© ARTHIMEDES/SHUTTERSTOCK.COMIt’s a compelling narrative: A parent learns that his or her child has a fatal disease with no cure, and, though not a scientist, embarks on a quest to find some treatment. Such stories have played out in the plotlines of films such as Lorenzo’s Oil and Extraordinary Measures, on national morning shows and local news segments, and on crowdfunding pages to drum up support for the cause.  

Parent-led funding campaigns to develop gene therapies for rare diseases are especially prevalent, and for good reason. Rather than finding a drug that can fill the void left by a protein lost to a single-gene disorder, gene therapy holds the promise of replacing the defective gene itself—of a cure. Just one of the thousands of single-gene disorders has an FDA-approved gene therapy, but through hard work and determination, some parents hope to change that.

Some crowdfunding campaigns...

Still, participation in trials gives families some hope of a longer and healthier future for their children, a hope denied to the parents of kids who don’t make it in. “Gene therapy clinical trials are relatively small in terms of number of patients who can be enrolled. . . . Whenever you design stringent criteria, you know that as a physician you have to say a number of ‘no’s’ to parents who are desperately looking for treatments for their children,” says Alessandra Biffi, a gene therapy researcher at Dana-Farber Cancer Institute in Boston. “This choice, which is very rational, is also very difficult for me.”

Yet for the families raising funds to combat rare diseases, any gain—whether in prolonging the life of one’s own child, sparing other families the same heartache, or some combination of the two—counts. Thanks in part to contacts made through the National Organization for Rare Disorders, The Scientist spoke with several parents whose children’s diagnoses sparked fundraising efforts to help make gene therapies a clinical reality.

Saving Eliza

When Eliza O’Neill was 3 years old, her parents, Glenn and Cara, noted that her development began to diverge from that of her peers. Their once fast-learning, gregarious child faced difficulties in school, and her improvements in areas such as social communication and speech began to slow. It took about six months and multiple visits to the doctor for Eliza to be diagnosed with Sanfilippo syndrome, a rare lysosomal storage disease in which sugar molecules called glycosaminoglycans build up in the central nervous system, destroying cells and eventually causing severe dementia, seizures, and a loss of mobility. The disease strikes between 1 and 9 out of 1,000,000 people, and most children affected do not survive beyond their teens. The diagnosis, which Eliza’s doctors made in July 2013, was like “a lightning bolt out of the sky,” Glenn recalls. “I didn’t even know that a disease as terrible as this could even exist.”

I didn’t even know that a disease as terrible as this could even exist.

—Glenn O’Neill

In the weeks following Eliza’s diagnosis, the O’Neills combed the scientific literature looking for a way to save their daughter. Their research led them to a potential gene therapy for Sanfilippo under investigation at Nationwide Children’s Hospital (NCH) in Columbus, Ohio. At the time, the work was still in the preclinical stage, but “the data were amazing,” says Cara, a pediatrician.1 Once she found this study, she contacted Haiyan Fu, a scientist at NCH’s Center for Gene Therapy working on the experiments, who walked her through the research. “That was the first moment that I had a real solid hope in the science,” Cara recalls.

Fu’s work on Sanfilippo had begun in the late 1990s, during her postdoctoral studies at the University of North Carolina at Chapel Hill. Her initial focus was on Sanfilippo type B, and her project was supported by the Children’s Medical Research Foundation, which was established by the Wilsons, a family in Illinois whose daughter was born with the disease. Sanfilippo, which is caused by the loss of an enzyme needed to break down glycosaminoglycans, has four subtypes, A–D, each with a different enzyme deficiency and unique genetic mutations. Fu tells The Scientist that she and her colleagues thought that “if we could deliver [the missing] gene where it’s supposed to be, we wouldn’t have to treat 100 percent of cells—we could treat some cells, [and those could] provide other cells with the secreted protein.”

THE O’NEILLS: Eliza and her family in West VirginiaTHE O’NEILL FAMILY

A handful of patient foundations supported the research for more than a decade, even after Fu moved to NCH and began working with another researcher, Douglas McCarty, to complete the preclinical work on a gene therapy for Sanfilippo types A and B.2 Although still in the preclinical stages when the O’Neills contacted Fu, it was the only research effort that looked like it would be able to treat Eliza, who has Sanfilippo type A, in time, Glenn says. But much more money was needed to start a clinical trial—which often costs in the millions of dollars to initiate.

