Research Stories

UConn Hosts Prader-Willi Stem Cell Biobank

Stem cells provided through a new biobank hosted at UConn will allow researchers around the world to better understand Prader-Willi syndrome and look for potential therapies for the rare genetic disease.

Stem cells provided through a new biobank hosted at UConn will allow researchers around the world to better understand Prader-Willi syndrome and look for potential therapies for the rare genetic disease.


A new collaboration between UConn Health and the Foundation for Prader-Willi Research will create a centralized, high-quality biobank of stem cells to help researchers better understand Prader-Willi syndrome, a rare genetic disease that may hold insights into obesity, developmental delays, autism spectrum disorders, and many other conditions.

The foundation (FPWR) and the UConn–Wesleyan University Stem Cell Core will jointly support the biobank of induced-pluripotent stem cells for Prader-Willi syndrome. These special stem cells are made from adult cells, and they have the potential to grow into any bodily tissue, including skin, stomach, brain, blood, and more. The biobank will be able to supply induced-pluripotent stem cells for Prader-Willi syndrome to researchers throughout the world.

Prader-Willi syndrome occurs in approximately 1 in 15,000 to 30,000 births. It’s caused when certain genes that are normally found on chromosome 15 are missing or not working. In most individuals with Prader-Willi syndrome, certain genes on chromosome 15 that should be specifically expressed from the father’s chromosome are missing. Geneticists don’t understand why, but the mother’s version of these genes is always turned off.

It’s these genes, and how their absence affects the rest of the genome’s and cells’ functions, that researchers will be able to investigate thanks to the biobank. Researchers will be able to use the induced-pluripotent stem cells to look for potential therapies for Prader-Willi syndrome. They may also be able to use the cells to explore the genetic and biomolecular basis of some of the syndrome’s symptoms, such as sleep disorders, developmental delays, and disordered eating.

UConn will host the centralized repository in the Stem Cell Core on the UConn Health medical school campus. Each Prader-Willi syndrome induced-pluripotent stem cell sample provided through the biobank will have undergone a select set of validation assays. The biobank will help facilitate research on cellular phenotypic abnormalities in Prader-Willi syndrome and ensure that precious research dollars are not spent re-creating stem cell resources that may already exist.

“The objective of FPWR’s translational research program is to reduce the amount of time and resources needed to move therapeutic studies forward,” says Nathalie Kayadjanian, director of translational research at FPWR. “Stem cells stored at the UConn Core will provide Prader-Willi syndrome researchers and pharmaceutical companies pursuing Prader-Willi syndrome therapeutics high-quality cellular resources to perform robust experiments in a timely manner.”

Currently the Prader-Willi syndrome biobank has two cell lines, one with a deletion of certain genes on the father’s copy of chromosome 15, the other with two copies of chromosome 15 from the mother and none from the father. Both cell lines were contributed by Stormy Chamberlain, Ph.D., and Marc Lalande, Ph.D., UConn Health researchers who study Prader-Willi syndrome and its sibling genetic disorder Angelman’s syndrome. More cell lines will be banked at the facility in the coming years.

Old Drug, New Hope for Pediatric Brain Cancer

Dr. Ching C. Lau sees a patient.

Dr. Ching C. Lau sees a patient.


Some drugs for heart disease might also work against brain cancer, according to an analysis by researchers from The Jackson Laboratory (JAX), Connecticut Children’s Medical Center, and UConn Health. The researchers used a new approach to identify five heart medicines that might also be effective at fighting the most common type of childhood brain cancer, they report in Science Translational Medicine.

Medulloblastoma is the most common malignant brain tumor in children, accounting for 20 to 25 percent of pediatric brain tumors. Current treatments have significantly increased the survival rate, but many children face difficult side effects that impact their brains, hormones, and fertility for the rest of their lives. There are also a handful of patients who either don’t respond to available treatment options or suffer and die from relapses.

To quicken the long route to developing cancer drugs, the research team used a process called drug repositioning, reanalyzing drugs previously approved by the FDA and looking for crossover among the diseases that a drug is likely to treat. Using computational modeling methods, they compared approved drugs’ effects on gene expression profiles — that is, what genes they work with or against — to the genes active in patients with various diseases.

