If ten science writers were asked to write a book about gene therapy, a biotechnology with roots going back to the 1950s, they could tell ten different stories.
VARIATIONS ON THE THEME
Any account of gene therapy would include the first experiment in humans, on a 4-year-old in 1990. The narrative would tell of the dual tragedies that until recently defined the field: 18-year-old Jesse Gelsinger, whose immune system lethally rejected treatment for a urea cycle disorder in 1999, and then the young boys who, shortly after, developed leukemia following successful treatment of their inherited immune deficiency. The cancer hadn’t happened in the mice used to clear the gene transfer protocol for clinical trials.
After revisiting the tragedies, my book The Forever Fix: Gene Therapy and the Boy Who Saved It introduces adrenoleukodystrophy (ALD) to showcase family activism, giant axonal neuropathy (GAN) to tell what it takes to get a gene therapy clinical trial up and running, and then Canavan disease to see what happens years after gene therapy. Sandwiching those cases is the experience of Corey Haas, who would surely be blind if not for gene therapy in 2008, when he was 8.
But I could have told, instead, other ongoing stories of the evolving gene therapy — hemophilia B, battling Batten disease, Wiskott-Aldrich syndrome, metachromatic leukodystrophy, cancers or HIV … I cover some of them here at DNA Science, and at Medscape Medical News, as the successes accrue. It’s finally happening.
I recently realized, though, after learning of 4-year-old Eliza O’Neill’s future with Sanfilippo syndrome, that The Forever Fix only touched on two types of experiences.
The lucky, like Corey, found gene therapy because a physician knew about a clinical trial, and they fit the criteria. The many more unlucky are the parents who receive a deadly diagnosis and then discover that no one is pursuing treatment. It’s up to them.
The families are a key part of many gene therapy advances. For ALD it’s a pioneering trio of sisters (Amber Salzman, Rachel Salzman, and Eve Lapin). And the soon-to-start gene therapy clinical trial for GAN is largely possible thanks to the Herculean efforts of Lori and Matt Sames. (Their beautiful daughter Hannah, now 10, graces the cover of the new edition of my human genetics textbook, not for the neural destruction of GAN, but for her unusually kinky curls, also part of the phenotype.)
Exquisite little Eliza represents a third group: a gene therapy clinical trial nearly ready to go that runs out of money. Creating, selecting, and scaling up the viral vector that delivers the healing genes is expensive. Still, Eliza’s parents, Cara and Glenn, didn’t have to start from scratch like the Sames’ and the Salzman sisters. They and other Sanfilippo families are desperately trying to fund the making of the medicine that is gene therapy.
Racing against a rapid killer must go beyond golf tournaments and bake sales, road races and dances, and other classic fundraising routes that work when one has more time. The families need to raise about $2.5 million, and soon. Thanks to a video (Saving Eliza) that went viral in April and the media appearances that followed, donations are coming in. But social media are ephemeral, and the amount raised isn’t enough, yet.
Gene therapy introduces working copies of a gene that is absent or malfunctioning in a disease, usually aboard a virus or encased in fatty bubbles. Technically it’s “gene transfer” until evidence shows that it works.
The gene therapy for Sanfilippo syndrome uses a viral vector that enters the brain, meaning that the treatment is a simple infusion – not the skull-piercing catheters once used to deliver genes to children who have Canavan disease.
Sanfilippo syndrome is a lysosomal storage disease (LSD). The lysosomes are the “suicide sacs” of the cell, each housing 43 types of enzymes that dismantle specific molecules. A mutation that robs a cell of just one of these enzymes sets into motion an LSD.
Some LSDs, like Tay-Sachs disease, have telltale signs even before birth, if one could look, in addition to the detectable enzyme deficiency. The molecule that the enzyme should destroy builds up, as the molecule that would result from its action ebbs away, like a knot in a filled garden hose causing a backup at one end and a dribble at the other. In Sanfilippo syndrome, aka mucopolysaccharidosis (MPS) type IIIA, the missing enzyme is heparin sulfate sulfatase.
