EP cells have two advantages over these other stem cell types: they do not form tumors when transplanted into animals, and they can form functional pancreatic beta cells in the laboratory. Both ESCs and iPSCs in the undifferentiated state will form a type of tumor called a teratoma when transplanted in animal studies, so it has been critical that any cell generated from ESCs or iPSCs and used for transplantation is purified to exclude undifferentiated cells with tumor-forming potential, Dr. Gadue pointed out.

In addition to producing beta cells, the researchers also directed EP cells to develop into liver cells and intestinal cells — both of which normally develop from the endoderm tissue layer early in human development. The challenge, Dr. Gadue said, has been to differentiate stem cells into one particular cell type in culture, as ESCs and iPSCs can form any cell type in the body. EP cells seem to be limited to cells of the endodermal lineage such as liver, pancreas, and intestine, making it easier to generate pure populations of cells from these organs.

“Our cell line offers a powerful new tool for modeling how many human diseases develop,” said Dr. Gadue, who along with Deborah L. French, PhD, is the co-director of CHOP’s human embryonic stem cell/induced pluripotent Stem Cell (hESC/iPSC) core facility. “Additionally, pancreatic beta cells generated from EP cells display better functional ability in the laboratory than beta cells derived from other stem cell populations.”

In a follow-up review published in fiscal 2013 in Current Opinion in Cell Biology, Dr. Gadue and colleagues discussed the generation of endodermal cells from pluripotent stem cells, including EP cells. Stem cells such as EP cells “can be expanded robustly in culture” and “provide a powerful system to study and model human diseases in vitro, as well as generating a source of cells for transplantation.”

Indeed, there is a big push to use stem cells to perform disease modeling with human cells as opposed to mice, as well as to use stem cells to perform drug and toxicity screenings, Dr. Gadue pointed out, noting that while mouse models offer an incredibly valuable resource they are not perfect and using human cells when possible is important. And once they are created, EP cells can be expanded almost without limit — to the point that Dr. Gadue estimates his laboratory has grown “trillions” of cells — which offers researchers a wealth of research resources.

Going forward, Dr. Gadue, has been working with a number of colleagues, including endocrinologist Diva D. De León-Crutchlow, MD, to better understand and hopefully develop treatments for diabetes.


Permanent link to this article: http://www.research.chop.edu/blog/treating-chicken-egg/

Jan 23 2014

Success Seen in New Bullying Prevention Program

Bully_Free_ZoneSince September, a Children’s Hospital team composed of researchers and educational facilitators has been working with 4th and 5th grade students and their teachers from Childs Elementary School (located in South Philadelphia’s Point Breeze section) on a classroom-based anti-bullying program.

The 10-week program, called Preventing Relational Aggression in Schools Everyday (PRAISE, meets twice weekly to teach students problem-solving strategies for multiple forms of bullying, including physical, cyber, and relational aggression (such as the spreading of rumors). The program also stresses the empathy and perspective-taking skills.

The students learn these skills through innovative and engaging modalities, cartoons, videotape illustrations and role plays, developed by partnering with students, teachers, and parents over the past 10 years.

PRAISE is one component of CHOP’s Partner for Prevention program, a school-based bullying prevention program designed to help at-risk 3rd-5th grade students learn to recognize and control their anger while promoting friendship-making skills.

Study leader Stephen Leff, PhD, talked about the program in a recent blog post on the Center for Injury Research and Prevention website. He notes that the students had an opportunity last week to creatively share and explain what they’ve learned with Childs’ second grade students. And WHYY was there to cover the event.

You can read or listen to a feature on the event from WHYY’s Newsworks program covered the event. You can read or listen to a feature of the event here.

Permanent link to this article: http://www.research.chop.edu/blog/success-seen-new-bullying-prevention-program/

Jan 21 2014

Honing in on the Biological Markers of Autism

Tim RobertsThe prevalence of autism spectrum disorders, or ASD, is staggering — an estimated 1 out of 88 children have some form of ASD. As the word “spectrum” in the name suggests, ASD varies in its range and severity among those affected. The various forms of the disorder share some common characteristics, however, one of which centers on language and communication deficits.