But medulloblastoma tumors are complex and often very different from patient to patient, and even internally in a single patient. Dr. Ching C. Lau thought drug repositioning could work to find better drugs for medulloblastoma, but suspected the technique could be improved. Lau, who is jointly appointed as a professor at JAX, UConn Health, and Connecticut Children’s Medical Center, heads the division of pediatric hematology-oncology at UConn Health and is the medical director of hematology-oncology at Connecticut Children’s.

Lau worked with a team of researchers from those institutions, as well as from Houston Methodist Research Institute and Texas Children’s Hospital, to devise a new integrated drug repositioning method that could work against something as complicated as medulloblastoma.

Their new method has identified eight drugs as possible medulloblastoma-fighting agents, including three already used as chemotherapy against other cancers and five previously used to treat heart failure.

The researchers also showed that one of the heart drugs, digoxin, helped mice with medulloblastomas live longer. The mice survived even longer when digoxin was combined with radiation.

“This is exciting because not only can we potentially improve overall survival of medulloblastoma patients with digoxin, but the results also suggest that we could potentially reduce the dose of radiation necessary when combined with digoxin, and thereby minimize long-term side effects of radiation among the survivors,” says Lau. “Because digoxin has been used for so many years to treat heart failure, its potential side effects are well known, and could potentially help speed up the subsequent clinical trial.”

Curators Versus Cancer

By Kim Krieger | Illustrations by Kailey Whitman

illustration of scientist look over hundreds of books

A special team of medical literature experts are on the hunt for cancer’s kryptonite, one mutation at a time.


If the genetic code is like a book, then a mutation is like a typo. Some typos are meaningless. Others have such dramatic consequences for a book, or a life, that the error alone could have an entire novel written about it.

Cancer mutations are like that. As oncology moves toward precision medicine — the idea that if we knew exactly which genetic mutations make a particular cancer tick, we could pick exactly the right treatments — oncologists have to keep up with an ever-expanding library of mutations and the drugs that might foil them. The number of cancer research papers published increases every year; there were about 35,000 published in 2015 just in the U.S. It’s far more than any one person can keep up with.

In the same way that a university has research librarians who keep up with the literature in specific fields, JAX has experts who keep up with cancer gene and drug research, even studies that are ongoing and not yet published.

A new collaboration between UConn Health and The Jackson Laboratory (JAX) hopes to help oncologists find the right treatments by keeping up with research for them — and using the institutions’ combined expertise in cancer treatment, molecular biology, and genetics to improve patient outcomes for cancers that currently don’t have good treatments. In the same way that a university has research librarians who keep up with the literature in specific fields, JAX has experts who keep up with cancer gene and drug research, even studies that are ongoing and not yet published. JAX already successfully connects these experts with doctors in the Maine Cancer Genomics Initiative, a philanthropy-funded statewide precision medicine program. UConn Health and JAX hope to expand the concept and demonstrate its feasibility more widely.

A UConn Health researcher holds a tumor sample.

A UConn Health researcher holds a tumor sample. Kristin Wallace

Bull’s Eye Treatment

Imagine that a patient has surgery or a needle biopsy to diagnose a tumor. It’s a particularly ugly tumor, the surgeon, oncologist, and pathologist all agree. Invasive, spreading, and perhaps this isn’t the first time this patient has had to come in for cancer surgery. The tumor is sampled and sent for genetic testing. In about two weeks, the results come back: there are three genetic variants in the tumor that might be drug targets.

At UConn Health, oncologists can send portions of particularly malignant tumors to a team at the JAX Clinical Laboratory. JAX sends back a report with information the oncologist can use to pick a drug regimen with the best chance to shrink that ugly tumor. “The goal is to define the optimal treatment regimen for each individual patient” who may not have good options otherwise, says Dr. Ketan R. Bulsara, chief of neurosurgery at UConn Health and one of the principal investigators on the project.

At UConn Health, oncologists can send portions of particularly malignant tumors to a team at the JAX Clinical Laboratory. JAX sends back a report with information the oncologist can use to pick a drug regimen with the best chance to shrink that ugly tumor.

