By the time 2-year-old Calliope Joy Carr, of Bala Cynwyd, was diagnosed with an incurable degenerative brain disease, two children with the same deadly ailment, just 20 miles away, were being offered a tenuous lifeline.
Eli and Ella Vivian, 7- and 4-year-old siblings from Upper Providence Township, also had metachromatic leukodystrophy, a genetic disease that robs its victims, mostly children, of their motor and mental skills and, eventually, their lives. But because their symptoms were less severe than Calliope's, the Vivian children were eligible for a gene therapy clinical trial in Milan, Italy, that she was not.
Today, at 7, Calliope is bedridden, able to smile at her family and favorite TV programs and move her head slightly, but unable to speak. MLD continues to take its toll, as well, on Eli and Ella Vivian, 11 and 8. But they attend school, play, and are rambunctious in a way that Calliope has not been since three months after her diagnosis, when she spoke for the last time, saying "Daddy."
Eli and Ella "shouldn't be able to do what they are doing," said their mother, Becky Vivian. "We have hope and we are grateful, but we are realistic. It may not save their lives, just prolong it."
One in 40,000 infants is born with MLD. Now, gene therapy - the transfer of normal genes into cells to replace missing or defective ones - is engendering hope in families that their children can be more effectively treated, if not as yet cured.
Other recent developments have further boosted that optimism.
Alessandra Biffi, the physician/researcher who led the trial at Milan's San Raffaele Hospital, now directs the gene therapy program at Dana-Farber/Boston Children's Cancer and Blood Disorders Center. Further, the experimental treatment has been licensed by GlaxoSmithKline, which has major operations in Philadelphia. And the Leukodystrophy Center at Children's Hospital of Philadelphia, opened in 2015, is delivering cutting-edge care.
Andrew Shenker, vice president in GSK's rare diseases unit and project physician leader for its MLD program, cautions that the research begun in Italy in 2009 is ongoing. The pharmaceutical company expects to submit data from the trial to government regulators in 2018, after which those agencies will conduct their own reviews.
Children with MLD lack an enzyme in key cells needed for the production and maintenance of myelin, which protects nerves and facilitates the transmission of impulses within the brain. Without myelin, communication is disrupted. The patient loses basic functions, resulting in paralysis, blindness, seizures, and eventual death.
The condition is passed down from two carrier parents; any child they produce has a 1 in 4 chance of having the disease. Survival ages vary, depending on when MLD is discovered and the level of medical care. In the absence of treatment, the mean age of death for a child diagnosed at 1 to 2 years of age is 4.2 years; for those diagnosed between 4 and 14, the mean age is 17.4 years.
The most common form of treatment is stem cell therapy, but results have been "mixed" and "disappointing," Shenker said.
Other researchers are investigating treatments including enzyme replacement and gene therapy, and screening procedures to diagnose the disease at birth, said Dean Suhr, president of the Oregon-based MLD Foundation.
Results published so far on the Milan trial indicate that when treatment is administered before patients show obvious signs of the disease, the onset of symptoms is delayed, and their severity lessened.
Gene therapy appears most effective with children diagnosed before age 2 and treated before they show symptoms, Shenker said. Research on the treatment's benefit for older youngsters is ongoing.
Two children who were treated after the onset of symptoms died while participating in the trial, but their deaths were attributed to the progression of the disease, not the safety of the closely-monitored treatment, Shenker said.
Ella Vivian was one of the test cases. Because his symptoms were more advanced than hers, Eli was not part of the trial, but was treated under a "compassionate use protocol." The Inquirer published an article about the siblings in January of 2013 before the family left for Italy.
They spent six months in Milan, during which they received massive doses of chemotherapy to kill the diseased stem cells and make room for new cells containing the healthy gene to take hold. Researchers used a form of the HIV virus, minus the disease component, as a transfer agent to insert the genes.
Becky Vivian, 44, a Gymboree teacher, accompanied her children to Milan, while husband Steve stayed home with older sons Eric and Evan.
"Right now, we know they are a miracle," she said. ". . . Unfortunately, we can still see progression of the disease, albeit slowly."
Eli has difficulty standing up straight and walking, and cannot run. Ella has pain in her arms and legs, and her walking is getting slower, her writing less legible.
They have regular physical and occupational therapy, but are on no medication, their mother said. They also return to Milan every six months for checkups. In several weeks, they will be visiting Biffi in Boston for testing.
The Vivian siblings give Calliope's parents hope - if not for their daughter, then for other children with the disease and those diagnosed in the future.
Calliope, called "Cal," was diagnosed at 21/2, shortly after her parents noticed she was losing her balance on stairs.
"When we found out Cal was sick, we were really lost," said her mother, Maria Kefalas, 49, a sociology professor at Saint Joseph's University.
Three months later, Cal said her last word.
"It was like she fell off a cliff," said her father, Patrick Carr, 50, an associate professor and director of the Criminal Justice Program at Rutgers University-New Brunswick.
Cal has been in hospice care for four years, but the little girl her family knew at 2 is still there, Carr says. She loves her favorite TV shows and dolls, and smiles when brother P.J., 12, gets scolded.
Shortly after their daughter was diagnosed, Kefalas and Carr created the Calliope Joy Foundation, which has raised $300,000 - much of it by selling cupcakes - for research and patient care, including $60,000 for the Leukodystrophy Center of Excellence. The annual fund-raiser is May 6 at Lincoln Financial Field.
The charity also supports families like the Vivians, who got a donation to help with travel to Italy.
Becky Vivian says she is in a desperate race to save her children. And the family isn't letting up.
When Eli struggles with a tall chair and asks for a boost, his mother says no.
"Once we give in, it'll be time for a wheelchair. So I say, 'Eli, you've got to do it yourself.' "
For information on the Calliope Joy Foundation, visit www.thecalliopejoyfoundation.org/