A Children’s Hospital investigator is taking a unique approach to determine how those with autism process sounds, words, and images, and then use those findings to develop potential interventions. Rather than looking at autism from a behavioral or clinical perspective, Timothy Roberts, PhD, vice chair of the Department of Radiology, is using sophisticated imaging to hone in on the biological basis for autism.

Since 2007, Dr. Roberts, who also holds the Oberkircher Family Endowed Chair in Pediatric Radiology, has used magnetoencephalography (MEG) and advanced magnetic resonance imaging (MRI) to look at the “signatures” of brain functioning to reveal the biological nature of ASD. Dr. Roberts and his team observe not just where in the brain things are happening but also the differences in the timing, or frequency, of these signals. These split-second differences can lead to auditory processing delays seen in some children with ASD.

But knowing some of the autism signatures is not enough to move on to possible interventions. What’s needed, Dr. Roberts says, is “a little bit of biology” that can shed light on what’s giving rise to those signatures in the first place. Identifying and understanding potential biomarkers may then lead to more options for treating ASD.

With a multi-modal approach using MEG and MRI, Dr. Roberts and colleague James (Chris) Edgar, PhD, have found a biomarker in the white matter of the brain that may be the cause of delayed auditory processing. And he’s found a second one in a neurotransmitter called GABA. An inhibitory neuron, GABA must be in balance with another neurotransmitter — the excitatory glutamate.

“Those with ASD who have lower levels of GABA end up with a more ‘noisy brain,’” Dr. Roberts says. “This is a problem because it means these children are trying to encode their perceptual reality, their world — and they are trying to encode it with rhythms in a sea of noise.”

The tremendous variability, or heterogeneity, seen in children with ASD suggests that the problem for some may arise from abnormal white matter development and for others may stem from reduced levels of GABA. Knowing the biological differences at play has led Dr. Roberts toward existing drugs that target GABA — the effectiveness of which he could measure using advanced imaging techniques — and toward developing a novel intervention for those whose ASD may arise from auditory processing difficulties.

“Five years ago we didn’t have signatures,” says Dr. Roberts. “Now we not only have signatures but we’ve transitioned into candidates for biomarkers. And we’ve filed a provisional patent application on the use of MEG as a biomarker for clinical trial design and, ultimately, therapeutic monitoring for those with ASD who have a GABA-glutamate imbalance.”

For those whose ASD stems from an abnormal structural connectivity in the language pathway of the brain, Dr. Roberts and his colleagues, including David Embick, PhD, from the Department of Linguistics at the University of Pennsylvania, are looking at ways to enhance what is called “repetition priming.” It works like this: saying the word “cat” likely conjures an image of a four-legged, green-eyed, furry animal with pointy ears and whiskers. The specifics of the cat’s characteristics — its color and so forth — vary among people, but the overall representation of a cat is the same for all of us.

For children with more severe forms of ASD whose problems arise from the brain’s language pathway, significant amounts of time and energy may be spent focusing on the details and differences in how people actually say the word “cat” — our individual intonations and so forth — and as a result they create separate representations each time they hear the same word.

“These children may be working too hard on the details and are unable to form an object in their mind or categorize it,” Dr. Roberts says. “They may be unable to group things together or cluster them and therefore are treating them all as different. It just becomes a multi-sensory overload.”

Repetition priming speeds up our responses to things that are similar. If children with ASD aren’t able to grow a healthy language because they are doing too much work processing the myriad stimuli they receive, then helping them “cluster” these representations would help them make advance their language and communication.

Drs. Roberts and Embick are developing a device along the lines of a hearing aid (also with a provisional patent application filed) that would filter the incoming language, remove the subtle variations in how we all speak (therefore making everyone sounds the same) and produce one voice that would help children with ASD better form the representations that build their language and vocabulary. And by watching key parts of the brain through imaging, Dr. Roberts can measure whether it’s working.