To help raise funds, the O’Neills established the Cure Sanfilippo Foundation (Cure SFF) in 2014. While they hoped their daughter would be chosen for the study, Glenn explains, their primary purpose was simply to help get the clinical trial up and running. After raising $250,000 over the first six months, the pair realized that they needed a way to raise much more money, quickly—and decided to try making a viral video. So they reached out to Karen Cheng, a videographer in California, for advice. To their surprise, she contacted a colleague, Canadian photographer Benjamin Von Wong, who travelled to the O’Neills’ home and shot a short film that went live on a GoFundMe page in April 2014. By the end of the year, the campaign had raised a whopping $2 million.

In 2016, the research team at NCH received investigational new drug (IND) approvals from the FDA to start testing the treatments, which involve an intravenous injection of an adeno-associated viral vector that is able to cross the blood-brain barrier, carrying the gene encoding a replacement N-sulfoglucosamine sulfohydrolase (SGSH) enzyme. This delivers the treatment throughout the body, allowing SGSH to be produced both in the central nervous system—the main target—and in other organs, such as the liver, that are also affected by the disease. Shortly after, the INDs were transferred to Texas-based Abeona Therapeutics, which sponsored two Phase 1/2 clinical trials, one for Sanfilippo A that began in 2016, and another for Sanfilippo B that started late last year. Both are being conducted by another group of investigators, led by NCH’s Kevin Flanigan.  

A group of 12 foundations, including Cure SFF, granted Abeona the funds to develop those therapies. Other funds raised by Cure SFF—more than $5 million in total—have financed a variety of Sanfilippo-focused investigations around the world. Nowadays, the O’Neills are not alone: more than 50 families have joined their foundation’s fundraising efforts. Their ultimate goal, Glenn says, is to have routine newborn screening and a proven treatment within the next 10 years. Because the gradual buildup of glycosaminoglycan worsens symptoms, he adds, the sooner the disease is caught and treated, the better.

“I think patient foundations play a critical role as a catalyst for research for rare diseases,” Flanigan says. But he notes that helping fund a treatment does not guarantee enrollment in a clinical trial.

Eliza, however, was a good candidate for one of the Abeona trials, and in 2016, at age six, she finally received the gene therapy. “She was the first child in the world treated with this—she was pretty progressed in the disease, but we were very lucky, blessed, and thrilled that she was even getting a chance,” Glenn says.

According to the latest results from the Abeona-sponsored trial of the Sanfilippo A treatment, presented this February at the WORLD Symposium for Lysosomal Diseases, 10 patients have been treated, and investigators have seen a significant reduction in glycosaminoglycan buildup in cerebral spinal fluid and urine, as well as some evidence of cognitive improvement six months after treatment. “We have, most importantly, no evidence of systemic toxicity with delivery,” Flanigan says. “We’re very optimistic about it.”

The results look promising, but they are preliminary, says Kim Hemsley, a neuroscientist who studies Sanfilippo at the South Australian Health and Medical Research Institute but is not involved in the Abeona study. “The true test of [gene therapies] will come with time.”

Hemsley, who has also received support from patient foundations for her work on Sanfilippo, says “the real unsung heroes” of our society are the families who fundraise for this work. “Not only are they having a quite extraordinary battle in their own life with a devastating disease in their family, but they still find the strength to advocate, to raise funds, to talk to clinicians and researchers around the world to try to establish research programs that have eventually led to the trials that are ongoing today,” she adds.  

MOTHERLY LOVE: Eliza and Cara O’Neil

As for Eliza, the O’Neills say that her symptoms don’t appear to have worsened since her treatment. And although she has not regained her speech, which she had completely lost, the family has found other ways to connect, such as through eye contact, music, and TV shows. “I’d say with Eliza, we’re in this uncharted territory where her future is unknown and uncertain,” Glenn says. “And that’s a good thing for Sanfilippo, because if your child is not treated, their future is certain, and it’s not good.”—Diana Kwon

Cupcakes for a cure

By the time Maria Kefalas and Patrick Carr noticed anything wrong with their youngest daughter, it was too late. Shortly after her second birthday, Calliope Joy—Cal to her parents—started to lose her balance. The family, who live in a Philadelphia suburb, visited the Children’s Hospital of Philadelphia, and in July 2012, Cal’s doctors returned a diagnosis: metachromatic leukodystrophy (MLD), a rare neurodegenerative disease that affects 1 in 40,000 infants and is caused by a genetic mutation in the ARSA gene on chromosome 22.

