Global Leukodystrophy Initiative Promotes Trial Readiness for Rare Disease

In the Vanderver lab, researchers study samples from the biobank to develop robust understanding of leukodystrophies.

The Global Leukodystrophy Initiative Clinical Trials Network (GLIA-CTN), a research-based consortium for which Children's Hospital of Philadelphia serves as the lead study site, is working with patient advocates and a network of other institutions to propel research on leukodystrophies toward clinical trial readiness, with support from the National Institute of Neurological Disorders and Stroke.

Adeline Vanderver, MD, a leader of the GLIA-CTN and attending physician in the Division of Neurology at CHOP Research Institute, has developed her passion for investigating rare diseases into a leadership position in the largest research initiative for leukodystrophies in the country.

"We estimate based on patient numbers collected from our expanded network that we're probably in touch with about 30% of the children in the country who live with this disorder," said Dr. Vanderver, who is the contact principal investigator for GLIA-CTN and the Program Director for the Leukodystrophy Center at CHOP. "Our network has become a very powerful way to disseminate new knowledge and therapies."

Leukodystrophies are rare genetic disorders characterized by abnormal growth of white matter in the brain that damages supporting glial cells surrounding the myelin sheath, which protects nerve cells in the brain and spinal cord. While leukodystrophies primarily affect the brain, each can cause unique problems with other organs and blood cells. Understanding the different complications of leukodystrophies and how they affect patients is critical to keeping a clinical trial moving, so events that occur during treatment can be appropriately attributed to the disease instead of a drug or vice versa.

With CHOP as the lead study site in GLIA-CTN, Dr. Vanderver often partners with internal collaborators such as Stefano Rivella, PhD — who recently published preclinical findings that used data from Dr. Vanderver's lab to determine if gene therapy could be an effective treatment for Metachromatic Leukodystrophy (MLD) — and external pharmaceutical companies who contact her to help determine whether their treatment is working for a certain leukodystrophy.

One of the Food and Drug Administration's benchmarks for demonstrating that a drug works is whether it changes how a patient feels or functions. There is a complex interplay between what parents see and feel about how their child is doing, or patient-reported outcomes, and what physicians can easily measure through clinical outcomes assessments, according to Dr. Vanderver. The NIH grant supports data collection via patient-reported outcomes and clinical outcomes assessments, merging any potential gaps in information and providing a more detailed report of how the drug is performing.

"These approaches will help make ongoing trials more effective," Dr. Vanderver said. "We hope having these ready-made datasets will increase pharmaceutical companies' willingness to do this kind of work for rare diseases."

Scale for heatmaps displayed during the GLIA Scientific Meetings to compare treatment readiness for key disorders and change over time.

The larger network, composed of principal investigators from Massachusetts General Hospital, the Kennedy Krieger Institute, Children's National Medical Center, Stanford, Texas Childrens, University of Utah, and Emory University among many others across the country, has supplied data to support multiple ongoing clinical trials for Pelizaeus-Merzbacher disease (PMD), MLD, Aicardi Goutieres Syndrome (AGS) and Alexander disease. They also work with over a dozen industry partners to help enable different treatment options.

The second aim of this grant is to optimize data extracted from electronic health records on thousands of patients from institutions involved in GLIA-CTN, to obtain large-scale natural history data on leukodystrophies. Using artificial intelligence and natural language processing techniques, researchers are beginning to develop a sense of wellness for a broader number of patients.

This heatmap identifies areas of success and opportunities for improvements across 22 leukodystrophies in terms of advocacy, care, and therapeutic development.

Advanced data analysis techniques will help them understand when children start losing ambulation, when they need help with nutrition, and when and why they start to be hospitalized, among other insights. This is important to patients and advocacy partners, as they advise caregivers of persons living with these disorders.

"For some of these bigger picture questions related to wellness, symptom management, and standard of care for each disease, you need thousands of children, which is difficult when studying rare diseases," Dr. Vanderver said. "For the first time, electronic health record data has enabled us to answer some of these questions, and that is transformative."

In addition to MLD, PMD, and Alexander disease, GLIA-CTN focuses on disorders in imminent need of clinical trial readiness due to clear preclinical study results that will lead to treatment in clinical trials with approved therapies. These include Adrenoleukodystrophy, POLR3 disorder, TUBB4A disorder, and Vanishing White Matter.

A Community that 'Thrives' through Collaboration

As more research is conducted and technology advances, GLIA-CTN seeks to expand its reach to include leukodystrophies that remain understudied in terms of what may cause a disorder, how well symptoms are managed, and whether there are approved therapies available to treat each disorder. Starting with a core 10 disorders at the beginning of their NIH grant, Dr. Vanderver shared the group is well on its way to supporting studies for 15 different leukodystrophies.

Patient Rafaella Cordova (left), Dr. Vanderver (middle), and Devon Cordova (right) at the 2025 GLIA Scientific Meeting and Advocacy Workshop hosted at CHOP.

Every several years, Dr. Vanderver also hosts the Global Leukodystrophy Initiative Scientific Meeting and Advocacy Workshop to address some of the most meaningful discoveries in leukodystrophy research. In the 2025 conference, held at CHOP in February, more than 250 scientists, industry partners, and advocates in the field were invited to discuss their breakthroughs in clinical management and disease-modifying therapies, as well as to identify opportunities to address unmet needs in advocacy and scientific development.

This meeting showcased recent advances in individual leukodystrophies, as well as approaches for common needs in this community, such as newborn screening, biomarker development, and access to therapies.

Dr. Vanderver closed the conference by reminding attendees that at a time of immense challenges for rare disease research, this community is thriving through collaborative work.