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Adeline Vanderver, MD, and her team of researchers aim to define novel homogeneous groups of patients with previously unclassified leukodystrophies, uncover the genetic causes of these disorders, and establish the molecular disease mechanisms in selected known leukodystrophies. The team is also working to assess the validity of advanced genetic sequencing techniques in the diagnosis of these disorders, and develop the next generation of therapeutic clinical trials through natural history and biomarker discovery studies.
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 lab is currently focused on exploring 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).
At the center of the discovery program is the Myelin Disorders Biorepository Project (MDBP), a biobank that houses clinical data and biological samples from over 1,500 individuals worldwide affected by leukodystrophies and other white matter disorders. Much of the lab's clinical and basic science work occurs under the regulatory umbrella of this biorepository. Novel gene identification is supported by LeukoSEQ, a program that offers whole-genome sequencing (WGS) to patients with a suspected leukodystrophy. This biorepository also supports groundbreaking work on biomarker discovery in Aicardi-Goutières Syndrome and Alexander Disease (AxD), specifically.
The lab has also spearheaded the launch of a series of natural history studies, designed to better understand the diverse clinical characteristics and natural of individual leukodystrophies. A list of current natural history studies is available under the "Project Highlights" for the Myelin Disorders Biorepository Project.
The laboratory recently participated in a multi-site compassionate use trial of baricitinib, a JAK1/2-inhibitor, to treat the inflammatory symptoms associated with Aicardi-Goutières Syndrome (AGS). The first phase of study, known as JAGA, had enrolled dozens of participants upon closing in August 2018. A formal clinical trial is slated to begin in early 2019.
- New Diagnostic Approaches in Leukodystrophy: The Myelin Disorders Biorepository and Natural History Project (MDBP): By collecting and analyzing clinical data and biological samples from patients affected by leukodystrophies and related disorders, the MDBP seeks to support the ongoing basic science effort to uncover novel genetic etiologies for individual leukodystrophies, characterize biomarkers for use in future clinical trials, and better understand the natural history of these diseases. This is the world's largest multi-center sample and data repository for this group of disorders, having enrolled over 1,500 individuals affected by leukodystrophies. A number of disease-specific projects have been launched under the regulatory umbrella of the MDBP: natural history and disease characterization; animal and cell models of N-ABC and TUBB4A-related Leukodystrophy; and Animal and Cell Models of Aicardi-Goutières Syndrome.
- LeukoSEQ: Whole Genome Sequencing as a First-Line Diagnostic Tool for Leukodystrophies: This study, now in its second phase, seeks to determine whether clinical whole genome sequencing (WGS) performed as a first-line diagnostic test in patients with suspected leukodystrophies will result in changes to clinical management relative to standard diagnostic approaches. The first phase of the LeukoSEQ study, completed in May 2018, demonstrated that the diagnostic efficacy of WGS significant relative to standard diagnostic approaches, and that the time to diagnosis was significantly reduced in those patients who received immediate WGS.
- Janus Kinase Inhibitor (Baricitinib) for Aicardi Goutières Syndrome: This is a single-site open-label Phase II clinical study designed to assess safety as well as efficacy of baricitinib, a JAK 1/2 inhibitor, in patients with Aicardi-Goutières Syndrome. Secondary objectives include assessment of safety parameters, therapeutic endpoints, interferon signaling gene scores, and other motor and neurological functional outcome measures.
Program Director, Leukodystrophy Center of Excellence
Using translational approaches that encompass genomic studies, biomarker development, disease modeling, natural history studies, and clinical trials, Dr. Vanderver seeks to improve the quality of life and lifespan of individuals living with leukodystrophies or heritable disorder of myelin. She leads the Leukodystrophy Center of Excellence at Children's Hospital of Philadelphia.