PARTY TIME: The Calliope Joy Foundation organizes regular “cupcake celebrations” to raise money for research on leukodystrophy. The funds have helped send young patients (four of whom are shown above) to Milan to receive an experimental stem cell treatment for one variation of the disease, metachromatic leukodystrophy (MLD).THE CALLIOPE JOY FOUNDATION

Children with MLD cannot produce arylsulfatase-A, an enzyme that breaks down sulfatides. So the compounds accumulate in the nervous system, where they attack the myelin sheaths that cover nerve axons, leading to loss of mobility and eventual paralysis. There was no cure, the doctors explained. Cal would be unlikely to see her sixth birthday.

To help assuage their grief, Cal’s parents established The Calliope Joy Foundation (TCJF) to raise money to support research into the disease. They hosted cupcake sales, and over the course of several months built up a network of families struggling with MLD or any of the more than 50 variations of leukodystrophy, all of which involve myelin damage. Then, one year after her daughter’s diagnosis, Kefalas, a sociology professor at Saint Joseph’s University in Philadelphia, came across a paper in Science written by a group of researchers at the San Raffaele Scientific Institute in Milan.3

She will have a legacy that’s so beautiful—I’ll get to see the children that her life helped save.

—Maria Kefelas

The paper described a radical approach to treating MLD: researchers had used a self-inactivating HIV vector to insert functional ARSA sequences into patient-derived stem cells ex vivo, and then implanted the cells back into patients’ bone marrow to produce the missing enzyme. “I have to admit, it sounded like mad science,” Kefalas says. “The idea of infecting children with an inert virus seemed to me a very frightening prospect.”

But the approach had a track record: San Raffaele’s Alessandra Biffi and her colleagues had shown in the early 2000s that it slowed the progression of MLD in a mouse model, and in 2010, GlaxoSmithKline (GSK) announced it would get involved in the research. In the 2013 paper, the team presented data from its first human study of three presymptomatic children—each of whom had been diagnosed after an older sibling started showing symptoms of the disease. The therapy, the team reported, stopped MLD in its tracks. “It was the best outcome we could have predicted,” Biffi, now director of the Gene Therapy Program at the Dana-Farber Cancer Institute in Boston, tells The Scientist.

TOUCHDOWN: A fundraiser for MLD research 

At first, the news was difficult to swallow for Cal’s family. “I remember calling my daughter’s doctor in Philadelphia, in tears of despair over the fact we’d missed our chance to help Cal,” Kefalas says. But as Cal’s doctor pointed out, the study showed that the treatment could halt MLD’s progression—it could do little to improve the symptoms of children already displaying signs of severe nerve damage. What’s more, the trial had recruited only presymptomatic patients; Cal, by the time she was diagnosed, wouldn’t have been eligible. However, Cal’s doctor also had a suggestion: that Kefalas help recruit participants for the next trial in Milan. “You’ve mistaken me for somebody brave,” Kefalas remembers replying.

Yet brave is exactly what she was. In 2014, The Calliope Joy Foundation helped raise money for the family of Cecelia Price, another child diagnosed with MLD, to travel to Milan. More families followed, from the U.S., Australia, and several European countries. By the end of last year, TCJF had raised hundreds of thousands of dollars through cupcake sales and other efforts, which helped fund travel for 10 children and establish the Leukodystrophy Center of Excellence at the Children’s Hospital of Philadelphia. In 2017, the Italian team published an update on their study results: Of the first 21 presymptomatic and early onset patients treated with the therapy, 19—some of whom had been treated more than five years previously—had survived without significant disease progression.4

“Alessandra Biffi’s work is very, very promising, and very positive,” says Dolan Sondhi, a medical geneticist at Weill Cornell Medical College who is not involved in the research. She notes that wiping out existing bone marrow stem cells by chemotherapy—a pre-treatment necessary for the stem cell therapy to work—raises the risk of infection; other groups are developing therapies that avoid this step. The biotech company Shire, for example, is trialing an enzyme replacement therapy, and Sondhi is involved in developing a therapy that uses an attenuated adenovirus to deliver ARSA directly into the central nervous system—although neither is as far along as the Italian group’s approach, and none of the treatments have shown promise in reversing the damage caused in patients with later stages of the disease.

