Adopting an Orphan Disease
words by maryann brinley
aola Leone was shocked. There she was, director of the Cell and Gene Therapy Center at UMDNJ-School of Osteopathic Medicine (SOM) and seated in a large audience listening to a speaker who was questioning the value of the Human Genome Project. Completed in 2003, this large-scale, international investigation had been aimed at identifying all the 20,000 – 25,000 genes in human DNA and lasted 13 years. “On stage, this person, a doctor, trivialized and belittled the project, asking if someone would please stand up and tell him why it had cost so much money and taken so many years. Could even a single disease discovery be linked to all the effort?”
She recalls, “His comments hit me so deeply because just the week before, an important discovery had been made” in her field of Canavan disease (CD), a rare, neurological disorder caused by a defective gene. “He was talking to an audience of future physicians and his ignorance was unacceptable. The Human Genome Project decoded the roadmap to cure all diseases and has already enabled very many discoveries.”
Leone knows intimately how far genetic research has come since 1995 when she first heard the words and put a little face to Canavan disease at Yale University. At the time, she was studying Parkinson’s disease as a bench scientist. That was a point in her career when she had little clinical connection to actual patients. Now, “I’m a magnet.” And she sees herself as “the missing link” between patients all over the world and the ongoing research. “Not all scientists have the ability or the willingness to work with patients but I love it and embrace it as a mission.”
Back in 1995, the first CD baby she encountered was Lindsay Karlin who had been brought to the Yale lab by her parents. Leone remembers a tall man and “a woman with the glazed eyes of a person who has faced the depths of desperation. They were carrying this teeny, tiny baby, just three months old, who had been diagnosed with Canavan. I looked at that little girl and thought: this is a mission that I would love to undertake.”
Canavan is an orphan disease, so identified because the disorder affects just a small percentage of the population. Rare and often debilitating, orphan diseases can face uphill struggles on many fronts, even with the passage by the U.S. Congress of the Orphan Drug Act in 1983, which offered incentives to encourage companies and researchers to adopt the orphans. “One of the biggest problems is getting the funding to study the diseases,” Leone admits. With so few patients for each disorder, biotech and pharmaceutical companies must look at the financial risk/benefit ratios for developing drug therapies. How many people will benefit? Will the company be able to make any gains for their efforts?
Another orphan stumbling block, according to Leone, is “that there aren’t enough motivated researchers who want to dedicate their lives and careers to studying the pathology and the mechanisms of these diseases.” It can be frustrating. “Believe me, there are a lot of genetic mutations associated with disorders like Parkinson’s, multiple sclerosis as well as Canavan. And no one really understands the true mechanisms behind them so how can you hope to develop treatments for something when you don’t know the causes?”
Yet, these hurdles didn’t stop an innovator like Leone. Her patients have been coming for years from “the other side of the planet and sometimes in shame because they live in places where nothing is known about this and where people tell them they must be cursed.” When she started, there was no cure or standard course of treatment. “I didn’t know then what I was getting myself into.”
Born on the island of Sardinia and educated in Padua, Leone arrived in Canada in 1987 after earning her PhD. She went to work at the University of Concordia in Montreal, where she taught microdialysis, a technique to collect brain neurochemicals. Though she considered returning to Italy after two years, she decided to stay in North America and her path eventually included stints at Yale, Thomas Jefferson University Hospital in Philadelphia, Cooper University Hospital and Robert Wood Johnson Medical School in Camden. “I was looking for my true self,” she explains. “I’m a scientist who has always been intrigued by the complexity of nature.”
Certainly, complex is exactly what she found in Canavan disease. First described in 1931 and named after Myrtell Canavan, this disorder affects the myelin sheathing on the brain’s nerve fibers. Children lack aspartoacylase (ASPA) and are unable to break down an acid that builds up and leads to spongy deterioration of the brain’s white matter. One of several neurodegenerative, metabolic conditions, in a category called leukodystrophy, which used to be found mainly in Jewish families of Northern European descent, CD can cause blindness, seizures, abnormal muscle tone (floppiness or stiffness), poor head control, loss of motor skills, and paralysis. Though normal at birth, if children aren’t treated right away, they become unresponsive, unable ever to sit, walk or talk. Before Leone began her crusade, these kids would often die by age 4 and average life expectancy was 10 years. That’s no longer true.
