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CHOP Researchers Improving Metachromatic Leukodystrophy Diagnostics and Care

Published on June 13, 2024 in Cornerstone Blog · Last updated 3 weeks 1 day ago


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DNA strand

Metachromatic Leukodystrophy (MLD) is a rare genetic disorder that affects the brain's white matter.

By Lauren Ingeno

A new gene therapy offers hope to families affected by a rare disorder called metachromatic leukodystrophy (MLD), yet a major challenge remains: how to find children with MLD while the treatment still has the potential to help.

Children's Hospital of Philadelphia is a Qualified Treatment Center to offer the therapy, atidarsagene autotemcel (Lenmeldy™, Orchard Therapeutics). The treatment works best when children are diagnosed before irreversible injury has begun, and not all disease subtypes are eligible to receive it, according to Laura Adang, MD, PhD, an attending physician in the Division of Neurology at CHOP who specializes in the care of children with leukodystrophies.

"Because it is a rare disease with subtle early signs, families affected by MLD face an unacceptably long journey to diagnosis," Dr. Adang said. By the time a MLD diagnosis is reached, most children have begun to lose critical skills, like walking on their own.

At CHOP's Leukodystrophy Center, Dr. Adang and colleagues aim to reduce the length of that odyssey through research and advocacy. In addition to championing the fight for MLD to be included in newborn screening tests, CHOP researchers have developed consensus guidelines for the management of the disorder.

The research team also has spent nearly a decade developing a longitudinal natural history study to use existing medical records to better understand rare, progressive childhood diseases, including MLD. They describe the method in a new paper published in Molecular Genetics and Metabolism.

These efforts, along with the arrival of gene therapy, offer new avenues for patients with the disease to have long, healthy futures.

"We're going to be able to save lives," Dr. Adang said.

A New Kind of Natural History Study

The central nervous system's white matter is made of nerve fibers that are protected by an insulating layer called myelin. Leukodystrophies are a group of genetic diseases that result in the abnormal growth or development of myelin, which slows down or blocks messages between the brain and body.

In MLD, patients lack a properly functioning arylsulfatase A (ARSA) enzyme, rendering them unable to recycle sulfatides, or fatty substances. Over time, this leads to a toxic buildup that injures the myelin. Affecting about one in 40,000 individuals in the United States, the progressive disease causes issues with movement and speech. Most children soon lose the ability to walk and talk, and death eventually occurs between 10 and 20 years after diagnosis.

The newly-approved gene therapy for MLD works by extracting and genetically modifying a patient's own hematopoietic stem cells to include functional copies of the ARSA gene. The modified stem cells are then transplanted back into the patient, helping the body to produce the ARSA enzyme, which breaks down sulfatides and may stop MLD from progressing.

To develop new therapies for MLD and other leukodystrophies, as well as to aid in their early diagnosis and management, it is essential to have demographic, genetic, and environmental data that correlate with the disease's development and outcomes.

The current gold standard for gathering this data is a pre-planned, prospective natural history study, in which children receive standardized assessments over a period of time.

However, there are drawbacks to using this approach to characterize extremely rare diseases, such as MLD, Dr. Adang said. Since these studies only capture information post-diagnosis, it becomes challenging to chart the full course of the disease.

Prospective natural history studies miss the opportunity for researchers to identify early symptoms and other variables that could help clinicians better counsel families, design future clinical trials, and ultimately offer appropriate interventions earlier in the disease course.

"We need to focus on gathering information before the child has lost neurologic skills and treatments are less likely to be effective," Dr. Adang said.

As part of the Global Leukodystrophy Initiative Clinical Trials Network (GLIA-CTN), a network of research institutions across the U.S. supported by a multicenter biorepository protocol, CHOP researchers have developed a standardized approach for creating a longitudinal natural history study using real-world data in the form of existing medical records. Dr. Adang, along with Anjana Sevagamoorthy, MD, a clinical research associate, and a team of scientists are leading the effort.

Using a "blinded" study approach that is often used in clinical trials, the researchers reported in Molecular Genetics and Metabolism that they were able to perform retrospective assessments that gave them a better understanding of leukodystrophies.

This method could also be used to track the progression of other rare diseases.

"Now, we can look back at the medical record of a patient whose parent had concerns about their development," Dr. Adang said. "And even if they were provided reassurance at the time, we now have a concrete source about the child's lack of a developmental skill at a particular age, and we can start to map the very early findings of a disease."

Dr. Adang emphasized that, ultimately, she and her colleagues hope that this study and their wide portfolio of research on MLD will help to "bring value" to every moment of a patient's life.

"When families consent to participate in research, it is our responsibility to honor their child's legacy by maximizing the impact of their important contribution," she said.