NFunFest Fundraiser for Washington University NF Center A Rousing Success
Amanda and Brian Walk hosted their annual NFunFest event this fall to support research at the Washington University NF Center. Despite the challenges of the ongoing COVID-19 pandemic, the Walks have continued to be ardent supporters of the work ongoing in the center to understand why specific medical problems arise in children and adults with NF1, as well as to discover new treatments and management strategies.
We thank the Walk family for partnering with us to change the way we care for people affected with NF.
PATIENT SPOTLIGHT: CARTER
Carter Hoss is a goofy, caring, and fun-loving sixth grader. He has also raised over $1500 to benefit NF Midwest through participation in the organization’s annual Walk 4 NF event. Both aspects of Carter stem from his drive to constantly improve himself and the world around him, always on a mission to help however he can.
Carter first visited the Washington University NF Clinic Program at St. Louis Children’s Hospital as a toddler after his pediatrician referred him to Dr. David H. Gutmann. At this time, he received a diagnosis of NF1. Since then, Carter has been an enthusiastic participant in Club NF, the Washington University NF Center’s school-aged free therapy program – he has enjoyed going ice-skating and swimming in particular.
Carter prefers to be active and outside, playing baseball, basketball, soccer, and nerf games with his little brother. He always looks forward to fishing for catfish with his grandpa or baking with his grandma and has a particular passion for meeting new people and trying new things. He is a reliable friend to his classmates, often standing up for his peers in the face of bullying and serving as a go-to resource for anyone who needs a laugh. When Carter’s little brother was nervous for his first day of Kindergarten, Carter reassured him, wisely remarking that everyone has to start somewhere. His mom describes him as “ready to
defeat the world.”
It was that caring and go-getter attitude that spurred Carter’s participation in Walk 4 NF. Walk 4 NF is an annual fundraising event held in several Midwestern locations. Its mission is to end NF by funding research and raising awareness. Participants put together their own fundraising teams before coming together to walk, enjoy live music, hear speeches, and connect with other members of the NF community.
Carter’s team, called Carter’s Cardinals, first participated in Walk 4 NF in 2020. Though that event was virtual, Carter hugely enjoyed the strong sense of community and belonging it generated and was super excited to be featured in an official NF Midwest video played at the event’s conclusion.
For the 2021 Walk 4 NF, held in Columbia, MO, Carter increased his fundraising goal, motivated both by the opportunity to help the NF community and his ambition to outdo himself. Not only did Carter meet his goal, but he also won second place in fundraising overall, raising more than twice his original objective. Additionally, he interacted with over 200 people in the NF community – he loved talking with a diverse group of individuals affected by NF, especially those older than him, with wisdom to share. Carter’s parents particularly enjoyed talking to other parents of children with NF, exchanging stories and advice. Carter and his family are determined to continue their participation in Walk 4 NF for years to come – where Carter will focus on raising a little bit more every year.
For Carter and his family, the joy of participation in both Walk 4 NF, and Club NF comes from the sense of community present in these events and the feeling of accomplishment that they offer. Carter walks away knowing that he produced tangible change, that he actually did something, and that he is never alone in doing so. For these reasons, the Hoss family strongly encourages all families affected by NF to get involved, both in these events and in all others like them. As put by mother, Moriah, knowing that the money goes “toward something near and dear to our hearts” is the ultimate reward.
New Study Identifies Immune Cell Target for Blocking Tumor Growth
Previous studies from the laboratory of NF Center director, David H. Gutmann, MD, PhD, have shown that immune system-like cells, called microglia, are important non-cancerous regulators of NF1 optic glioma formation and growth. Using a combination of RNA sequencing, genetically engineered mouse strains, and human tumor specimens, Amanda de Andrade Costa and colleagues discovered that brain tumor-associated microglia express a protein called CD11A.
In this study, recently published in the journal Neuro-Oncology, Dr. Costa found that CD11A was not only expressed on microglia in numerous strains of Nf1-mutant mice that develop optic gliomas, but also on human brain tumor-associated microglia. To determine whether CD11A was also important for microglia function, Dr. Jit Chatterjee, another postdoctoral fellow in the Gutmann laboratory, used microglia from mice lacking CD11a, and showed that these CD11a-deficient microglia had reduced migration and expression of a key growth factor needed for Nf1 mouse optic glioma growth. Consistent with an essential role for CD11a-expressing microglia in controlling Nf1 optic glioma growth, Dr. Costa used antibodies to block CD11a, resulting in reduced tumor growth in vivo.
Taken together, these findings establish CD11A as a critical microglia regulator of NF1 optic glioma growth, suggesting alternative treatment strategies for pediatric brain tumors.