The report is intended to be a standalone reference an oncologist can use to inform a treatment plan. But if the oncologist is unfamiliar with one of the mutations identified in the report or just wants more information, they can request that a genomic tumor board be convened. The board is composed of surgeons, pathologists, and molecular oncologists who act as external advisors, sharing their opinions with the oncologist. In just 15 minutes, the oncologist can get a wealth of expert opinion to combine with their own expertise and judgment. In the end, the oncologist and patient decide on the best treatment, based on all the available information.

“In a multidisciplinary fashion, doctors and scientists work hand in hand in this with one common goal: identify the best treatment regimen for that particular patient’s pathology,” Bulsara says.
The focus is always on the patient. But behind the scenes, there’s an entire team of researchers whose work goes into the genetic tumor report. Scientists at JAX Clinical Laboratory sequence the tumor’s genetic code and report information on more than 200 cancer-related genes. The genes were picked because they are associated with both malignancy and potential drug treatments. Any mutations or variants in these genes might be a clue to the cancer’s weakness. Or a red herring.

“A typical tumor might have 2,000 mutations. Not all of them really matter,” says Andrey Antov, the program director for the Maine Cancer Genome Initiative at JAX. Finding the key mutations that matter, the two or ten or twenty that could possibly inform treatment and a better outcome for the patient, is the job of the clinical genomic curators.

Personal Librarians

The clinical genomic curators are specialists in fields such as molecular oncology and oncological pharmacology. They’re dedicated to keeping up with the literature on cancer genes and the drugs that target them. More and more of these drug-gene connections are being discovered every day. It’s exciting, but the sheer volume of papers can be overwhelming. Navigating that ocean of scientific papers is the medical curators’ full-time job. They’re like librarians curating a Boston Public Library–size collection of genes and drugs with no cross references in the card catalog and only an imperfect search function. The hope is that just as a good librarian’s knowledge of the subject matter can unearth texts a researcher would never otherwise find, a medical curator’s grasp of oncological genetics and pharmacology can identify potential treatments that would otherwise remain obscure.

Each mutation identified by the genetic panel might require 10 to 20 scientific publications to understand. Once the curators have a handle on the variants’ significance, the clinical laboratory decides which two or three should be described in the report to the oncologist.

illustration of books in a library cart

Sifting the information down to something relevant and digestible is the ultimate goal.

“Today, all this information is disorganized and may not all be in the oncologist’s head. We’re trying to bring it together,” says Jens Rueter, medical director for the Maine Cancer Genome Initiative.

The ideal outcome of a tumor genetic analysis would be to identify a mutation such as the HER2 gene that is turned on in the most aggressive breast cancers. HER2 is responsible for the cancer’s malignancy. But it’s also the cancer’s Achilles’ heel. Once drugs were developed to block the HER2 protein, survival rates climbed sharply.

The goal of the Maine Cancer Genomics Initiative is to enable oncologists to identify other drug-gene connections as potent as the ones found for HER2. Although more and more of these drug-gene connections are being discovered, it remains difficult to provide a patient with access to these drugs. Many of them are only available if a patient participates in a clinical trial. And often, there are barriers to accessing clinical trials, and getting drugs off-label is the only way to get patients to treatments. That’s another benefit that Antov, Bulsara, and Rueter hope UConn Health’s collaboration with JAX will bring.

Positive Outcomes

Ultimately, the researchers hope to demonstrate that this approach leads to better outcomes for patients. During the past year more than 350 patients and 70 oncology practitioners (more than 80 percent of the Maine oncology community) enrolled in the Maine Cancer Genomics Initiative study protocol. A few patients have already been offered a targeted treatment through a trial or a compassionate drug access program as a result of enrollment in the program. And Maine health care professionals have logged more than 1,200 certified education hours through 35 genomic tumor boards, online modules, and annual forums held by JAX.

So far, five patients have done this at UConn Health within the last two months. Generous donors have given enough to fund 20 more.