The path to regulatory approval for the Milan group’s therapy remains uncertain. Last summer, GSK’s new CEO Emma Walmsley announced that the company would be moving away from rare-disease research. Kefalas responded with an open letter that included a photo of several children who had taken part in the San Raffaele trial, “in case you have any doubts about the lives GSK’s gene therapy for MLD has changed.” GSK currently remains involved with San Raffaele’s ongoing Phase 3 trial, but is looking to “secure an appropriate partner to take over further development and commercialization of these medicines,” GSK spokesperson Mary Anne Rhyne writes in an email to The Scientist.

Calliope Joy, meanwhile, is now 8 years old. Her symptoms have worsened; she can no longer walk, see, or speak. But TCJF is a constant source of motivation for her mother. “Whenever I feel sad, I look at pictures of [children treated in the trial] playing basketball,” Kefalas says. “I’m just so happy that a child gets to do that.” It’s an outcome that seemed impossible only a few years ago. “I’m very proud of that,” Kefalas says. “My daughter is going to die. But at least she will have a legacy that is so beautiful—I will get to be able to see children that her life helped save.”
—Catherine Offord

Good news, bad news

Twenty years ago, Ilyce Randell and her husband received devastating news: their son Maxie, who was a little over four months old at the time, had Canavan disease. Maxie would never walk or talk, and he likely wouldn’t live past age 10. Not much could be done to help their son, the couple was told, though a geneticist offhandedly remarked that researchers were developing a gene therapy that might lessen Maxie’s symptoms or extend his life. But the Randells also learned that there was no funding available for a clinical trial on the gene therapy. Recently married, the couple contacted the same people they had invited to their wedding. Randell wrote a letter describing her son’s illness and included a photo of Maxie grinning. “That was my first fundraising campaign,” she says. It was also the start of Canavan Research Illinois, the Randell family’s foundation.

Canavan disease is caused by mutations to the ASPA gene, which encodes an enzyme, aspartoacylase, that breaks down N-acetyl-L-aspartic acid. Without aspartoacylase, the acid builds up in the brain’s neurons and prevents their axons from being coated in fatty myelin sheaths. As a result, electrical signals don’t travel as efficiently from nerve cell to nerve cell. Neurons in the brain break down, leaving the organ spongy and leading to intellectual disabilities, loss of movement, abnormal muscle tone, and seizures, among other symptoms. In the first US trial of a gene therapy for Canavan, researchers tried encasing healthy copies of ASPA in liposomes and injecting them into the brain through an intraventricular catheter attached to a small, plastic, dome-shaped reservoir placed just beneath the scalp. The researchers injected the gene therapy into the reservoir, and it then diffused into the cerebrospinal fluid. In 1999, Maxie became one of 16 patients to receive the treatment. Maxie and his cohort showed some improvements in vision and movement, but the children weren’t cured.5

All of this could have never happened without the support and devotion, the passion of patient advocacy groups, specifically families.

—Paola Leone, Rowan University

“We knew all along . . . that the ideal way to deliver a gene to the brain was with a viral vector,” says Paola Leone, a neuroscientist now at Rowan University who worked on the initial clinical trial at Thomas Jefferson University. As that trial proceeded, she and her collaborators began work on a second gene therapy with an adeno-associated viral (AAV) vector. Then, in 1999, a young man named Jesse Gelsinger died following an adenoviral-based gene therapy to treat a different disease. Even though Leone and colleagues were using an AAV vector, not an adenoviral vector, their research stalled along with the rest of the gene therapy field. Slowly, after working to show the safety of the AAV vectors, Leone and others pushed forward on a new gene therapy for Canavan, and started the first trial in June 2001. The treatment moved through both Phase 1 and Phase 2 clinical trials, and in 2012, the team published the first long-term study that tracked the safety of the treatment, along with some measures of efficacy. Injecting 900 million vector genomes directly into a patient’s brain appeared to decrease the levels of N-acetyl-L-aspartic acid, slow brain atrophy, and reduce the frequency of seizures, the team reported.6

THE RANDELLS: Maxie and his family at Canavan Research Illinois’s 19th Annual Canavan Ball in October 2017

Based on the results of the study, a drug company could have moved the therapy to a Phase 3 clinical trial. The funding was there, but “there wasn’t any interest,” Leone says. The disease was too rare, with just 2,000 people affected worldwide.

