INDIANAPOLIS — A new study led by Indiana University School of Medicine researchers revealed a potential strategy to address neurobehavioral challenges associated with neurofibromatosis type 1, or NF1, a genetic disease that primarily affects the skin and nervous system. The findings, recently published in the Journal of Clinical Investigation , may also have implications for treating hundreds of other rare genetic diseases.
Approximately 1 in 3,000 people worldwide are affected by NF1. While the disease is best known for causing nerve tumors, a significant and under-addressed concern is the high rate of neurodevelopmental disorders. An estimated 50 to 70% of children with NF1 are diagnosed with autism spectrum disorder or attention deficit hyperactivity disorder (ADHD).
"Other than getting conventional medications prescribed by their doctors, there's really nothing tailored to treating kids who have NF1 that are affected by neurobehavioral disorders," said Steve Angus, PhD , the study's co-author and assistant professor of pediatrics at the IU School of Medicine. "We want to begin to address these challenges therapeutically."
NF1 is caused by mutations in a gene that produces neurofibromin, a protein that plays a key role in regulating cell growth and processes in the brain. In people with NF1, a mutation in just one copy of the gene means their bodies only make half the normal amount of neurofibromin. This condition, known as haploinsufficiency, can disrupt brain development and function, even when tumors are not present.
"If one copy of the gene is non-functional but the other is still good, it's like having two brakes for a car and one is disabled — when you attempt to brake, the car still runs out of control," Angus said. "In our study, we asked, 'If we could block this pathway of neurofibromin degradation, could we let more of the good copy accumulate?'"
Using NF1 mouse models and genetic screening tools, the research team identified a pathway that regulates the breakdown of neurofibromin. After genetically blocking the pathway, the mice showed improvements in impulsivity, hyperactivity, social interactions and other behaviors associated with autism spectrum disorder and ADHD.
Beyond NF1, the researchers believe this strategy could apply to other diseases driven by similar genetic disruptions.
"We believe our strategy could potentially be useful for up to 700 other rare disease conditions caused by haploinsufficiency," said D. Wade Clapp, MD , co-author of the study, chair of the department of pediatrics and senior associate dean for entrepreneurial research and commercialization at the IU School of Medicine. "Future steps include identifying drug candidates that will achieve this process of increasing levels of functional proteins and ultimately correcting the whole disease state."
Looking ahead, the research team will continue exploring safe delivery method strategies for potential therapies to advance future human studies.
This research was supported by funding from the National Institutes of Health and the Gilbert Family Foundation.
Additional IU authors include Su Jung Park, Jodi L. Lukkes, Ka-Kui Chan, Hayley P. Drozd, Callie B. Burgin, Shaomin Qian, Morgan McKenzie Sullivan, Cesar Gabriel Guevara, Nolen Cunningham, Stephanie Arenas, Makenna A. Collins, Jacob Zucker, JinHee Won, Abbi Smith, Li Jiang, Dana K. Mitchell and Steven D. Rhodes.
