Rare Disease Report

Vision Improving 15 Years After Gene Therapy for Canavan Disease

AUGUST 22, 2016
Ricki Lewis, PhD
The first thing that Max Randell’s parents noticed after gene therapy for Canavan disease in 1998, when he was nearing his first birthday, was better vision.
“Within two to three weeks, he started tracking with his eyes, and he got glasses. He became more verbal and his motor skills improved. His vision is still so good that his ophthalmologist only sees him once a year, like any other kid with glasses. She calls him ‘Miracle Max’,” his mom Ilyce told me in 2010, when I was writing my book about gene therapy that has four chapters on Canavan.

 A Mother Checks In

 Max had a second gene therapy in 2002, after a delay in the wake of the death of 18-year-old Jesse Gelsinger in a gene therapy trial for a different disease. I’ve stayed in touch with the Randell family, but was flabbergasted to receive this email from Ilyce today:
“ I wanted to give you a little update on Maxie. He's going to be 19 on October 9th. He graduated from high school in June and is beginning a work program on Monday. (He is taking a gap year now to decide if he wants to take a couple college classes next year.) It's been very exciting to watch him grow into a young man!
Max had an appointment with his ophthalmologist this week and his vision continues to improve. His doctor is very interested in gene therapy and she said that the gene is still active in his brain because his optic nerve shows absolutely no signs of degeneration and looks the same each year. I wish we could have been able to express the gene throughout more of his brain, but I am grateful for the treatments because of the progress he's made.
The only real issues Max has are orthopedic and he is still making cognitive improvements across the board, he even improved in math as a senior! His vocalizations are increasing and are more clear and closer to the words he's trying to say, definitely not baseline for his age.
Even though gene therapy wasn't a cure for Max, the things we are experiencing definitely give me a lot of hope that once the delivery system is perfected, I can see a potential cure for Canavan disease in the future. Just knowing that the gene is still there 15 years later gives me confidence that a one-time gene transfer would actually work. I've spent millions of dollars funding so much different research and everything always comes back to gene therapy being the best option. Truly amazing!”
Max’s vision isn’t part of a paper being published in a prestigious medical journal, nor part of a talk at a conference, nor part of an official clinical trial result because it is past the typical 15-year period of follow-up. It just is -- an observation by a parent and a health care provider. But it’s so powerful.

The Evolution of Canavan Gene Therapy

The Randell family founded Canavan Research Illinois, which over the years has supported the work of Paola Leone, PhD, Canavan guru who is now at the Cell and Gene Therapy Center Rowan University. The great news is that Bamboo Therapeutics has taken over the Canavan gene therapy project, and Pfizer has taken over Bamboo!
Canavan gene therapy circa 2002 targeted less than 1% of brain cells with fewer viral vectors than is attempted in clinical trials today. But it looks like some of the vectors made their way to Max’s optic nerves, and clearly elsewhere judging by his interest in math and critical thinking. The first gene therapy trial used liposomes to carry the healing genes into his brain. In the second, viruses delivered the genes, through catheters snaked into six tiny burr holes in the skull.
Fewer than 1,000 people in the US are known to have Canavan disease, which strips the insulating myelin from brain neurons, due to deficiency of an enzyme (aspartoacylase, or ASPA). The white matter becomes a spongy mass of fluid-filled bubbles. Gene therapy provides the ASPA gene.
Babies with Canavan disease are limp and listless, not even granted the months or years of neuronal normalcy of a child with Tay-Sachs disease, giant axonal neuropathy, adrenoleukodystrophy, or Sanfilippo syndrome. 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 flutters her fingers as if they are on a keyboard when a friend plays piano. They’re smart kids, as Ilyce Randell knows well.
Like other genetic diseases, Canavan was once considered uniformly lethal in childhood because doctors didn’t recognize patients with milder or atypical cases – some likely still go undiagnosed. But people with Canavan disease can live into adulthood. Some have milder mutations; others with devastating mutations can outlive the odds thanks to excellent supportive care. At one of Max’s birthday parties I met a young woman in her mid 20s with Canavan disease.

A Race to the Finish Line for Gene Therapies

 I’ve told snippets of Max’s story in every edition of my human genetics textbook since he was 3 years old, after reading about him in an article from 2001 in The Scientist. For anyone describing gene therapy as a “breakthrough,” the year of that excellent article is a wake-up call: biotechnologies take years to prove themselves, and clinical trials take more than a decade to unfold. (For more recent coverage of Max’s story see my blog DNA Science)
I’m working now on the new (twelfth!) edition of my textbook. After much thought, I replaced Max Randell as the story that introduces the chapter that includes gene therapy with 6-year-old Eliza O’Neill, who recently had gene therapy for Sanfilippo syndrome type A. Not because I’ve lost interest – I love the Randells -- but because gene therapy has become a competition of sorts to see which diseases are responding the fastest, and which will be the first to cross the finish line to FDA approval (See 3 Gene Therapy Trials Report Good News. And that day is fast approaching!

 Miracle Babies or is it Hard Work and Good Science?

I can’t imagine what it feels like, as a parent, to fundraise 24/7 for years, to watch your child decline, and to finally witness your child receiving gene therapy. On Facebook, such announcements are often followed with dozens of comments evoking miracles, and the media coverage tends to do the same. Max’s eye doctor calls him Miracle Max. But to me, the merging of science and medicine isn’t about miracles. It’s about the curiosity, creativity, risk-taking, dedication, and follow-through – and immense talent and compassion – of the researchers and family members who make it happen.

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