The response isn’t uncommon. The development of therapies for rare diseases is often funded by parents of sick children, either through individual donations or foundations like Randell’s, Leone adds: “All of this could have never happened without the support and devotion, the passion of patient advocacy groups, specifically families.”

Randell says the reason Maxie is alive today, and gearing up for his 21st birthday, is because he received both the liposome and AAV treatments. Still, Maxie is far from cured. He is severely disabled, without the ability to move his arms and legs. He’s learned to use several different eye scan and retinal-gaze computers, but his favorite mode of communication, she says, is blinking his eyes. “You’ll say, ‘Oh Maxie, I love you so much,’ and he’ll squeeze his eyes shut really tight. The longer he does it, the more meaning it has.”

But there is still no FDA-approved gene therapy for Canavan disease. Randell continues to push for the development of new and improved gene therapy treatments that Maxie could try; she’s holding out hope, not just for her own son, but also for parents with children newly diagnosed with the disease. Some such parents have launched funding efforts of their own. The Landsman family, for example, launched a GoFundMe campaign to develop a treatment for Canavan after their two young sons were diagnosed with the disease; it raised $1.1 million in its first three months.   

BROTHERS: Maxie (left) and Alex RandellILYCE RANDELL

Randell, the Landsmans, and others affected by Canavan could get their wish. Two groups, one that includes Leone and one led by Guangping Gao of the University of Massachusetts Medical School, are racing to get the regulatory OK for another round of gene therapy trials to treat Canavan. The treatments in development have the potential to vastly improve upon earlier versions. Leone and her collaborators are working on a viral vector targeted at the white matter of the brain, specifically the myelin-making oligodendrocytes, rather than neurons. Aspartoacylase is naturally produced in oligodendrocytes, and it’s there that the enzyme breaks down N-acetyl-L-aspartic acid, Leone explains. The vector would still be injected into the brain through holes drilled into skull, but by homing in on oligodendrocytes, the treatment could boost the myelination of neuronal axons and improve patients’ motor function and development.7

In contrast, Gao and his collaborator Dominic Gessler are developing an intravenous injection that would travel across the blood-brain-barrier. “Interestingly, if you look at the expression of ASPA, which is the defective enzyme, it’s actually expressed almost in every cell in the body,” Gessler says. “For that reason we highly advocate this intravenous injection approach, where we use a single dose to treat the entire body.” The approach has shown promising results in a mouse model of the disease.8

Crowdfunding supports both groups’ work, and the researchers involved say that their findings on Canavan disease could also be applied to more common neurodegenerative diseases, such as amyotrophic lateral sclerosis or Parkinson’s. If the vector can effectively deliver the gene to the targeted cells, it could give clues to how to deliver corrective genes in other diseases. The work could, Gessler says, “actually be beneficial for many more people than just the ones directly affected by Canavan disease.”
—Ashley Yeager


  1. H. Fu et al., “Correction of neurological disease of mucopolysaccharidosis IIIB in adult mice by rAAV9 trans-blood–brain barrier gene delivery,” Mol Ther, 19:1025-33, 2011.
  2. F.J. Duncan et al., “Broad functional correction of molecular impairments by systemic delivery of scAAVrh74-hSGSH gene delivery in MPS IIIA mice,” Mol Ther, 23:638-47, 2015.
  3. A. Biffi et al., “Lentiviral hematopoietic stem cell gene therapy benefits metachromatic leukodystrophy,” Science, 341:1233158, 2013.
  4. F. Fumagalli et al., “Update on safety and efficacy of lentiviral hematopoietic stem cell gene therapy (HSC-GT) for metachromatic leukodystrophy (MLD),” Eur J Paediatr Neuro, 21:e20, 2017.
  5. P. Leone et al., “Global CNS gene transfer for a childhood neurogenetic enzyme deficiency: Canavan disease,” Curr Opin Mol Ther, 1:487-92, 1999.
  6. P. Leone et al., “Long-term follow-up after gene therapy for Canavan disease,” Sci Transl Med, 4:165ra163, 2012.
  7. J.S. Francis et al., “N-acetylaspartate supports the energetic demands of developmental myelination via oligodendroglial aspartoacylase,” Neurobiol Dis, 96:323-34, 2016.
  8. D. Gessler et al., “Redirecting N-acetylaspartate metabolism in the central nervous system normalizes myelination and rescues Canavan disease,” JCI Insight, 2:e90807, 2017.

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