Current Research Focus

Overview

The Vanderver Lab’s translational research is focused on four key areas, all of which share a common goal of advancing our understanding of leukodystrophies and leukoencephalopathies in order to refine clinical diagnostic tools and accelerate the development of therapeutic treatments.

Specifically, Dr. Vanderver and her team of researchers hope to (1) define novel homogeneous groups of patients with previously unclassified leukodystrophies and to uncover the genetic causes of these disorders, (2) to establish the molecular disease mechanisms in selected known leukodystrophies, (3) to assess the validity of advanced genetic sequencing techniques in the diagnosis of these disorders, and (4) to develop the next generation of therapeutic clinical trials through natural history and biomarker discovery studies.

Discovery Program

The Discovery Program, one of the four arms of CHOP’s Leukodystrophy Center of Excellence, seeks to promote cutting edge research to better understand the underlying causes and biology of leukodystrophies. The Vanderver Lab is currently focused on explore therapeutic targets using novel cell and animal models in two specific disorders: Hypomyelination with Atrophy of the Basal Ganglia and Cerebellum (H-ABC) and Aicardi Goutières Syndrome (AGS).

Hypomyelination with Atrophy of the Basal Ganglia and Cerebellum (H-ABC)

Our researchers are working with collaborators at CHOP and at the University of Pittsburgh to establish cell-specific disease mechanisms in H-ABC. In order to explore these processes, the research teams are using TUBB4A mutated cell and animal models to define cellular targets for future molecular therapies in human populations. Researchers are also exploring the role of mutant Tubb4a in disease pathogenesis, specifically to establish the presence of accumulated mutant Tubb4a in affected cells. Finally, this project will explore the effect of down regulation of TUBB4A expression on disease pathogenesis in both cell and animal models.

Aicardi-Goutières Syndrome (AGS)

Our researchers are working with collaborators at the University of Pennsylvania School of Veterinary Medicine to investigate the role of circulating immune cells in Aicardi-Goutières Syndrome. Using a novel animal model of disease, the investigators will examine immune activation of circulating immune cells within the blood, and assess correlating neuroimaging and neuropathology. Investigators will focus specifically on those immune cell subtypes most relevant to disease mechanisms in order to identify therapeutic targets for future clinical trials.

Myelin Disorders Biorepository Project (MDBP)

Much of the laboratory’s basic science work occurs under the umbrella of the Myelin Disorders Biorepository Project (MDBP). This includes gene discovery and protein/biomarker characterization for a variety of diseases. The Vanderver Lab also routinely provides laboratory support to collaborating CHOP and non-CHOP investigators who do not have access to the same bench research infrastructure.

Clinical Research

Breakthroughs do not happen in a vacuum, which is why basic science researchers in the Leukodystrophy Center’s Discovery Program – which includes the Vanderver Lab – work hand-in-hand with clinicians and investigators around the world to understand these disorders.

At the center of the Vanderver Lab’s clinical research program is the Myelin Disorders Biorepository Project (MDBP), a biobank that houses clinical data and biological samples from over 1,500 individuals worldwide who have been affected by leukodystrophies and other white matter disorders. All of the Vanderver Lab’s basic science research projects, as well as many of its clinical studies and trials, are conducted under the regulatory umbrella of the MDBP.

Research conducted under the MDBP umbrella includes a series of recently-launched natural history studies on Aicardi-Goutières Syndrome (AGS), Hypomyelination with Atrophy of the Basal Ganglia and Cerebellum (H-ABC), and Metachromatic Leukodystrophy (MLD). These disease-specific studies are designed to collect health information to better understand when and how these disorders develop, and are an essential component in the planning of future therapeutic trials. The Vanderver Lab expects to launch additional natural history studies in 2018.

More recently, the Vanderver Lab has assumed a key role in a multi-site compassionate use trial of baricitinib, a JAK1/2-inhibitor with the potential to treat many of the symptoms associated with Aicardi-Goutières Syndrome (AGS). The study, known as JAGA, has enrolled over a dozen participants so far. A second trial, using a reverse transciptase inhibitor to mediate the autoimmune response seen in AGS, is pending regulatory approval.

The Myelin Disorders Biorepository Project (MDBP)

The Myelin Disorders Biorepository Project (MDBP) seeks to collect and analyze clinical data and biological samples from leukodystrophy patients worldwide to support ongoing and future scientific research projects in the leukodystrophy field. The MDBP is the world’s largest leukodystrophy biorepository, having enrolled over 1,500 individuals affected by leukodystrophies.

Researchers working on this project hope to uncover new genetic etiologies for individual leukodystrophies, develop biomarkers for use in future clinical trials, and better understand the natural history of these diseases. The knowledge gained from these efforts may help improve the diagnostic tools and treatment options available to patients in the future.

This study is open to any individual with a diagnosed or undiagnosed leukodystrophy or other disorder affecting the white matter of the brain. Study participants will be asked to submit copies of relevant medical records (clinical notes, test reports, and radiology images), as well as a one-time research blood sample for analysis in Dr. Vanderver’s laboratory. The study team may also ask the individual’s biological parents and other immediate family members to submit research blood samples to be used for reference.

This study is open to participants worldwide, and a visit to the Children’s Hospital of Philadelphia is NOT required to participate. To learn more about the study, or to begin the enrollment process, please complete and submit our team’s Referral Survey.

LeukoSEQ: Whole Genome Sequencing as a First-Line Diagnostic Tool

The LeukoSEQ study was launched in 2015 to investigate the use of whole genome sequencing (WGS) as a first-line diagnostic tool for unsolved leukodystrophies. Specifically, investigators are focusing on the diagnostic efficacy, clinical utility, and cost-effectiveness of whole genome sequencing in the absence of other diagnostic testing.

Participants will receive results of CLIA-certified whole genome sequencing within six (6) months of study enrollment, unless a diagnosis is achieved by other means. Results will not be released directly to families, and must be disclosed by a designated genetic counselor or qualified physician. In certain circumstances, a CHOP genetic counselor may be available to disclose test results over the phone. The study team will follow up with families for 18 months to monitor changes in the individual’s health and medical care – both before and after disclosure of the test results.

The study is open to participants who live and are eligible to receive medical care in the United States. A visit to the Children’s Hospital of Philadelphia is not required to participate – samples can be collected locally and shipped to the study coordinators in the Vanderver Lab.

JAGA: Compassionate Use Protocol for the Treatment of Autoinflammatory Syndromes

The JAGA Compassionate Use Protocol for the Treatment of Autoinflammatory Syndromes is a multi-center study designed to investigate whether treatment with baricitinib, a JAK1/JAK2 inhibitor, results in the reduction of some of the autoinflammatory symptoms seen in the context of Aicardi-Goutières Syndrome (AGS).

Patients who have a confirmed diagnosis of Aicardi-Goutières Syndrome (AGS) may be eligible to participate in this study. Study duration is approximately five (5) years and participants will be required to make periodic annual visits to an approved study site in Philadelphia or Washington D.C.

Baricitinib dosing must occur at an approved study site and will be based on a defined dose-escalation scheme. Patients who are unresponsive to treatment may have their dose escalated. Demographics, vital signs, safety laboratories, ADS, adverse events (AEs) and prednisone doses are captured at each visit.

Compassionate use studies, also known as expanded access programs, allow pharmaceutical companies to provide their experimental drugs to individuals outside of formal clinical trials who may benefit from their use. For more information about this study, please contact the JAGA study coordinator using the ‘Contact Us’ form.