Eliza’s 7-year-old brother Beckham describes his sister’s “very bad disease” more clearly than I just did, in this second video: “It clogs up her brain and that makes her not learn very well. She’s hyper.” The condition is autosomal recessive, inherited from two carrier parents. Therefore each child has a one in four chance of sharing Eliza’s fate.
So here, from Glenn O’Neill, is the first part of Eliza’s story.
“We found out the terrible news today. For now, I want to focus on her wonderful personality and life every day. One of my goals is to keep her happy and smiling for as long as possible. I love her so much.”
This was my journal entry on the evening of July 17th, 2013. I never kept a journal before this. Earlier that day, our 4-year-old daughter Eliza was diagnosed with a rare terminal genetic disease called Sanfilippo syndrome type A. In one terrifying instant, we were told that we would have to watch Eliza fade away before our eyes. My journal entry words reflected the lack of hope a parent first feels when told their child has a disease that has no cure and no treatment.
Eliza and other children with this disease are missing an essential enzyme for normal cellular function. Over time, a toxic material called heparin sulfate builds up in their brain and body, leading to severe disability and death before they even reach their teens. This disease affects both genders, all races, all countries and continents. It is rare, but it is everywhere and the world needs to know.
ELIZA TODAY AND HER FUTURE
Right now Eliza is a fun-loving 4-year-old who loves to talk, sing, run and MOST of all, cuddle. She loves to play dress-up and horse around with her rowdy big brother Beckham, who fortunately does not have Sanfilippo. She is, however, beginning to show signs of the disease in her learning and attention. And if nothing changes, it will only get worse. And quickly.
By age 6, most children with her disease have irreversible brain damage and lose the ability to speak. As the disease continues to tear through her brain and body, she will lose the ability to walk and eventually she won’t even be able to feed herself. Seizures and painful movement disorders will take over. Life expectancy is usually early teens but preceded by this severe disability.
These devastating changes are a 100% certainty if she doesn’t get treated, and soon. It is a parent’s worst nightmare, and an unfair sentence for any innocent child.
After diagnosis, we quickly began looking for researchers working on Sanfilippo, here in the US and around the world. There weren’t many. My wife Cara, who is a pediatrician for special needs children (ironically), made some key contacts who pointed us in the right directions.
What we found was amazing.
What we found was HOPE, and near term! There is a gene therapy trial being scheduled for late 2014 that is specifically for children with Sanfilippo syndrome types A and B, the two most common forms of the disease.
Researchers at Nationwide Children’s Hospital in Columbus, Ohio, have shown that the gene therapy stopped the disease in animal models. It is a one-time injection, delivering the gene that encodes the enzyme missing in the disease using the vector AAV9, which has the ability to cross the blood-brain barrier and clear the storage.
This treatment could save Eliza. In addition, this delivery method, if successful, has great possibility to be used in other MPS disorders as well as more common neurological diseases.
One of the main things standing between Eliza and her miracle is money. The trial is lacking funding to make the medicine, administer the treatment, and remain on schedule. Every moment counts as Eliza approaches the tipping point when her disease will take an irreversible turn for the worst.
The total amount needed to fund both production of the medicine (gene therapy viral vector) and conducting the clinical trial for Sanfilippo type A is $2.5 million. What would you do if you knew that money was the only thing standing between your child and her chance at a full and happy life? What would any parent do?
We could not just stand by and watch our little girl lose everything she is, suffer unimaginable pain and frustration and ultimately die. What would we tell her big brother in a few years, when the disease has taken over completely? What would we tell ourselves?
Eliza’s Journey will continue next week with Glenn’s description of their campaign, which brought Eliza’s plight before the world. I’ll follow up with more on the science. In the meantime, please help. I learned from chatter last week at the American Society of Gene and Cell Therapy annual meeting that one reason why Europe leads the way in gene therapy is that funding comes largely from charity. That means US.
Thanks to Glenn O’Neill for family photos.