Older Siblings Made Possible Just-Approved Gene Therapy for Metachromatic Leukodystrophy

The Food and Drug Administration just announced approval of Lenmeldy (atidarsagene autotemcel), a gene therapy to treat the neurological condition metachromatic leukodystrophy (MLD). Available in Italy for three years, Lenmeldy (atidarsagene autotemcel), from Orchard Therapeutics, is groundbreaking, but comes at quite a cost – the $4.25 million price tag for the one-time infusion, and for the older siblings who contributed to developing the gene treatment, but were too sick to receive it.

An Ultrarare Neurological Condition

MLD affects the white matter in the brain, causing progressive loss of mobility and sensation, as well as intellectual decline and, ultimately, unresponsiveness. Lenmeldy adds functional genes that encode the enzyme arylsulfatase A (ARSA) 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. Once infused into the bloodstream, the bolstered stem cells migrate to the brain, where they give rise to corrected glial (support) cells that make the needed enzyme. If done early enough, symptoms never even begin.

But the need to treat early is the crux of the problem. Because MLD is so rare, it still isn’t included in most newborn screening panels. And in order to work, the infusion must happen before symptoms begin. In states without MLD newborn screening, the diagnostic odyssey would only lead to suspicion of the condition if an older sibling was already diagnosed, and the health team knew to test.

Incidence in the US ranges from 1 in 40,000 to 1 in 160,000; that’s only 40 or so children a year. Screening newborns in parts of Germany and New York State identified 4 cases among a quarter million babies.

The MLD Foundation is attempting to have the condition included on the Recommended Uniform Screening Panel from the Health Resources and Services Administration. That would enable identification of children before symptoms begin. The history of gene therapy for MLD is compelling – DNA Science covered it for Rare Disease Day in 2021, here.

A Long and Winding Diagnostic Road

The story begins in 2011, with Alessandra Biffi, MD, head of the clinical trial for MLD at the San Raffaele Telethon Institute for Gene Therapy in Milan.

Gene therapy had progressed faster in Europe over the previous decade than in the US, due to delays in clinical trials in the wake of the death of 18-year-old Jesse Gelsinger in a trial to treat a urea cycle disorder, and then after five boys developed leukemia, with one death, in a trial for a form of severe combined immune deficiency in 2001. I told the story of one family with MLD, the Prices, as part of a post celebrating the moms of gene therapy in 2018. Two of their children, Liviana and Giovanni, participated in the clinical trial.

Liviana 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. Developmental milestones ebbed and vanished. She was diagnosed with MLD at the end of the year.

Giovanni was born in January 2010. When his sister’s symptoms finally had a name by year’s end, he had genetic testing. Giovanni also had inherited MLD but hadn’t yet developed symptoms. It was classic autosomal recessive inheritance; Amy and her husband Brad are carriers. Each of their children would face a 1 in 4 chance of inheriting the disease.

The boy was accepted into the clinical trial in Italy and received the gene therapy 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 – she had gene therapy at 9 months. Photos of the kids are at Liviana’s Journey.

Antonio Regalado told the Price’s story in MIT Technology Review in 2016, and updated it with the gene therapy news. But like CNN’s headline “A lifesaving therapy for children with a rare disease is now the world’s most expensive drug, raising questions about access” and those of other outlets, Regalado, too, focuses on the cost. He compares it to “a Brooklyn brownstone or a Miami mansion, and more than the average person will earn in a lifetime.” I wonder what families will actually end of paying for the one-and-done treatment. The gene therapy drug Glybera was taken off the market in Europe due to its high cost – $1.4 million, a lot less than the MLD treatment.

But what is the value of a child’s life? The Price children who received the gene therapy are today leading normal lives.

Yes, the cost is horrifying. And yes, a treatment for a deadly disease is wonderful. But I can’t get out of my head the final line of the paper in The Lancet in 2016 reporting the clinical trial results for the gene therapy for MLD:

“In memory of Baily, Valentina, Carlos, Dennis, Liviana, Mustafa, Randa, and Amany.” The eight children who died, as their younger siblings lived.

For further information on what it is like to raise a child with MLD, Maria J. Kefalas wrote Harnessing Grief: A Mother’s Quest for Meaning and Miracles. Her daughter 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.