UMDNJ Magazine - fall 2004 VOLUME 1 NUMBER 1

ONCE UPON A TIME, HAUNTINGLY HANDSOME LITTLE BOYS LIKE LLOYD PHILIP PAUL HUMPHRIES, AGE 6, DIDN'T STAND A CHANCE AT LIFE. BORN WITH CANAVAN DISEASE, A GENETIC DISORDER THAT STARTS TO TURN BRAINS INTO SPONGY TISSUE BETWEEN 12 AND 36 MONTHS OF AGE, LLOYD IS LUCKY TO HAVE FOUND LEONE, THE ONLY RESEARCHER IN THE WORLD WHO IS ALTERING THE FATE OF KIDS LIKE HIMSELF. SINCE HER FIRST ENCOUNTER WITH CANAVAN IN A YALE UNIVERSITY LABORATORY IN 1995,SHE HASN'T BEEN ABLE TO TURN HER GAZE AWAY FROM THESE CHILDREN AND THEIR FAMILIES.

"I didn't plan this work for my life but there is a destiny about it. I have always been deeply moved by seeing or hearing about sickness. I refuse to accept that 'terminal' is equal to 'hopeless.' As far as Canavan disease, I simply refuse to stand still and watch," says this Italian-born crusader, an associate professor at UMDNJ-Robert Wood Johnson Medical School (RWJMS) in Camden. After shifting from a neurological focus on drug abuse and addiction, she was studying brain neurochemistry, epilepsy and gene transfer as part of a research team which had just published a paper about genetic therapy for Parkinson's disease. "A tall man and woman walked into the lab to speak with my supervisor. They were carrying this tiny baby, just three months old, who had been diagnosed with Canavan." These parents, Roger and Helene Karlin, wanted someone to save their daughter Lindsay and the lives of other children like her. "I looked at this little girl," Leone recalls, "and thought: 'I would love this project. To feel that I was working on something so relevant to human disease, to life, to children would be personally fulfilling.' I didn't know then what I was getting into."

Canavan disease, one of several neurodegenerative disorders found mainly in Jewish families of Northern European descent, causes blindness, seizures, abnormal muscle tone (floppiness or stiffness), poor head control, loss of motor skills, and paralysis. Gradually, kids become unresponsive, unable ever to walk or talk. According to the National Institute of Neurological Disorders and Stroke (NINDS), death often occurs by age 4 and average life expectancy is about 10 years. There is no cure and no standard course of treatment.

"I have developed strong, beautiful friendships with these families. We see each other for birthdays, Bar Mitzvahs, fundraisers and social events, and we stay in close contact." Leone knows Canavan children like Lindsay Karlin, Max Randell, Lana Swancey, Rachel Epstein, and Jacob Sontag intimately. Their parents call from Guatemala, from the Azores in Spain, "from the other side of the planet, and sometimes in shame because they live in places where nothing is known about this disease, where people tell them their marriage obviously must have been cursed."

Though genetic screening can alert and prevent couples from having more than one child afflicted, Leone knows parents who have given birth to three Canavan children. Some, like the Humphries, come to Camden up to five times a year from as far away as Stoke-on-Kent, an English village, for the treatment made possible by the fundraising efforts of this British family's supporters. Here in the U.S., foundations begun by devoted parents have raised millions and awareness.

Born on the island of Sardinia and educated in Padua, Leone traveled to Canada in 1989 after receiving her PhD to teach microdialysis (a technique that allows collection of brain neurochemicals) and to learn deep brain stimulation techniques at the University of Concordia in Montreal. After two years, she had the opportunity to go back to Italy with a research fellowship but decided to stay in North America. It was at Yale University that she began focusing on the genetic compounds that could replace the missing gene and the brain enzyme responsible for Canavan disease.

Named after Myrtelle Canavan, this leukodystrophic disorder affects the myelin sheathing on the brain's nerve fibers and was first described in 1931. Children lack aspartoacylase and are unable to break down an acid which builds up and leads to spongy deterioration. Leone's therapy calls for inserting six catheters into the brain through which 600 to 900 billion liquid viral particles carrying new genetic material are delivered. The results may last forever, depending upon the stage of the disease progression, and can be astonishing. After treatment, Lindsay Karlin opened her eyes wide and appeared to look at her parents for the first time. "It was as though she had awakened," her father Roger reported. She also started moving, vocalizing, holding her head up, eating and drinking more easily.

Paola Leone, PhD, with patient Lloyd Paul Humphries.

With a $2.7 million grant from the National Institutes of Health (NIH) and approval in 1998 from the U.S. Food and Drug Administration, Leone is cautious about her progress but admits, "The trial is going well because we haven't had any major or severe side effects and the children are showing improvement. But I always have to remind these families that anything can happen during brain surgery. Even in healthy children, there are dangers. Imagine operating on children with severe problems. We've been very lucky. " At Cooper, she has worked with neurosurgeon Michael Feely, MD, and Chris Janson, MD.

Collection and analysis of data from this Phase 1 trial is ongoing. Multiple papers looking at various clinical aspects are being prepared for publication and more funding is being sought. Leone is also finalizing research that will show "the relevance of dynamic triggers in the endogenous stem cells in the brain. It's exciting."

Meanwhile, for these children, time is also of the essence. "We want to be able to start surgery sooner rather than later. We've had children who could hold their heads up, eat with a spoon, and vocalize. They lose these skills and may never regain them." So far, 10 children have been treated successfully and 10 are scheduled for a new procedure.

Often in the news, Leone has been on NBC Dateline, ABC Action News, and in The New York Times. In reality, "the good news is that we are not having any bad news about the trial. I look at life through dark glasses and when people ask me, 'Don't you want to have your own children?' all I can say is that, for me, it would be the most selfish act. If I were to be the creator of two more eyes watching everything I watch, then I would be the creator of a lot of pain. So I keep saying, 'I already have a lot of children. They may not be my own but I am devoting my life to them.' "