September 2017

Myelin Biorepository Fuels Understanding of Leukodystrophies

A decade after seeing her patients (and oftentimes beyond that), Adeline Vanderver, MD, program director of the Leukodystrophy Center of Excellence at Children’s Hospital of Philadelphia, still calls up families when she discovers something new about their child’s leukodystrophy. Like most pediatricians who treat rare disease, Dr. Vanderver knows that many families seek knowledge about their child’s condition whether or not he or she has passed away. They would like to learn what went wrong inside their child’s body and help other children and families who struggle through a similar pain.

Now, a 10-year biobank project that first began at D.C.’s Children’s National Medical Center in 2003 and moved to its new headquarters at CHOP in 2016, will allow Dr. Vanderver and her team at the Leukodystrophy Center to do this with even more acuity. Through the Myelin Disorder Biorepository Project (MDBP), researchers at CHOP will collect the blood, tissue, cells, and myelin from children with various types of leukodystrophies in order to diagnose unclassified forms of the condition, understand the underlying mechanisms of known types, and test new therapies.

With an estimated one in every 7,000 babies inheriting the progressive disorder, the biobank has the potential to change the lives of clinicians, parents, and patients – beginning with providing a clearer picture of the genetic disorder itself.

What are Leukodystrophies?

Children with different forms of leukodystrophies have one common characteristic: the presence of damaged myelin, also known as “white matter,” in their brain and spinal cord. Because the central nervous system (CNS) operates as our control center, directing nerve tissues throughout the entire body, this impairment can disrupt every aspect of a child’s mental and physical development.

“White matter works as insulation to convey the information that the brain is trying to send to the body, like speech, movement, and everything else that our brains contribute to our lives,” Dr. Vanderver said. “When you have leukodystrophy and that myelin is broken, you’re not able to convey all that information.”

Because leukodystrophies are a degenerative condition, symptoms can also emerge or worsen late into adolescence or adulthood as the myelin damage spreads. Despite such an extensive impact, leukodystrophies remain difficult for clinicians to diagnose. Many different types of leukodystrophies exist, with a different gene abnormality underlying each form. Researchers currently know of 30 types of leukodystrophy, and Dr. Vanderver guesses that there are many more. Through the biorepository, she hopes to drive what she describes as the “broken train” of leukodystrophy research forward – an analogy she uses to describe the disorder with her patient’s parents.

“Think of train tracks that aren’t working properly,” Dr. Vanderver said. “There are train cars that are running on those tracks, and some leukodystrophies are at the front of the train.”

These, she said, are the forms of the disorder that researchers know the most about, including the gene responsible for the damaged myelin and its effect on the child’s CNS. For these types of leukodystrophies, developing new therapies and testing their impact is a top priority.

Next, there are leukodystrophies in the middle of the train.

“For these forms, we might know what the gene is, but we don’t understand what the broken gene does to the myelin, and we certainly don’t have therapies,” Dr. Vanderver said.

Finally, there are the leukodystrophies at the back of the train: the ones that need the most fuel and perhaps the most help. Researchers don’t know the cause of these leukodystrophies at all.

“My hope is that through this biorepository project, we can bring the whole train forward so that ultimately, leukodystrophies are easier to diagnose, understand, and care for,” Dr. Vanderver said.

Fueling Research

Currently, the biorepository stores the DNA and RNA from more than 1,200 families. According to Dr. Vanderver, the genomic data has already helped researchers make significant progress.

“The biorepository has contributed in a direct and indirect way to uncovering the findings of about a dozen leukodystrophies,” Dr. Vanderver said. “And at this point now, we’re actually achieving diagnosis in about 80 percent of cases.”

Next-generation sequencing (NGS) technologies that utilize patient samples drive these breakthroughs. Through whole exome sequencing and whole genome sequencing, researchers can identify genetic variations of leukodystrophies by piecing together an individual child’s genetic code. Previously, clinicians were able to identify leukodystrophies by observing white matter abnormalities in a child’s CNS through neuroimaging, but even then, more than half of these conditions still don’t have a definitive diagnosis, referred to vaguely as “leukodystrophies of unknown etiology.”

Adding to this, it can be difficult for patients to receive a diagnosis: The diagnostic odyssey averages about eight years long, with $8,000 in test expenses per patient. Through the MDBP and other ongoing studies, Dr. Vanderver hopes to assess the further usefulness of NGS, which may yield faster and more cost-effective approaches. The technology has already shown promise in modernizing medical research into rare diseases, since an estimated 80 percent of rare diseases have a genetic origin. In an ongoing study called LeukoSEQ, Dr. Vanderver and her team will use NGS to help diagnose a group of patients who have suspected leukodystrophies (according to clinical symptoms observed through MRI imaging) but no particular genetic diagnosis.

In addition to genomic-level data, banked tissues, cells, and blood samples will help the team understand and establish the mechanisms of existing and unclassified leukodystrophies, as well as track current care and natural history of the disease.

“We continue to work on diagnosis, but the next step has been understanding the mechanisms of disease and working on therapies,” Dr. Vanderver said.

Molecular data gives the team the ability to recreate and understand how a gene variant wreaks havoc in a child’s body. Researchers can make induced pluripotent stem (iPS) cells, or stem cells re-programmed with the ability to produce any kind of cell or tissue in the human body, to model and investigate a given leukodystrophy. On top of that, Dr. Vanderver’s team can also make neurons and dendrites (in order to see what happens with the broken gene at a cellular level) as well as develop biomarkers to test the impact of novel therapies.

A Patient’s Role

So far, Dr. Vanderver has witnessed an astonishing level of enthusiasm from families and patients who are willing to donate samples. She equates the effect to what happens during a snowstorm.

“When you’re in a situation where things are challenging, people really do band together to try to recruit others,” Dr. Vanderver said. “Families are amazingly altruistic, and they understand that oftentimes, they’re giving samples that may never help their individual child.”

By the time researchers understand what causes the disease and how to treat it, too much time may have passed for the donation to have an impact on their own baby or child. Nevertheless, families still want to help.

“It seems so unfair to have this enemy that you don’t even know what it’s doing,” Dr. Vanderver said

As a result, families consent to participate and provide the team with clinical records, DNA, and blood samples for both child and parent, but their participation doesn’t just stop at donating samples. The registry has allowed Dr. Vanderver to put families in contact with one another, to have them attend family meetings and join together.

“Its goal really is to provide a network,” Dr. Vanderver said.

Naturally, that network also includes the collaboration of other researchers outside of the Vanderver lab and across different disciplines.

“If researchers have families that they think should be participating, it’s a huge gift to help us connect those dots,” Dr. Vanderver said. “There are more than 30 myelin disorders and no way that my lab can do all the work. The big goal of the registry is to share samples and information so that we can, in essence, advance the whole train forward better.”

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