Duke Researchers Identify Genetic Mechanism in Brain Lesion Formation Using Single-Cell DNA Sequencing from Mission Bio

Tapestri Platform powers Nature Cardiovascular Research publication that identifies two somatic mutations associated with sporadic brain blood vessel disorder

SOUTH SAN FRANCISCO, March 14, 2022 /PRNewswire/ -- Mission Bio, the pioneer in high-throughput single-cell DNA and multi-omics analysis, announced new findings by Daniel Snellings from the lab of Douglas Marchuk, PhD, at Duke University School of Medicine using single-cell DNA sequencing to identify genetic mechanisms leading to the development of cerebral cavernous malformations (CCMs). The study, published today in the journal Nature Cardiovascular Research, is the latest demonstration of how Mission Bio's Tapestri Platform is allowing researchers to probe new aspects of biology at a single-cell resolution not possible with bulk sequencing. Dr. Marchuk is Professor of Molecular Genetics and Microbiology at Duke.

CCMs, a blood vessel abnormality that can lead to brain hemorrhages, have long been associated with developmental venous anomalies (DVAs), a typically benign but irregular vascular arrangement often found near sporadic CCMs – though researchers had yet to prove a link. In the paper,  Snellings and colleagues sequenced DNA from three CCM patient samples to see if somatic mutations in MAP3K3 or PIK3CA – common in patients with CCMs – co-existed in the same cells. Single-cell DNA sequencing with Tapestri found co-occurring mutations in the cells of  all three samples, a pattern that could not be determined by bulk sequencing. Further, the group found that the CCMs and the associated DVAs harbored identical mutations in PIK3CA, but that mutations in MAP3K3 were only found in the CCMs. Because of the pattern of PIK3CA and MAP3K3 co-occurrence in CCMs, the team could assess the temporal pattern of genetic mutations associated with disease progression. They determined that DVA is the first lesion to occur, and that CCM development happens only after acquisition of an activating MAP3K3 mutation in a cell of the existing DVA.sazsz

"It was surprising to find that something as common as DVAs—which are present in up to 16% of people—could be caused by a cancer driver mutation. This explains why sporadic CCMs are often found in the vicinity of a DVA, and may explain why other diseases like pontine gliomas are also found near DVAs," said Snellings.

Tapestri is regularly deployed in cancer research to detect somatic mutations in clonal populations as a way of tracking tumor development, and the researchers adapted that methodology to evaluate the relationship between DVAs and CCMs. Since DVAs are not regularly biopsied, the researchers also confirmed the presence of circulating mRNAs in patients with both CCM and DVA related to this biological pathway, in plasma – a first step toward establishing a biomarker for CCM risk in patients with DVAs.

"We expect this research will have a meaningful impact for patients at risk for developing spontaneous cerebral cavernous malformations, which can lead to strokes or even death," said Yan Zhang, PhD, CEO of Mission Bio. "This paper is a powerful new demonstration that there are many disease areas where single-cell DNA sequencing is helping elucidate the mechanisms of disease development, and identifying potential targets for diagnostics or therapeutics."

The Duke researchers and their work in CCM has been highlighted in Mission Bio's Researcher Spotlight and on Episode 4 of our On The Drop podcast.

To learn more about Mission Bio and the Tapestri platform, please visit www.missionbio.com.

About Mission Bio
Mission Bio is a life sciences company that accelerates discoveries and cures for a wide range of diseases by equipping researchers with the tools they need to better measure and predict our resistance and response to new therapies. Mission Bio's multi-omics approach improves time-to-market for new therapeutics, including innovative cell and gene therapies that provide new pathways to health. Founded in 2014, Mission Bio has secured investment from Novo Growth, Cota Capital, Agilent Technologies, Mayfield Fund, and others.

The company's Tapestri platform gives researchers around the globe the power to interrogate every molecule in a cell together, providing a comprehensive understanding of activity from a single sample. Tapestri is the only commercialized multi-omics platform capable of analyzing DNA and protein simultaneously from the same sample at single-cell resolution.  The Tapestri Platform is being utilized by customers at leading research centers, pharmaceutical, and diagnostics companies worldwide to develop treatments and eventually cures for cancer.

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