NIH grant supports UMMS research on ‘off switch’ for extra chromosome in Down syndrome

	Jeanne Lawrence, PhD
	Jaime Rivera, PhD

UMass Chan Medical School scientists Jeanne Lawrence, PhD, and Jaime Rivera, PhD, received a five-year, $2.8 million grant from the Eunice Kennedy Shriver National Institute of Child Health & Human Development at the National Institutes of Health to test a strategy in a mouse model for silencing the extra chromosome that causes Down syndrome.

In 2013, Dr. Lawrence, professor of neurology and pediatrics, was the first to suppress the extra chromosome that causes Down syndrome in cell cultures, using an RNA gene called XIST, a naturally occurring “off switch” responsible for neutralizing genes on the extra X chromosome found in female mammals. This process allows for a similar level of X chromosome-linked genes to be present in both men and women. More recently, Lawrence demonstrated that silencing the extra copy of chromosome 21 can effectively correct cell function and development to prevent the development of Down syndrome blood cell pathology in stem cells differentiated in culture.

“These proof-of-principle studies have shown that we can effectively neutralize the extra chromosome that causes trisomy 21 in the lab,” said Lawrence. “The next challenge is to test this potentially transformative approach in a mouse model.”

Humans are born with 23 pairs of chromosomes, including two sex chromosomes, for a total of 46 in each cell. People with Down syndrome are born with three (rather than two) copies of chromosome 21—known as trisomy 21. The key issue for individuals with trisomy 21, however, is that hundreds of genes are over-represented, resulting in a vast range of negative health outcomes, including cognitive disability; early-onset Alzheimer’s disease; and a greater risk of childhood leukemia, heart defects, and immune and endocrine system dysfunction. While great advances have been made to correct single-gene disorders, the genetic correction of hundreds of genes across an entire extra chromosome has remained outside the realm of possibility. It is not known which of the more than 200 genes on chromosome 21 are responsible for the various aspects of the syndrome, which suggested research to test the potential of essentially silencing all the genes on the extra chromosome.

Key to this approach is Lawrence’s previous research, which has been instrumental in establishing that non-coding RNAs can, through a complex series of genetic events, suppress expression of the X-chromosome. Collaborating with Dr. Rivera, associate professor of pediatrics and a mammalian development expert, Lawrence hopes to translate these laboratory results to an animal model. Rivera is the director of the UMMS transgenic animal modeling core; his lab recently developed a novel technology for using recombinant adeno-associated viral vectors to manipulate mammalian embryos and allow the development of genetically modified animals. They plan to use this and other transgenic technologies to test the chromosome silencing technique in a trisomic mouse model of Down syndrome.

Jun Jiang, PhD, assistant professor of neurology, who spearheaded the Lawrence lab work showing the potential of XIST for trisomy silencing in cultured cells, will serve as a bridge between the Lawrence and Rivera laboratories. The project will also use human cerebral organoids to study the potential for delivery of XIST and phenotypic effects in these 3-D culture models of human tissues.

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