The hope is that just as a good librarian’s knowledge of the subject matter can unearth texts a researcher would never otherwise find, a medical curator’s grasp of oncological genetics and pharmacology can identify potential treatments that would otherwise remain obscure.

“We hope to get funding for at least 100 patients to show the feasibility of this approach,” Bulsara says. “We want to show we can do this reliably, and that it reliably improves patient care.”

UConn Health already has the infrastructure to do this, in particular a biorepository for tumors set up by Neag Cancer Center Director Dr. Pramod Srivastava and pathologist Dr. Melinda Sanders. With that foundation and support from UConn medical school Dean Dr. Bruce Liang and UConn Health CEO Dr. Andrew Agwunobi, the program was piloted in the Department of Surgery by Bulsara, its chief of neurosurgery, with support from Department of Surgery Chairman Dr. David McFadden, hematology and oncology chief Dr. Susan Tannenbaum, anatomical pathology chief Dr. Qian Wu, and JAX Clinical Laboratory Director Honey Reddi.

If the UConn Health–JAX initiative does prove its feasibility, the approach will continue to spread and become a standard of care.

More oncologists could have access to the library of knowledge and advice of a genetic tumor board, and more cancer patients could benefit from longer, healthier lives.

Tumor samples are housed in UConn Health's research biorepository.

Tumor samples are housed in UConn Health’s research biorepository. Kristin Wallace

Unraveling

By Kim Krieger | Illustrations by Yesenia Carrero

illustration; two silhouettes, one with a scribble pattern overlayed over top. looks to scribbled circular dot between them

PTSD can undo a sufferer’s life. MDMA may help patients untangle their trauma and find their way back to mental health.


When lasting trauma is caused by callous acts of violence, the key to recovery can be making meaning from meaninglessness.

This year UConn Health will host a phase 3 FDA trial that tests whether the drug MDMA, known on the street as ecstasy or molly, is a safe and effective treatment for post-traumatic stress disorder. The disorder is difficult to treat, and many people have a tough time handling the treatment. MDMA not only might make therapy more tolerable but it also may help open a window for patients into their own mind. The insight allows them to process a shattering, horrific event into something that makes them stronger.

The American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders defines post-traumatic stress disorder, or PTSD, as when a person is traumatized in some way and then continues to reexperience the trauma through flashbacks, nightmares, or unwanted intrusive memories. The person with PTSD avoids people or places associated with the trauma; becomes overly negative in thoughts and speech about themselves and other people; and has heightened arousal that can include a hair-trigger startle reflex, inability to sleep, hypervigilance, irritability, and aggression. At its worst, people are unable to cope with everyday life and may even become suicidal.

Often the source of the trauma is a shocking event involving interpersonal violence, such as rape, combat, or sexual abuse. Racial discrimination and harassment, particularly when it is shocking or pervasive, can also cause PTSD. UConn psychologist Monnica Williams began focusing on race-based trauma when she was at the University of Pennsylvania and had a very successful, high-achieving, black client come in with PTSD stemming from racial discrimination she’d suffered on the job. Williams was taken aback and began studying the link between racism and post-traumatic stress disorder.

Deconstructing the Trauma

But no matter what type of trauma causes the PTSD, the most effective treatment for it is exposure-based therapy, such as “prolonged exposure.” Essentially, the therapist has the patient discuss the traumatic event in excruciating detail, over and over again, until it ceases to cause overwhelming fear and anxiety.

Prolonged exposure works — indeed, it has the most evidence behind it. But it’s terribly difficult for the patients, who often get visibly upset during sessions, and many quit therapy because the experience is too much like the original trauma.

The MDMA-assisted therapy session was utterly without the distress, tension, and fear PTSD patients typically show during prolonged exposure treatment.

MDMA-assisted psychotherapy could be one way to change that. The drug stimulates the release of neurotransmitters that promote a feeling of trust and well-being and might also help the brain rewire itself. But when Williams first heard of it, she was skeptical.

“It sounded weird, like junk science, and I didn’t want to be part of that,” she says. But she agreed to take a look at an article in Psychopharmacology. She was fascinated to see that researchers had used MDMA as an adjunct to psychotherapy for PTSD and had gotten really good results. She was pleasantly surprised again when she first watched a video of an MDMA-assisted therapy session.

