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Gene Therapy for Canavan Disease: Max’s Story

Max Randell had his first gene therapy for Canavan disease shortly before his first birthday. His mother Ilyce holds him. (Photo: Mike Randell)

I’m thrilled about the encouraging gene therapy results just published in Science Translational Medicine from Paola Leone, PhD and Jude Samulski, PhD, colleagues. “Long-term follow-up after gene therapy for Canavan Disease” updates a project that has its origins in the mid 1990s. Canavan disease is a brain disorder present from birth.

I’ve been following some of the kids who’ve had the gene therapy. One patient in particular – Max Randell – has been in my  human genetics textbook since age three, his progress updated with each edition.

Max has had two gene therapies. For the first, when he was 11 months old, liposomes carried the healing genes into his brain. For the second gene therapy, as part of the clinical trial reported this week, viruses delivered the genes, through catheters snaked into six tiny burr holes in his skull.

Max celebrated his 15th birthday on October 13, 2012. His best friend is his brother Alex, a future neuroscientist.

Without gene therapy, Max might not have lived past age 8 – but I recently attended his 15th birthday party fundraiser, where I sat next to Dr. Leone. She’s an associate professor of cell biology at the University of Medicine and Dentistry of New Jersey, and is widely recognized as an international leader in Canavan disease translational research. But to the Canavan families who adore her, she’s Auntie Paola.

I saw her in action at Max’s birthday party. The diminutive neuroscientist knelt beside a little girl in a wheelchair, took her hand, and began to nay and whinny, shaking her silky hair against the girl’s cheek. The child’s face exploded with joy at the researcher who had remembered her favorite animal. Dr. Leone moved around the table to another child, and became a chicken.

Max’s little brother Alex, a fifth grader, told me that night that he plans to become a neuroscientist, just like Dr. Leone, so he can help Max and others. “How I feel about Max is beyond words. He is my hero.”


Fewer than 1,000 people in the US are known to have Canavan disease. Due to deficiency of an enzyme (aspartoacylase, or ASPA), the cells that make myelin, the white insulation on brain neurons, can’t process certain precursors. As a result, N-acetyl aspartic acid (NAA) builds up in the brain, which turns the white matter into a spongy mass of fluid-filled bubbles. Gene therapy provides the ASPA gene that enables brain neurons to secrete the enzyme, allowing production of some myelin.

Babies with Canavan disease are limp and listless from day one, given not even the few months or years of nervous system normalcy of a child with Tay-Sachs disease or adrenoleukodystrophy. Most never speak, walk, or even turn over. Yet their facial expressions and responses indicate an uncanny awareness. A child laughs when his dad makes a fart-like noise; a little girl moves her fingers as if they are on a keyboard when a friend plays piano. They’re smart kids.

Like other genetic diseases, Canavan was once considered uniformly lethal in childhood because doctors didn’t recognize patients with milder cases. But patients can live into adulthood. Some have milder mutations; others with devastating mutations can outlive the odds thanks to excellent supportive care.

The small Canavan disease community has experienced more than its share of drama.
• The initial case description, in 1931, came from Myrtelle Canavan, a Harvard physician never granted full faculty status because of her two X chromosomes.
• The disease came to the Jewish community in the US from the Vilna ghetto in Lithuania in 1943. After the Nazis massacred 60,000 people, 250 or so survivors escaped to the forest,  and of the handful of refugees who made it here, two were carriers of Canavan disease.
• The first two children to receive gene therapy – both now in their late teens – did so in New Zealand in 1996, where the initial principle investigator (Matt During, MD) has citizenship. He was accused in the pages of Science of trying to skirt FDA regulations.
• In the classic case “Greenberg et al. v. Miami Children’s Hospital Researcher Institute,” filed in 2000, the discoverer of the Canavan gene patented it, and as a result parents who’d donated their children’s brains to help his research faced fees for diagnostic tests for their other children. (The case was settled, which is why “gene patent” is today synonymous with “BRCA” and not Canavan.)
• In 1998, 14 children, including Max, received gene therapy at Yale University. Some of the kids did well, recovering vision and becoming more mobile, but they all needed a second gene therapy. In 1999, after Dr. Leone had begun collaborating with Dr. Samulski, who directs the University of North Carolina’s Gene Therapy Center, to develop a viral vector to replace the less efficient liposomes, 18-year-old Jesse Gelsinger died following gene therapy for a different disease, using adenovirus. As gene therapy trials stalled, the Canavan kids backslid.


