Gene Therapy for Metachromatic Leukodystrophy (MLD)
What is metachromatic leukodystrophy?
Metachromatic leukodystrophy (MLD) is a rare genetic disorder that causes childhood dementia. It is a type of leukodystrophy, a group of conditions that affect the white matter of the brain. In MLD, fatty substances (called sulfatides) build up and damage the myelin sheath — the protective coating around nerve cells in the brain, spinal cord and peripheral nerves — which helps messages travel quickly between cells. Without healthy myelin, messages from the brain travel slowly or stop altogether, leading to loss of the ability to talk or move.
How is gene therapy used to treat metachromatic leukodystrophy?
People with MLD are born with changes in the ARSA gene. This gene makes a helpful protein that breaks down sulfatides. In people with MLD, the body doesn't make enough of this protein, so sulfatides build up and damage the nerves.
There have been recent advancements in treating MLD with gene therapy. Gene therapy for MLD is called atidarsagene autotemcel (brand name: Lenmeldy™). Lenmeldy™ is the first FDA-approved gene therapy for babies and young children with early signs of MLD. Lenmeldy™ has the potential to stop or slow disease progression with a single treatment.
Lenmeldy™ should be given before symptoms of MLD appear. This means newborn screening for MLD is very important – so babies can be identified as having this disease very early, before symptoms appear. In 2025, MLD was added to the recommended federal guidelines for newborn screenings. Each state must now decide when to add this condition to their screening panels. Several states, including Pennsylvania and New York, already screen for MLD.
Lenmeldy™ is a type of ex-vivo gene therapy. In this type of therapy, doctors remove a child’s own stem cells, add the healthy ARSA gene, and return the cells to the child’s body. The child receives chemotherapy to prepare their body for the ex vivo gene therapy infusion. When ready, the Cellular Therapy and Transplant team infuses the corrected cells back in a process called an autologous stem cell transplant. Because this is a highly specialized, multi-step treatment, children typically remain in the hospital for several weeks while their immune system recovers.
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Narrator: Our team at Children's Hospital of Philadelphia wants to help you understand ex vivo gene therapy. But before we can get into what ex vivo means, we should start by explaining, what is gene therapy? Gene therapy is a way to treat or prevent disease by using genetic material like DNA. First, the basics.
Our bodies are made up of cells, and inside each cell, is its DNA. DNA is divided into short sections called genes. Genes act as instruction manuals, telling ourselves how to make proteins. Proteins are necessary for our bodies to function. Proteins do important work, like helping us digest food and helping our blood clot when we get a cut.
But sometimes, a gene's instructions for making a protein are not correct. This can cause changes in how a protein works. These incorrect instructions can result in a genetic disease. Gene therapy can deliver new instructions to the body to make proteins that function correctly.
Paulina: My leukemia kept coming back. After receiving ex vivo gene therapy, my body was able to conquer the cancer cells.
Narrator: How does gene therapy work? There are two types of gene therapy, ex vivo and in vivo. In vivo means inside the body. When a child receives in vivo gene therapy, that means they'll get an injection or an infusion to fix defective genes.
Ex vivo means, outside the body. Let's talk more about how ex vivo gene therapy works. For ex vivo gene therapy, we remove a child's cells and modify them in a lab. We can either add a new gene or fix the gene that is causing the disease. The modified cells are then returned to the patient. This can require pre-treatment and an infusion during a hospital stay, or in other cases, it can require a stem cell transplant procedure.
One condition that can be treated with an ex vivo gene therapy is sickle cell disease, which is a blood disease that causes episodes of terrible pain. People with this disease now can receive ex vivo gene therapy that fixes the problem.
Temi: Because I received gene therapy for sickle cell disease, I am living a pain-free life.
Narrator: Gene therapy is changing and saving children's lives, and CHOP has been at the forefront of gene therapy breakthroughs from the start. CHOP was the first in the world to use an ex vivo gene therapy to treat a child with leukemia, and we've pioneered many other groundbreaking discoveries. Our determined researchers are exploring the use of ex vivo gene therapy for all kinds of diseases, so that more children worldwide will have bright futures.
Metachromatic leukodystrophy treatment options at CHOP
Children’s Hospital of Philadelphia (CHOP) is a designated Qualified Treatment Center (QTC) for atidarsagene autotemcel (brand name: Lenmeldy™).
CHOP’s Leukodystrophy Center is one of only a small number of programs in the country dedicated to caring for infants and children with leukodystrophies with a special focus on the care of children with MLD. Our multidisciplinary team brings together experts in diagnosis, clinical care and advanced therapies, and is among the most experienced in the world in treating metachromatic leukodystrophy (MLD).
Children receiving Lenmeldy™ at CHOP are cared for through a close partnership between the Leukodystrophy Center and CHOP’s Cellular Therapy and Transplant Section. This team specializes in the complex care children need during cellular therapies and has maintained continuous accreditation from the Foundation for the Accreditation of Cellular Therapy (FACT) — the global standard for excellence in this field.
Your child will be cared for in our state-of-the-art facility, designed with safety, comfort and families in mind. From the first visit through treatment and follow-up, our team supports not just your child, but your entire family, guiding you every step of the way.