“People were sitting in a chair, relaxed. They’re processing it on their own, and would sometimes share new insights with the therapist,” Williams says. It was utterly unlike the distress, tension, and fear PTSD patients typically show during prolonged exposure. “They would say things like, ‘Wow. Now I understand the trauma didn’t happen to me because I’m a bad person — I was just in the wrong place at the wrong time.’ And we’re like, ‘Yes! Yes! They finally get it!’” she recalls. The MDMA helps them look at the big picture, to understand that the violence against them didn’t mean what they thought it had.

‘It’s got to come out’

It takes a while for psychoactive drugs to work their way through the FDA approval process. MAPS has been testing MDMA-assisted therapy for PTSD for more than a decade. Many of the early participants experienced lasting improvement.

Rachel Hope, who experienced a cascade of abusive events as a child that left her with severe PTSD, “did 20 years of psychotherapy” prior to participating in an MDMA-assisted therapy session. “When I got into the outer limits of the really hardcore stuff, I’d start to destabilize and get sicker … I’d start vomiting or have to leave the room. I knew that I had to tell it — the story has a soul of its own. It’s got to be seen, got to be known. It’s got to come out. But I couldn’t get it out,” she says.

Hope had had good therapists and managed to run a real estate development company, but eventually the PTSD got so bad she couldn’t leave the house. Finally her personal assistant threatened to quit if she didn’t go back into therapy. And that’s how she came to participate in an MDMA-assisted psychotherapy trial in 2005. It was a revelation.

“The MDMA was a terrific antianxiety medicine,” she says; it didn’t make her fuzzy-headed like most antianxiety meds had. “It amplified access to memories and, really, I had access to everything, and I wasn’t terrified. I could actually tell someone, for the first time in my life, what had happened to me. I had so much access to my own mind.” She describes it as the perfect tool to help work through the trauma. “I was rebooting my mind under my own directive,” Hope says.

“They would say things like, ‘Wow. Now I understand the trauma didn’t happen to me because I’m a bad person — I was just in the wrong place at the wrong time.’ And we’re like, ‘Yes! Yes! They finally get it!’”

Williams agrees that the MDMA seems to help patients rapidly make connections and breakthroughs in a single therapy session. Typically, a patient in psychotherapy might have just one such realization every few months.

The participants in the phase 3 trial at UConn Health will have a total of 20 therapy sessions, three of which will include MDMA. Each session will have two therapists present. The MDMA-assisted sessions will be six to eight hours long, after which the participant will stay overnight in the hospital to rest, supervised by a night attendant. And as part of the effort to involve participants from communities of color, all but one of the therapists at UConn Health identifies as an ethnic, racial, and/or sexual minority.

“In Singapore, I was part of the majority, but I was curious how it felt to be Malay, Indian, or one of the other minorities,” says Terence Ching, a clinical psychology doctoral student involved in the study. Ching has also lived in Australia, New Zealand, and Kentucky, where he was not part of the majority ethnic group. “That led me to critically introspect my place in society as someone with many different identities. Having that multifaceted perspective allows me to experience a lot of empathy for people from marginalized groups in the U.S.,” Ching says.

To get a better understanding of what the MDMA-assisted psychotherapy would be like for study participants, Ching participated in a session himself as part of his training.

“It felt like a lot of insights happening constantly,” Ching says. “It’s been a year since the session, and every now and then I have a moment where I remember an insight from it, and/or have another one. It’s a wonderful thing.” Ching hopes that the participants benefit from their MDMA-assisted psychotherapy in the same way he did.

“For someone who has experienced trauma, MDMA-assisted psychotherapy might help them be able to make meaning of it. I really believe in this work,” Ching says.

For Anxiety, Single Intervention Is Not Enough

illustration on the concept of anxiety. Features a male with hands held to forhead in slumped possition. Mans face is scribbled.


No matter which treatment they get, only 20 percent of young people diagnosed with anxiety will stay well over the long term, UConn Health researchers report in the Journal of the American Academy of Child and Adolescent Psychiatry.