“What’s great about this multi-modality approach is that we are harnessing cutting-edge imaging technology and using what we learn to forge a path that can make a real difference in the lives of children with autism spectrum disorders,” says Dr. Roberts. “It’s an exciting and promising time.”

To read learn more about The Children’s Hospital of Philadelphia Research Institute is defining the future of pediatric medicine, see the 2013 Research Annual Report.

Permanent link to this article: http://www.research.chop.edu/blog/honing-biological-markers-autism/

Jan 16 2014

Repairing DNA, One Cell at a Time


Yannick Duwe was blind before receiving gene therapy, which restored much of his sight.

After decades of being “the next big thing,” gene therapy is here. And it’s working.

Of all the accomplishment a scientist can make, Katherine High, MD, can claim one of almost Biblical proportions: She made blind people see.

High would protest that it’s a bit more complicated — she worked together with Jean Bennett, MD, PhD, and Albert Maguire, MD, at the University of Pennsylvania, and their team restored only some of the patients’ sight — but the fact remains: This work allowed people who were legally blind to now recognize faces, see objects and better navigate the world.

High is one of the world’s leading experts in gene therapy, which has long been a “next big thing” in medicine: Take a person with a devastating genetic disease and replace their nonfunctional gene with a normal one — a cure built right into your DNA. It sounds elegantly simple, but it is among the most complex endeavors in all of medicine.

Finally, after decades of work, the future has arrived. High and her team at CHOP’s Center for Cellular and Molecular Therapeutics have produced clinical trials that show real results in humans, first with a type of inherited blindness called Leber’s congenital amaurosis (LCA), and more recently with the blood clotting disorder hemophilia B. Both are relatively rare conditions, but they are clear proof of concept — gene therapy works.


High (center) with Penn research collaborators Albert Maguire, MD (left) and Jean Bennett, MD, PhD (right).

At its most basic level, gene therapy is all in the delivery. To move microscopic snippets of DNA into the body, High’s team uses adeno-associated virus (AAV) vectors, essentially envelopes of molecules engineered to look like a common virus. But instead of delivering a nasty payload of viral DNA, it delivers a normal gene that the recipient needs. They are so essential to gene therapy research that when a biotechnology company stopped making them in 2004 — not enough short-term profits — CHOP created its own clinical-grade production facility. (It also produces lentivirus vectors used to treat cancer patients like Emma Whitehead. See Page 16.)

Precisely engineering these particles is just one challenge; preventing the immune system from destroying them is another. “In a sense, viruses and the human immune response have been conducting a war for millions of years,” explains High. “The human immune system evolves to fight the virus, and then the virus makes some change to get around the immune system. It’s like the arms race.”

It turns out gene therapy also has something in common with real estate: location, location, location. It has worked well in the eye, where the immune system is relatively less aggressive, but has been more difficult elsewhere. “It has become a set of problems where each tissue — liver, skeletal muscle, blood — has a different set of answers,” High explains.

High’s breakthrough clinical trial came in 2007. Twelve patients with LCA-related blindness, including four children, received a gene therapy injection in one eye and demonstrated dramatic improvement in vision. A follow-up study last year treated the second eye in the same patients, with similar success. The team now has approval for a new trial to treat both eyes simultaneously. If successful, the treatment could be submitted for Food and Drug Administration approval as soon as 2015, and treatments for numerous other retinal diseases could follow.


Katherine High, MD, in her lab.

High has also been working since the mid-1980s on gene therapy for hemophilia. The liver, where the blood’s clotting factors are made, is a trickier proposition. She led a clinical trial in 2001 that partially cured a man with hemophilia B, however the effects lasted only four weeks. His body’s immune system rallied to defeat the replacement gene. High, described by her colleagues as “energetic” and “dynamic,” returned to her lab and kept working.