Seeing, hearing, thinking, daydreaming — doing anything at all, in fact — activates neurons in the brain. But for people predisposed to developing brain tumors, the ordinary buzzing of their brains could be a problem. A study by researchers at Washington University School of Medicine in St. Louis and Stanford University School of Medicine shows that the normal day-to-day activity of neurons can drive the formation and growth of brain tumors.
The researchers studied mice genetically prone to developing tumors of their optic nerves, the bundle of neurons that carries visual signals from the eyes to the brain. The mice served as a model for children with the genetic condition neurofibromatosis type 1 (NF1). About one in six children with NF1 develops low-grade optic nerve tumors by age 7. In this study, mice with Nf1 mutations raised under normal lighting developed tumors; those kept in the dark during a critical period of development did not.
The findings, published May 26 in the journal Nature, suggest that neuronal activity plays an underappreciated role in nervous system cancers. The research opens up new avenues to preventing brain tumors in children at high risk for them.
“Optic gliomas are very common in children with NF1, and they can cause vision loss,” said co-senior author David H. Gutmann, MD, PhD, the Donald O. Schnuck Family Professor of Neurology at Washington University and the director of the university’s NF Center. “We don’t have a good way to predict who will develop tumors or any way to prevent them. But now that we know these brain tumors are caused by exposure to light and neuronal activity, we can start thinking of next-gen prevention strategies. Maybe we can give kids cool sunglasses to wear with filters or lenses to block out certain wavelengths of light, or repurpose drugs that suppress excessive neuronal activity, and protect these kids from developing brain tumors and losing their sight.”
Co-senior author Michelle Monje, MD, PhD, an associate professor of neurology at Stanford Medicine, previously demonstrated that neuronal activity drives the growth of an aggressive form of brain cancer. But it wasn’t clear whether neuronal activity itself sets in motion the process of tumor formation or if it only bolsters the growth of tumors initiated by other processes.
As part of this study, the researchers used mice with mutations in their Nf1 gene. Such mice start developing low-grade tumors of their optic nerves around 9 weeks of age, and virtually all have tumors by 12 weeks to 16 weeks old. Since the neurons in the optic nerve become active when exposed to light, the researchers investigated whether they could reduce neuronal activity — and, thereby, tumor formation — simply by keeping the mice away from light. They raised mice from age 9 weeks to 16 weeks in the dark and then checked for tumors.
“The results were so striking. Mice raised in the dark simply did not develop tumors, while all the mice raised in the light did, despite their identical genetic predisposition to develop optic nerve tumors,” Monje said. “While we had previously found that neuronal activity is an important regulator of glioma growth, these findings showed how crucial neuronal activity can be for tumor formation.”
Further experiments verified the crucial role of light exposure and narrowed down the critical window to age 6 weeks to 12 weeks. None of the mice reared in the dark during that time frame developed tumors by 24 weeks of age. Putting mice older than 12 weeks, when the tumors already had formed, into darkness slowed tumor growth but did not shrink them.
First author Pan Yuan, PhD, who first worked with Gutmann at Washington University and is now a postdoctoral researcher with Monje, showed that the link between light and tumors requires a protein called neuroligin 3. When their optic nerves are stimulated, mice with Nf1 mutations release abnormally high levels of neuroligin 3. Blocking the protein with a drug or genetically modifying mice to eliminate the neuroligin 3 gene resulted in fewer and smaller tumors.
Moreover, brain tumors from people are also high in neuroligin 3, which suggests the possibility of targeting the protein as a treatment for brain tumors. The researchers analyzed tissue samples from 19 people with low-grade brain tumors and found high levels of neuroligin 3, regardless of whether they arose in children with NF1 or not.
“All of this is teaching us that we may have ignored one really important cell type in nervous system cancers: the neuron,” Gutmann said. “As neurologists, we have been treating overactive neurons for decades with drugs. One of the directions our laboratories are pursuing is repurposing some of those drugs to see if we can shut off unwanted activity, maybe just for a short developmental period, and prevent brain tumors from forming. And there are other points at which we could intervene as well: by limiting light exposure, by targeting neuroligin 3 or inhibiting some other step in the pathway. It has really opened our eyes.”
Check out the NF Center 2021, Volume 2 Newsletter!
Check out the NF Center 2021, Volume 2 newsletter (pdf) to read about new research on NF1 brain tumors, meet our newest faculty member, and read updates on patient engagement.
Additionally, learn about:
The second NF Center Trainee to become a Francis S. Collins Scholar
Our resident PT, Makenzie Sledd’s latest Blog
If you haven’t already done so, be sure to also take a look at our previous issues of the NF Center newsletter for additional NF-related research updates and patient spotlights!