“When you see so few kids stay non-symptomatic after receiving the best treatments we have, that’s discouraging,” says UConn Health psychologist Golda Ginsburg. She suggests that regular mental health checkups may be a better way to treat anxiety than the current model.

The study followed 319 young people aged 10 to 25 who had been diagnosed with separation, social, or general anxiety disorders at sites in California, North Carolina, Maryland, and Pennsylvania.
They received evidence-based treatment with either sertraline (the generic form of Zoloft) or cognitive behavioral therapy or a combination of the two and then had follow-ups with the researchers every year for four years.

The follow-ups assessed anxiety levels but did not provide treatment. Other studies have done a single follow-up after one, two, five, or 10 years, but those were essentially snapshots in time. This is the first study to reassess youth treated for anxiety every year for four years.

We need a different model for mental health, one that includes regular checkups.

The sequential follow-ups meant that the researchers could identify people who relapsed, recovered, and relapsed again as well as people who stayed anxious and people who stayed well. They found that 20 percent of patients got well after treatment and stayed well, rating low on anxiety at each follow-up. But about half the patients relapsed at least once, and 30 percent were chronically anxious, meeting the diagnostic criteria for an anxiety disorder at every follow-up. Females were more likely to be chronically ill than males. Other predictors of chronic illness were experiencing more negative life events, having poor family communication, and having a diagnosis of social phobia.

On the bright side, the study found that young people who responded to treatment were more likely to stay well. The study also found no difference in long-term outcomes between treatment types. This means that if there is no cognitive behavioral therapist nearby, treatment with medication is just as likely to be effective.

The study also found that kids did better if their families were supportive and had positive communication styles. Parents should talk to their child and ask the therapist questions: Why do they suggest this treatment? (It should be supported by evidence.) Have they been trained in cognitive behavioral therapy? How can we reinforce what was learned in therapy this week?

But parents should also be aware that a single intervention may not be enough.

“If we can get them well, how do we keep them well?” says Ginsburg. “We need a different model for mental health, one that includes regular checkups.”

New 3-D Fabrication Technique Could Deliver Multiple Doses of Vaccine in One Shot

Engineering researcher Thanh Nguyen holds a slide showing a silicone mold loaded with drug-carrying microparticles. Nguyen invented the process using biocompatible polymers and a new 3-D fabrication technique.

Engineering researcher Thanh Nguyen holds a slide showing a silicone mold loaded with drug-carrying microparticles. Nguyen invented the process using biocompatible polymers and a new 3-D fabrication technique.


Anew 3-D fabrication technique invented by a UConn engineering professor could provide a safe and convenient way to deliver multiple doses of a drug over an extended period of time with a single injection.

Other 3-D printing techniques have been limited for such applications because they rely on printable inks that are potentially toxic to the human body.

But UConn assistant professor of mechanical engineering Thanh Nguyen circumvented those obstacles by adopting an additive manufacturing technique
commonly used for the manufacture of computer chips.

This … will help avoid the repetitive, painful, expensive, and inconvenient injections often required to administer drugs like growth hormones and pain medicine.

The technique, which Nguyen calls SEAL (StampEd Assembly of polymer Layers), can create hundreds of thousands of drug-carrying microparticles made of a biocompatible, FDA-approved polymer currently used for surgical sutures, implants, and prosthetic devices.

During the process, the polymer, PLGA, is shaped into a drug-carrying micro-shell designed to degrade and release its contents over an extended period, ranging from a few days to a few months. This allows for a drug’s release into the body in bursts, similar to what happens when a patient receives multiple injections over time.

“This application could enable the creation of a new set of single-injection vaccines or drugs, which will help avoid the repetitive, painful, expensive, and inconvenient injections often required to administer drugs like growth hormones and pain medicine,” says Nguyen, who invented the technique as a postdoctoral researcher in Professor Robert Langer’s lab at MIT. Nguyen joined UConn’s mechanical, biomedical, and regenerative engineering research teams last fall.

Details of the novel technique appear online in the journal Science.

Exercise Can Improve Alzheimer’s Symptoms

A new UConn analysis of years of previous research suggests there is ample evidence that exercise may delay the decline in cognitive function associated with Alzheimer’s disease.