In 2011, she was a collaborator in a study that took place in London that finally achieved the desired result: Six patients with hemophilia B are now producing enough clotting factor on their own to reduce or eliminate the need for clotting factor infusions. High hopes to extend this success with a new trial of 10 to 15 hemophilia patients that began at CHOP in January.

A mother of three, an avid late-night reader and a World War II buff, High grew up in North Carolina. She considered becoming a chemist like her grandfather — he taught at Penn, and a photo of him boating on the Schuylkill River sits atop her office shelves — but instead pursued medicine. As a hematology resident, she became interested in hemophilia A and B, the genes for which had just been identified.

“When I started in the 1980s, I thought it was going to be a big deal if we could just cure the disease in animals,” High says with a smile. “Now it’s much more fun because while there are still many problems that need to be solved, we know gene therapy works in certain subgroups of people.

We are working to develop solutions that will allow us to extend these therapies to ever larger numbers of patients.

It’s really exciting.”

From the latest issue of Children’s View.

Permanent link to this article: http://www.research.chop.edu/blog/repairing-dna-one-cell-at-a-time/

Jan 14 2014

Flipping a Gene Switch Reactivates Fetal Hemoglobin, May Reverse Sickle Cell Disease

Blood_Cell_CroppedHematologists have long sought to reactivate fetal hemoglobin as a treatment for children and adults with sickle cell disease (SCD), the painful, sometimes life-threatening genetic disorder that deforms red blood cells and disrupts normal circulation. Researchers at The Children’s Hospital of Philadelphia have manipulated key biological events in adult blood cells to produce a form of hemoglobin normally absent after the newborn period.

Because this fetal hemoglobin – the oxygen-carrying component of red blood cells – is unaffected by the genetic defect in SCD, the cell culture findings may open the door to a new therapy for the debilitating blood disorder.

“Our study shows the power of a technique called forced chromatin looping in reprogramming gene expression in blood-forming cells,” said hematology researcher Jeremy W. Rupon, MD, PhD. “If we can translate this approach to humans, we may enable new treatment options for patients.”

Dr. Rupon presented the team’s findings at a press conference during the recent annual meeting of the American Society of Hematology (ASH) in New Orleans. Dr. Rupon worked in collaboration with a former postdoctoral fellow, Wulan Deng, Ph.D., in the laboratory of Gerd Blobel, MD, PhD.

In the normal course of development, a biological switch flips during the production of hemoglobin. Regulatory elements in DNA shift the body from producing the fetal form of hemoglobin to producing the adult form instead. This transition occurs shortly after birth. When patients with SCD undergo this transition, their inherited gene mutation distorts adult hemoglobin, forcing red blood cells to assume a sickled shape.

In the current study, Drs. Rupon and Blobel reprogrammed gene expression to reverse the biological switch, causing cells to resume producing fetal hemoglobin, which is not affected by the SCD mutation, and produces normally shaped red blood cells.

The scientists built on previous work by Dr. Blobel’s team showing that chromatin looping, a tightly regulated interaction between widely separated DNA sequences, drives gene transcription—the conversion of DNA code into RNA messages to carry out biological processes.

In the current study, the researchers used a specialized tool – a genetically engineered zinc finger (ZF) protein –which they custom-designed to latch onto a specific DNA site carrying the code for fetal hemoglobin. They attached the ZF to another protein that forced a chromatin loop to form. The loop then activated gene expression that produced embryonic hemoglobin in blood-forming cells from adult mice. The team obtained similar results in human adult red blood cells, forcing the cells to produce fetal hemoglobin.

Drs. Rupon and Blobel will continue investigations aimed at moving their research toward clinical application. Rupon added that the approach may also prove useful in treating other diseases of hemoglobin, such as thalassemia.

Permanent link to this article: http://www.research.chop.edu/blog/flipping-gene-switch-reactivates-fetal-hemoglobin-may-reverse-sickle-cell-disease/

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