NF Center Trainee Selected as an O’Leary Prize Competition Finalist
Each year, the Office of Neuroscience Research awards an O’Leary Prize to a predoctoral or doctoral fellow to acknowledge the most original and important accomplishments in neuroscience research at Washington University School of Medicine. Michelle Wegscheid, an MD/PhD student in the laboratory of Dr. David H. Gutmann, was selected to present her research at the 2021 O’Leary Prize Competition as a finalist, where she showcased her exciting work on a new causative gene involved in NF1 and autism.
Gait Analysis in NF1 Mouse Model Revealed Developmental Abnormalities that Persist into Adulthood
As part of an investigation into share motor impairments across genetic liabilities for intellectual and developmental disorders (IDDs), a research group led by Drs. Susan Maloney and Joseph Dougherty, in collaboration with the Gutmann Lab, recently discovered altered gait development in mice harboring a patient-derived Nf1 gene mutation. This new study conducted a comprehensive analysis of gait across a critical developmental window in which gait matures in the mouse model. Nf1 mutant mice exhibited altered spatial, temporal, and postural subcomponents of gait compared to their control littermates, which persisted into adulthood. In addition, the pattern of disruption to gait development in the Nf1 model was also observed in a mouse model of Williams Syndrome, another IDD that features motor deficits. Overall, our findings indicate that IDDs may share features of atypical gait yet differ in resolution or persistence of these phenotypes. Therefore, gait may serve as a helpful outcome variable in studies of therapeutics’ efficacy in the long-term treatment of IDD.
Collaborative NF Team Reports NF1 Mutation in a Family without NF1
Children with NF1 are born with a genetic change, called a mutation, in one of their two NF1 genes. This mutation causes NF1. Work in many groups, including investigators in the Washington University NF Center, have found that the specific NF1 mutation may be one factor that determines the types of medical problems that a given person with NF1 is at risk for developing.
In addition, NF1 mutations have also been discovered in cancers in people without NF1, suggesting that the NF1 gene is similarly important for tumor formation or growth in the general population.
Extending this observation, a team composed of genetics expert, Dr. Tychele Turner, and Washington University team members, Mrs. Erika Ramirez, Dr. David Gutmann, and Dr. Stephanie Morris, now report a family without NF1 who has a mutation in the NF1 gene. This family does not have café-au-lait macules or other features of NF1, but does have another type of benign tumor not typically seen in people with NF1.
This work was recently published in Neurology: Genetics.
Springtime Fun with Virtual Club NF!
At the Washington University NF Center, providing care beyond the walls of the clinic is a high priority. The Covid-19 pandemic presented many obstacles to our essential therapy programs and challenged our team to find creative ways to continue offering them safely. Starting in the Fall of 2020 and continuing through Spring 2021, we pivoted all our Club NF activities to a virtual format, and it has been a great success.
On February 22, 2021, we held our first Club NF Cooks at Home event hosted by Schnucks Cooking School, led by Cooking School Manager Gay DeMichele. Activities included baking homemade cinnamon rolls and preparing a chicken tortilla soup. Participants were shipped all ingredients and some cooking supplies before the day of the event. Experts from Schnucks Cooking School guided all participants through each recipe during the event. Instruction moved along at an easy-to-follow pace, and one-on-one help was provided as needed. At the end of our event, everyone had made a delicious lunch for the whole family.
On April 3, 2021, we held a virtual singing event: Club NF Sings! Activities during this event included learning about the human voice, “why and how” we sing, and learning to sing and sign parts of the song “Let it Go” (from the movie Frozen). Additionally, participants learned how understanding sign language could impact one’s ability to communicate within their community. Our Club NF staff partnered with vocal expert Sandi Wright for vocal instruction and DEAF Inc. for sign language instruction. Participants ended the event by singing and signing the chorus to “Let it Go” and learned how to sign “Happy Birthday.”
Each of our play-based therapy events targeted the development of fine motor, executive function, and social skills, guided by experts within the field of each activity and supervised by our complementary care physical therapist, Makenzie Sledd. To participate in future events, please contact our NF Center Coordinator at email@example.com.
May is NF Awareness Month!
Dress in blue in support of NF Awareness on
World NF Awareness Day, May 17th, 2021!
May is NF Awareness Month, join the Washington University NF Center in raising awareness and supporting education and research, throughout the Neurofibromatosis community.
FACTS ABOUT NEUROFIBROMATOSIS
A set of complex genetic disorders that affects almost every organ system
NF1 affects one of every 3,000 births
Occurs worldwide, and in both sexes, as well as all races and ethnic groups
In the Washington University Neurofibromatosis (NF) Center, clinicians and laboratory scientists work together to accelerate the pace of scientific discovery and its application to the care of individuals with NF.