Aerobic exercise has possibly the most favorable effect, according to the study in the Journal of the American Geriatrics Society.

Led by Gregory Panza, a UConn kinesiology graduate student, this is the first analysis of a group of studies on a particular type of dementia — Alzheimer’s.

The authors examined data from 19 studies with 23 interventions that encompassed 1,125 participants who were at risk of Alzheimer’s. The studies were all conducted prior to August 2017 and published in peer-reviewed journals.

The studies led to the overall conclusion that moderate-intensity exercise training about three days a week for 45 minutes resulted in modestly better cognitive function for participants. The findings reinforce the World Health Organization (WHO) guidelines, which recommend exercise as a cost-effective lifestyle therapeutic option to improve brain health in older adults.

Lab Discovery Could Lead to Prader-Willi Treatment

DNA strand


Stem cell researchers at UConn Health have reversed Prader-Willi syndrome in brain cells growing in the lab, findings they recently published in Human Molecular Genetics.

The discovery provides clues that could lead to a treatment for Prader-Willi, a genetic disorder that occurs in about one out of every 15,000 births, and is the most common genetic cause of life-threatening childhood obesity.

Unlike many genetic syndromes that are caused by a mutation in a gene, people with Prader-Willi often have the right gene available — it’s simply that it’s been silenced.

The gene is silenced because it is on the part of their chromosome they inherited from their mother, and for mysterious reasons our cells use the father’s copy of this gene. But if the father’s copy is missing, the cells can’t express that gene at all.

UConn Health’s Maeva Langouet, a post-doctoral fellow; Marc Lalande, professor emeritus of genetics and genome sciences; and their colleagues wondered if it was possible to reverse the silencing of the mother’s copy.

Unlike many genetic syndromes that are caused by a mutation in a gene, people with Prader-Willi often have the right gene available — it’s simply that it’s been silenced.

The researchers noticed that a certain protein, called ZNF274, was involved in the process. It silences many other genes as well, but in those cases it usually acts with another protein. On the Prader-Willi region of our DNA, the protein seems to act alone, they said.

So Langouet and Lalande took stem cells donated by Prader-Willi patients and carefully deleted ZNF274. They then encouraged the stem cells to grow into neurons, a type of brain cell. And the cells seemed normal. They grew and developed, as expected.

Critically, the new cells also expressed the maternal copy of the Prader-Willi region.

“We still need to figure out if knocking out ZNF274 is doing anything else” that might be undesirable, says Langouet.

And many other questions still need to be answered: Does this work directly in human brain cells? Will it only work in embryos, or can it help the brain develop normally even after birth?

Currently, there is no cure for Prader-Willi syndrome, and most research has been targeted towards treating specific symptoms. For many individuals affected by the disorder, the elimination of some of the most difficult aspects of the syndrome, such as the insatiable appetite and obesity, would represent a significant improvement in quality of life and the ability to live independently.

But in the future, this new line of research may offer a therapeutic approach for kids with Prader-Willi, Langouet says.

The research was funded by the Foundation for Prader-Willi Research, the Cascade Fellowship, and the CT Regenerative Medicine Fund.

Weight Stigma Coping Tactics Affect Health

A new study by the Rudd Center for Food Policy and Obesity at the University of Connecticut shows that how people cope with being mistreated because of weight can affect their health.

The study, published online in Health Psychology, found that coping with the experience of being teased or bullied because of weight by engaging in healthy lifestyle behaviors (like exercise or eating healthy foods) was associated with better health, including better physical and psychological well-being and less frequent depressive symptoms. Responding to weight stigma with negative emotions and maladaptive eating (such as starving, bingeing, or purging) was linked with more depressive symptoms, lower self-esteem, and worse physical and emotional health.

Considerable evidence had previously linked the experience of weight stigma to poor health. Yet few studies had explored how individuals cope with mistreatment because of their weight, or the role that their coping responses may play in health outcomes. Doctors should offer support and positive coping strategies, the study authors say.