In 2007, Leone successfully completed a National Institutes of Health-sponsored Phase I/II study on “Gene Therapy for Canavan Disease,” in collaboration with Children’s Hospital of Philadelphia, Cooper University Hospital in Camden, and the University of North Carolina, Chapel Hill. This was the very first clinical trial for CD during which 900 billion copies of the human ASPA gene were surgically administered into the brains of 13 patients. This was also the first instance of viral gene transfer for a neurodegenerative disease. The results were encouraging and enlightening. In fact, Lindsay Karlin was the first patient to receive the gene transfer at age 6 and while she is handicapped and partially blind, she also turned 15 this year, a milestone for a Canavan child. “My laboratory collected and analyzed the data that enabled the human gene therapy protocol to begin in 2001,” Leone says. “Since then, we have attacked the unknowns inherent in the definition of CD and identified possible mechanisms that would account for the severity of Canavan.”
Follow-ups on participants from those trials will go on for their entire lives and yearly reports are collected on the children, per U.S. Food and Drug Administration (FDA) guidelines. Even if this data collection wasn’t required by the FDA, Leone would still keep in touch. “I have developed strong, beautiful friendships with these families. We see each other for birthdays, Bar Mitzvahs, fundraisers and social events. We stay in close contact.”
While currently there is no active clinical trial for Canavan patients, she has been funded to assess the effectiveness of embryonic stem cell usage in a transgenic mouse model of Canavan Disease. “Once we establish that efficacy, I can begin the approval process to receive clearance from the Food and Drug Administration.” With support from Jacob’s Cure Foundation, she is collaborating with Geron Corporation in California, a coup for her because this is the first company in the U.S. to receive approval for embryonic stem cell use with patients. Geron is proceeding with the first human clinical Phase I trial for embryonic stem cells in spinal cord injury patients. “We were chosen because we have already demonstrated our ability to move Canavan research from the bench to the bedside and have collected extensive clinical knowledge on CD. And, we’re in a stage of development just prior to clinical applications.”
The clinical trial work is just one facet of her amazing success in treating CD symptoms and stopping the brain deterioration that comes with this disorder. Her team of researchers, clinicians, surgeons, neurologists, and radiologists simply know so much more now than when she met Lindsay as an infant and had no hope to offer at first. “We have better ways of treating the symptoms pharmacologically with a combination of off-label prescriptions plus nutritional supplements. The beneficial effects of the continuous drug therapy are more pronounced in newly diagnosed patients. We use many drugs, some of which fuel energy in the brain cells.” Take for example Lavi Ben Moshe, who flew from Israel with his parents to be treated by Leone. Lavi, diagnosed with CD at 10 weeks, is still waiting to become part of the stem cell therapy program when it is fully approved. But in the meantime, after just five weeks of pharmacological treatments, he began smiling, seeing, reaching and reacting.
Children like Lavi are growing up and developing almost normally. Canavan, in truth, has turned out to be a starting point for her scientific journey into other neurological diseases of the brain’s white matter, like multiple sclerosis (MS), Parkinson’s, ALS, and Alzheimer’s disease. The Cell and Gene Therapy Center, established in 2001, adopts a multidisciplinary approach to study all brain diseases and employs a wide range of lab techniques. The improvement in patients is “the most gratifying reward,” she says.
Can she point to the biggest ‘aha’ moment in her career? “Every single little breakthrough has led up a ladder aiming to the top of a pyramid of knowledge. Being a scientist who has been given the opportunity to help society in this profound way is something for which I am really thankful.” There may never be a cure for Canavan, she explains, because the cure actually lies in the earliest possible diagnosis and immediate intervention after birth, not months or years later when the brain has already been subjected to irreversible changes.
Nowadays, between pharmacological therapy and the early knowledge about a baby’s genotype, success is right before her eyes. Her latest and happiest moment came recently when a little patient started to speak and learned to say “hi” to Leone. “Before, this same child would have been speechless, possibly immobile and blind. I hold onto happy moments like this one. My greatest gratification, however, is being able to treat this disease and now I’m looking forward to finding the common link to many other brain disorders."