Henry is the son of Richard Engel, NBC TV Chief Foreign Correspondent, and Mary Forrest, a freelance producer.
RESEARCH UPDATE | OCTOBER 3, 2018
Henry Engel is a happy, vivacious three-year-old who is also living with a rare medical condition. When Henry was born, he appeared to be a healthy baby, but over time he began to fall behind developmentally. His parents—Richard Engel, chief foreign correspondent for NBC News, and Mary Forrest, a freelance producer—did everything they could to find out what was wrong. At last they found a clue: Henry had a mutation in the MECP2 gene.
MECP2 mutations cause Rett syndrome, a disorder that typically affects girls after their first birthday, robbing them of learned skills and leaving them with cognitive deficits, loss of speech, seizures, and difficulties with a variety of motor skills. The MECP2 gene is on the X chromosome. Because females have two X chromosomes, when they have the MECP2 mutation that causes Rett syndrome, they are partially protected by the other normal copy of the gene.
Because boys have only one X chromosome, MECP2 mutations in them typically cause more severe problems and often premature death—usually before two years of age.
But Henry’s MECP2 mutation is different. In fact, it has never been seen before.
Not Enough of a Critical Protein
The MECP2 gene provides instructions for making the MeCP2 protein, which is important for the function of neurons in the brain. This protein maintains the proper size of neurons and the connections, or synapses, between them. Disease-causing MECP2 mutations results in lower levels of the MeCP2 protein and reduced functionality.
Studying Henry’s Cells
After learning about Dr. Huda Zoghbi’s research, the Engels came to meet her and her team. During this first visit, researchers collected some of Henry’s skin cells. They have since converted them into stem cells, which can be grown indefinitely and converted into neurons in a Petri dish. Culturing Henry’s neurons enables researchers to conduct studies aimed at determining what exactly is causing his disease.
“Based on patients with similar mutations in the MECP2 gene that causes Rett syndrome,” says Dr. Zoghbi, “we expect that Henry will have lower levels of the MeCP2 protein and that his neurons will be smaller and form fewer connections. Working with his cells will also allow us to test potential treatments. If our drugs can improve the health of Henry’s neurons in a Petri dish, then we will continue testing them in living animals.”
Creating a Mouse Model
NRI research assistant Yingyao Shao, a PhD candidate who has worked in Dr. Zoghbi’s lab since 2016, has genetically engineered mice with Henry’s mutation. Like experiments conducted on his neurons, experiments on these mice will help increase researchers’ understanding of exactly how Henry’s mutation is causing his condition. Additionally, the mice can show how his mutation affects the most debilitating disease symptoms, like coordination and learning. Ultimately, researchers will test therapies by looking for symptom improvement without side effects.
The brain cell and mouse experiments complement one another. Henry’s neurons will inform researchers about what is happening in his particular cells, and the mice will show how his mutation affects the brain and behavior in a living animal. Researchers will test potential therapies, when identified, in both to confirm that they can work to improve symptoms in humans.
Searching for Drug Targets
Based on experiments in mice with a mutation similar to Henry’s, researchers at the NRI expect that increasing his MeCP2 protein levels will improve his symptoms. However, while it is difficult to directly increase protein levels with a drug, it’s much easier to inhibit proteins. Thus, researchers are searching for other proteins that they can inhibit to indirectly increase MeCP2 protein levels. These other proteins will be their drug targets.
Thus far, researchers have tested about one-third of the protein-coding genes and have found a repressor protein they can inhibit to increase MeCP2 levels in two different human cell lines. They are currently testing the effect of inhibiting this protein in human neurons and mice.
Planning the Next Steps
According to Dr. Zoghbi, although Henry’s mutation is unique, it’s this uniqueness that makes it valuable. It will be simpler to test MeCP2 function and Rett syndrome therapies in Henry’s brain cells and mice because they all have the same single mutant copy of MECP2, unlike females who have one mutant copy and one healthy copy.
“If inhibiting this repressor protein in Henry’s neurons and mice canincrease their MeCP2 levels and improve the mice’s symptoms,” explains Dr. Zoghbi, “then we will begin formal drug development in collaboration with a pharmaceutical company.” When we do have a therapy, it won’t be only Henry who can be treated with this drug—the majority of girls with Rett syndrome, who have partially functioning MeCP2, should also benefit from a therapy that boosts MeCP2 levels.