3-D Printed Model Allows Brain Surgeons to Rehearse

by Kim Krieger

Dr. Charan K. Singh, right, threads a catheter through a 3-D printed model of arteries in the brain while speaking with Dr. Clifford Yang, one of the  model's creators, at UConn Health.

Dr. Charan K. Singh, right, threads a catheter through a 3-D printed model of arteries in the brain while speaking with Dr. Clifford Yang, one of the model’s creators, at UConn Health. Peter Morenus


The first time a young surgeon threads a wire through a stroke victim’s chest, up through the neck, and fishes a blood clot out of the brain may be one of the most harrowing moments in their career. Now, a UConn Health radiologist and a medical physicist have made it easier for them to get some practice first. The team made a life-size model of the arteries that wire must pass through, using brain scans and a 3-D printer. They will make the pattern freely available to any doctor who requests it.

Five years ago, the Food and Drug Administration (FDA) approved mechanical thrombectomy — using a wire to pull clots out of the brains of stroke victims. A trap at the end of the wire opens like a little snare that captures the clot, which is then dragged out of the patient.

After a couple months of tweaking, a UConn Health radiologist and a medical physicist found they could print a true-to-life teaching model of the brain’s major arteries for about $14.

A lot can go wrong on that journey. One of the most dangerous complications is also one of the most likely: another clot can be accidentally knocked loose from the walls of the arteries and get stuck in the heart, the lungs, or elsewhere in the brain. Computer simulations of the procedure exist, but they are prohibitively expensive for many medical schools to purchase. Yet interventional radiologists and neurosurgeons need to train extensively before they work on a real person.

UConn Health cardiac radiologist Dr. Clifford Yang and medical physicist intern David Brotman knew they could help young doctors feel more comfortable with the mechanics.


Because of the prohibitive costs of computer simulation programs, often the first time a surgeon threads a wire into a stroke victim’s brain to remove a blood clot is during the doctor’s first surgery. Using brain scans and a 3-D printer, a UConn team made a life-size model of the arteries surgeons must navigate during the procedure so they can practice first. The pattern is available for free to any doctor who requests it.


“What matters is the ability of the doctor to be confident in guiding the wire,” says Brotman. He and Yang found a brain scan of a patient with typical blood vessel structure and used the scan to design a 3-D model of the blood vessels. Finding a good scan was easy: UConn has an immense library of scans from computed tomography (CT) and magnetic resonance imaging (MRI) of patients. The tough part was converting the data into something a 3-D printer could interpret. Brotman and Yang found and modified publicly available software to do that, and after a couple months of tweaking, they found they could print a true-to-life teaching model of the brain’s major arteries for about $14.

Technically called a brain perfusion phantom, the model is surprisingly delicate. Holding it in your hand brings home just how small the arteries are, even in an adult man. The top arch of the aorta in the chest, big enough to slide an adult’s pinky finger through, connects to the carotid in the neck and then on to the Circle of Willis in the brain, which is no thicker than a fat piece of yarn. The circle has six branches. Each branch supplies blood to one-sixth of the brain. It is in these branches that clots are most likely to get stuck and cause serious damage.

“We are using this model to teach students,” says UConn interventional radiologist Dr. Charan Singh. “Obviously, it won’t feel like the human body. But it will improve their knowledge of anatomy and give them basic technique on how to move the catheter.”

What matters is the ability of the doctor to be confident in guiding the wire.

Singh demonstrates how a slight twist can violently flip the catheter, which is dangerous. It could knock off new clots into the bloodstream. The model isn’t perfect — there are several different ways a person’s aorta can be shaped, and the other veins can vary too. But students can get good practice with it, Singh says.

Dr. Ketan Bulsara, UConn’s chief of neurosurgery, also likes the technology. He cautions that individual anatomy varies too much for it to be used as the only training tool to learn mechanical thrombectomy, but says that it could potentially be used to visualize other conditions, such as brain tumors. Surgery for brain tumors has significant lead time, and modeling the tumor in advance could personalize and improve patient care.

“Creating these high-level 3-D models customized for individual patients has the potential to significantly improve outcomes and reduce operative times by enhancing surgical planning,” Bulsara says.