Agustin Caceres’s baptism was the only time his family was allowed close to him. Everyone had to wear masks, gloves and gowns. After that, he went into isolation, along with his mother Marcela, who came out only for meals.
His father, Alberto, and his four-year-old brother, Jeremias, lived in a separate bedroom, and Jeremias had to leave nursery school, for fear he’d bring home an infection his baby brother might catch. When Agustin’s relatives came to help out, they had to change their clothes and wash their hands, and still could not enter his room.
Born in Argentina, Agustin has a form of X-linked Severe Combined Immunodeficiency—or SCID-X1—better known as “bubble boy disease.” It affects only boys, leaving their bone marrow unable to make T-lymphocytes, the white blood cells that fight germs.
The Caceres’s first son died from SCID-X1 at 5 months. When Jeremias was born healthy, the family banked stem cells from his umbilical cord blood to benefit future siblings, but when Agustin was born, their tissue types turned out to be incompatible. With the clock ticking, finding a matched donor was a daunting problem. Without intervention, Agustin was likely to die from a bacterial or viral infection before his first birthday.
Agustin’s immunologist in Buenos Aires, Dr. Matías Oleastro, heard that Children’s Hospital Boston was recruiting for a clinical trial that was attempting to cure SCID-X1 with gene therapy. He had met Luigi Notarangelo, MD, and Sung-Yun Pai, MD, the trial’s principal investigators, at a medical conference.
Oleastro sent them a sample of Agustin’s blood, and Agustin was accepted as the first U.S. participant in the international trial, led by Children’s Chief of Hematology/Oncology, David Williams, MD. “It was our best possibility,” says Marcela through a translator.
Agustin’s only other option was a bone marrow transplant from a partially matched donor, perhaps one of his parents. His chances could be improved by giving him chemotherapy to kill the genetically defective cells in his bone marrow, but at the cost of highly toxic side effects. And with any bone marrow transplant, there’s a risk of graft-versus-host disease—the donor cells could launch a potentially fatal attack on Agustin himself.
“The main advantage of gene therapy is that patients would receive their own cells, so there is no chance of graft-versus-host disease,” explains Pai, of Children’s Division of Hematology/Oncology. “There’s also no time delay in finding a donor and no need for chemotherapy.”
When Agustin arrived at Children’s last October, he was not yet very sick, but had a mouth full of ulcers due to his inability to fight infection. He was admitted for 23 days to 6 West, the Hematopoietic Stem Cell Transplant Unit.
“We called a radio station in Jamaica Plain that plays tango music, and told our story,” Alberto says. “Someone heard our story and offered us a place to stay.” Later, the family moved to the Ronald McDonald House.
In December, Agustin underwent the gene therapy procedure. His bone marrow was extracted and purified and the blood stem cells manipulated in Dana Farber’s Cell Manipulation Core Facility (CMCF) to carry the new replacement gene. The gene was delivered by a specially engineered virus, called a vector—which Williams was instrumental in developing—that infects the cell without spreading in the body. A few days later, the treated cells were reinfused back into Agustin on 6 West.
The hope was that the treated cells would turn on the new gene, enabling them to make T-cells. Agustin’s T-cell count was only 5 when he arrived at Children’s, far too few to protect him. Over time, his doctors hoped, there would be enough healthy blood stem cells to make Agustin an ample supply of T-cells.
It’s early May and Agustin, now 10 months old, is chubby and full of smiles, sticking out his tongue and blowing bubbles as his parents cuddle him. “The oral ulcers have healed completely,” Notarangelo, of Children’s Division of Immunology, tells the family as he examines Agustin. “He has gained weight, and all of his organs are functioning normally. His muscle tone and behavior are appropriate for his age. Basically he’s a healthy child.”
Agustin’s T-lymphocyte count is up to about 170. “While it’s not yet a normal number, he’s producing more and more T-lymphocytes,” says Notarangelo, showing the family a graph of Agustin’s T-cell counts. “It’s a steady and impressive increase—like a rocket. It shouldn’t take too long before he reaches a normal count.”
Moreover, Agustin’s T-cell function—completely absent when he arrived at Children’s —has now tested completely normal, and Pai’s lab has shown that the cells are able to produce the protein that was missing. The gene therapy has been deemed a success so far.
“We are fortunate to have the technical expertise of Dana-Farber’s CMCF and the superb nursing and clinical research staff of Children’s,” says Williams.
Agustin is still unable to produce antibodies. He might be able to do so eventually, but for now he’ll need to keep receiving infusions of immunoglobulins every few weeks, possibly for the rest of his life, to protect him from infection.
The Caceres family is ready to return to Argentina, where PepsiCo is holding Alberto’s job. In Argentina, Oleastro will see Agustin weekly, conduct frequent clinical and laboratory exams—with research blood samples shipped to Boston—and stay in close contact with Children’s.
If all goes well, Agustin won’t need to return to Boston until a year from now, but he’ll need to be closely monitored until he is 15 years old. An earlier trial of gene therapy for SCID-X1, in Paris and London, reported leukemia as a serious side effect. Although laboratory studies in cells and experiments in animals show the newly designed vector to be safe, the team is being extra-cautious.
“Many people are watching us,” says Notarangelo. “A lot of eyes are on this trial.”