The Malan Syndrome Foundation awarded UNC Eshelman School of Pharmacy a two-year grant totaling $30,000. Erin Heinzen, associate professor in the Division of Drug Therapy and Experimental Therapeutics with a cross-appointment in the Department of Genetics, and Nate Hathaway, director of UNC’s CRISPR Screening Facility and associate professor of chemical biology and medicinal chemistry will lead this study.
Christal Delagrammatikas, co-founder and director of science and research at the Malan Syndrome Foundation, is personally grateful to have been connected to Heinzen soon after her son’s diagnosis in 2019. Speaking on behalf of the foundation, Delagrammatikas said, “Erin, and now Nate, have been generous with their time and knowledge. Both participated in the inaugural Family and Science Conference held in July 2022, where they met other clinicians and researchers interested in Malan syndrome and many affected families. They really care about those involved and affected by Malan Syndrome as much as they care about science.
Malan syndrome is a rare genetic disorder, with approximately 200 confirmed cases since its discovery in 2010. The syndrome is caused by genetic variants that affect the Nuclear Factor One X gene in neuronal cells. NF1X creates proteins that contribute to the development and function of the brain, muscles and skeleton. The variants reduce the amount of protein that can be made from NF1X, and too little of this protein leads to symptoms such as tall stature, low muscle tone, intellectual disability, enlarged aorta, and other physiological and behavioral complications.
Using CRISPR technology, Heinzen and Hathaway seek to identify any proteins in the genome that alter the amount of NF1X protein made. By doing so, they hope to find ways to increase the amount of protein produced in people with Malan syndrome. “This funding not only provides an opportunity to make discoveries about Malan syndrome, but can also show us how to find treatments for other rare genetic diseases,” Heinzen said.
The CRISPR screening facility at UNC-Chapel Hill opened in October 2021 thanks to the collaboration of the university’s medical and research community and a generous equipment grant from NC Biotech. The facility performs rapid and efficient genetic and epigenetic screening, which supports the search for new genetic targets and accelerates drug development. Using this technology, geneticists can modify or delete specific genetic information to observe how each change can alter the cellular function of DNA.
“This will be the first neuronal cell screen on this scale at our institution, and the process we will apply in this study is exactly what the CRISPR technology was intended for,” Hathaway explained.
During the study, Heinzen and Hathaway will apply a fluorescent marker to NF1X in the stem cells. These stem cells can then be transformed into millions of neurons. The CRISPR screen will delete one gene at a time, per neuron, to test how each genetic change affects the amount of NF1X protein made. The fluorescent element will be the indicator of how the NF1X reacts to each gene deletion. Brighter fluorescence will indicate that a gene deletion has made NF1X more expressive or activated. Once the study is complete, the researchers hope to have a list of genes that affect the amount of NF1X protein produced. From there, the data will be shared for further study with UNC researchers and the genetic science community, which could aid in the development of targeted therapies on the gene list.
“Anyone involved with the foundation is a parent or caregiver of a child diagnosed with Malan syndrome,” Delagrammatikas said. “Our mission is to advance the understanding of Malan Syndrome by funding research grants like this, which will hopefully lead to therapies that will alleviate some of the health and care challenges faced by affected families. by this debilitating disorder.”
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