Paola Leone, PhD, aka Auntie Paola

The clinical trial using adeno-associated virus subtype 2 (AAV2) began in 2001 at the Cell & Gene Therapy Center, University of Medicine & Dentistry of New Jersey, and treated 13 patients by 2005. “As the trial continued, the FDA let us go to younger and younger patients. We were successful in being able to treat a 3-month-old infant who was diagnosed in utero. That child is alive today and is the youngest person who has ever been treated with gene therapy,” Dr. Samulski said. The study compared the children who received the gene therapy for Canavan disease to 15 untreated patients. Max had his second gene therapy there.

Now, several years later, it’s clear that the viruses are safe. And the gene therapy appears to be working. For most of the children, brain levels of NAA have decreased, brain atrophy slowed, mobility and head control improved, and alertness increased. The younger the child when treated, the greater the slowing of the disease – something seen in gene therapies for other conditions too. For optimal effect, gene therapy will have to be tied in to newborn screening to find patients as young as possible.

Gene therapy for Canavan disease using AAV2 was delivered through 6 burr holes. Experiments in mice indicate that intravenous delivery with a different vector may be possible. (Credit: Paola Leone)

The research team is very careful to counter possible hype in the news release announcing the paper: “Today, all of the patients are alive and their quality of life has improved.” Gene therapy for the disease “can be” safe and effective, and “may offer the best opportunity” to reduce symptoms and stabilize neurological function. And efficacy is also a matter of perspective. As the parents of the very first child to receive the gene therapy point out in a video Dr. Leone has made, others may see no change, but they know gene therapy has helped their daughter. I remember speaking with them on Lindsay’s 16th birthday, when she was able to eat cake without a feeding tube.

I’d like to add a different sort of improvement I was privileged to be a part of, a response that is perhaps too emotional to capture on a brain scan or mobility rating scale. It happened when Max’s mom Ilyce read him the part of my gene therapy book describing a scene at his 13th birthday party fundraiser. I’d watched Max watching the other kids running around, and wondered what he was thinking. (The excerpt is on my website. Four of the book’s 20 chapters are on Canavan disease.)

Here’s part of Ilyce’s email:

“Hi Ricki,

I have to tell you how moved I was with your description of Maxie, and how meeting him helped change your view of some of these brain diseases. We have always felt that Max’s life and battle would help give hope to people. That is one of the reasons we started our foundation. When I read the part where you spoke about the fundraiser, I started crying so hard that Mike came to see what was wrong with me. Then after I tried to regain my composure I read it aloud to Mike, Max and Alex.

I sat on the couch where Max was laying down. I was sitting by his upper body, it was hard to read again and I was still crying, but Max managed to reach out his little hand and grab my arm. He does this pretty often when he wants to touch me, or get my attention. But this was different, he was comforting me. This time he looked me directly in the eyes, with a really serious look, I swear he was letting me know that he’s okay with his life, that he is happy. He was agreeing with your assessment of that night. I hope that people can see the happiness and love that children like Maxie bring to the world.” Ilyce

Reading that, I suddenly no longer cared that the New York Times had ignored my book. Max’s response was the best review any author could hope for – not to mention a validation of gene therapy.

For further information and to donate, see Canavan Research Illinois, Jacob’s Cure, and the Canavan Research Foundation. All three support Dr. Leone’s research, or donate directly to her research program.


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