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Rare Disease Day 2021: Gene Therapy Ups and Downs, Again

I can’t believe it’s been a decade since I researched and wrote The Forever Fix: Gene Therapy and the Boy Who Saved It. Since then I’ve shared stories of other families doing amazing things to help researchers develop treatments for their loved ones’ rare diseases. The need is all the more compelling in these days of the pandemic.

Now entering its fourth decade, gene therapy continues along what seems at times a never-ending rocky road, riding the waves of fantastic success and plunging setbacks.

A Slow Start

The US has approved just two gene therapies. Luxturna has provided vision to patients with a form of retinal blindness (the basis of The Forever Fix), while Zolgemsa treats spinal muscular atrophy, a disease typically lethal in young children.

The latest in a series of setbacks, beginning in 1999 with the death of 18-year-old Jesse Gelsinger, came just yesterday. The FDA placed a clinical hold on two gene therapy trials for sickle cell disease, following reports of blood cancer in two trial participants. But that’s not all.

Over the past year, three young boys have died in a gene therapy trial for myotubular myopathy, all in the highest dose group.

Gene therapy for Duchenne muscular dystrophy continues to struggle to demonstrate an effect greater than placebo. And Glybera, the first gene therapy approved in the EU, for a rare pancreatic disease, was pulled for its high cost and minuscule market, although it, like the others, works against the targeted disease.

Clinical trials for gene therapies for immune deficiencies and bleeding disorders in the works for decades trudge on.

Two families I’ve written about whose young daughters received gene therapy in 2016 for neurological conditions continue to watch and wait. They don’t say much, as is the way in clinical trials, as they try to weigh whether improvements, or lack of progression, reflect the gene therapy or the therapies that help day by day. Does hope get in the way of interpreting reality?

And then there are the families who’ve lost love ones, but continue to help the researchers and guide others. Laura King Edwards’ fantastic book Run to the Light tells the story of her young sister’s battle with Batten disease.

Given this backdrop, the success story of gene therapy for another inherited and horrific neurological disease, metachromatic leukodystrophy (MLD), is all the more wonderful. But the progress comes at an unimaginable cost: it can’t save a child unless an older sibling has already died of the disease, sending an alert to test the younger ones to find out before symptoms start.

MLD is so rare, with incidence in the US ranging from 1 in 40,000 to 1 in 160,000, that no state includes it in newborn screening panels. But results of a recent study suggest it may be coming soon, perhaps starting in New York.

With newborn screening, diagnosis could come before symptoms begin. But without it, parents must undergo the diagnostic odyssey as the symptoms become more specific. p

A Success: Metachromatic Leukodystrophy

MLD affects the white matter in the brain, causing progressive loss of mobility and sensation, as well as intellectual decline and, ultimately, unresponsiveness. Gene therapy adds corrected genes for the enzyme arylsulfatase A to bone marrow stem cells taken from children who have inherited the disease but haven’t yet developed symptoms, which typically begin around age 2 or 3. The bolstered cells are infused into the child and migrate to the brain, where they give rise to corrected glial (support) cells that make the needed enzyme. If gene therapy is done early enough, symptoms never even begin.

Alessandra Biffi, MD, headed the clinical trial at the San Raffaele Telethon Institute for Gene Therapy in Milan, beginning in 2011. Gene therapy had progressed faster in Europe over the previous decade, when many clinical trials in the US were delayed in the wake of the death of Jesse Gelsinger and then after five boys developed leukemia, with one death, in a trial for a different disease in 2001.

I told the story of one family, the Prices, here at DNA Science, as part of a post celebrating the moms of gene therapy for Mother’s Day 2018. They’ve had two children treated in the clinical trial.

Liviana Price was born in January 2008 in Omaha, Nebraska, and diagnosed with MLD in December 2010. Her symptoms began with an altered stance, then bouts of chills, and then she lost motor skills, her developmental milestones retreating. She was diagnosed with MLD at the end of the year. Giovanni was born in January 2010, and his sister’s diagnosis at year’s end led to his, with genetic testing. Amy and Brad Price were carriers. Each of their children would face a 1 in 4 chance of inheriting the disease.

Giovanni was accepted into the clinical trial in Italy and was treated in 2011, but it was too late for Liviana. She passed away in 2013. Then in 2014 Amy had triplets and one of them, Cecilia, inherited MLD too – she had gene therapy at 9 months. Antonio Regalado tells their story in MIT Technology Review as does Amy’s blog Liviana’s Journey. The treated children are leading normal lives.

The final line of the paper in The Lancet in 2016 reporting the clinical trial results is heartbreaking: “In memory of Baily, Valentina, Carlos, Dennis, Liviana, Mustafa, Randa, and Amany.” Those were the eight children who died, as their younger siblings lived.

Another Mother’s Tale

In a wonderful new book, Harnessing Grief: A Mother’s Quest for Meaning and Miracles, Maria J. Kefalas tells her family’s story of MLD. Her Calliope Joy didn’t have an older sibling to sound the warning. But her family’s efforts made it possible for several other children to make the trip to Italy to receive the gene therapy.

It’s quite an amazing story, beautifully told. Dr. Kefalas is a professor of sociology at Saint Joseph’s University in Philadelphia. Her book focuses more on the spiritual than the scientific, with an emphasis on “the superpower of grief” – how Maria has channeled what must have been unimaginable despair into helping others and uniting a community, through the Calliope Joy Foundation.

Cal’s first symptom was an odd buzzy whole-body shuddering while being fed in her high chair. She spoke a few words, but hers language acquisition stopped at 20. Then her unbounded energy didn’t match well with preschool. “It is accurate to say Cal ruined every class,” Maria wrote.

Developmental delays accrued, therapists descended, tests began. When Cal started walking on her tiptoes and could no longer manage stairs, her alarmed parents took her to the pediatrician on the Saturday before July 4. The doctor watched the child navigate and sent her to Children’s Hospital of Philadelphia – where much of my gene therapy book takes place.

An MRI revealed the white matter changes characteristic of MLD in Cal’s brain, and genetic testing confirmed the diagnosis. It was too late for the gene therapy, but Maria, in what she describes as a series of nervous breakdowns, threw her energy into fundraising, even if she at first didn’t have any idea where she’d donate funds. She led an effort to sell cupcakes, numbering around 50,000.

Then when Maria heard about and got to know Amy Price, she realized that the cupcake dough could go to help the families get to Italy.

Harnessing Grief: A Mother’s Quest for Meaning and Miracles is a terrific book. Cal has defied the odds and is still here. Maria tells about writing the book here.

The clinical trials in Italy for MLD began right while I was putting together my proposal for The Forever Fix – so my book missed the best gene therapy story of all. I hope it won’t be the last! For despite the backsliding, gene therapy does work, and I’m sure we’ll be hearing about new applications.


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