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Multi-site Study Builds Better Clinical Trials for Aicardi-Goutières Syndrome

Published on
Nov 21, 2019
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Leukodystrophy Center research teamAdeline Vanderver, MD, program director of the Leukodystrophy Center at CHOP, and her team are filling a gap in Aicardi-Goutières syndrome research and treatment.

By limjr [at] email.chop.edu (Jillian Rose Lim) 

Researchers have made strides in putting together the puzzle pieces of Aicardi-Goutières syndrome (AGS), an inherited disorder that affects the brain, spinal cord, and immune system. Alongside identifying the gene mutations that underlie AGS, scientists now recognize that the rare condition shares similar pathways with more common neurological disorders, such as psoriasis. 

These discoveries have allowed Children’s Hospital of Philadelphia neurologists to borrow therapies for these conditions and prescribe them in a compassionate use study — meaning that very ill children with no treatment options left may receive drugs not yet approved for AGS. Now, with support from a recent National Institutes of Health grant, Adeline Vanderver, MD, is leading a multi-center initiative to develop a validated framework for measuring the effectiveness of such treatments in clinical trials. Dr. Vanderver, who is program director of the Leukodystrophy Center at CHOP, believes the project is greatly needed to fill a gap in AGS research and treatment. 

“What excites me the most [about this project] is improving my ability to respond when families ask me, ‘Should I start my child or loved one on this medication?’” Dr. Vanderver said. “I want to be able to answer that question with the best possible answer I can give, based on the best information and the best data. Right now, I don’t have the tools to do that, and I hope this, and similar efforts by the members of our community, will give me the tools to be confident about clinical recommendations for [AGS].” 

Filling a Gap in AGS Clinical Research

In 2016, Dr. Vanderver and her colleagues began to enroll patients with AGS in a compassionate use study of baricitinib, a drug typically used for arthritis. Baricitinib, a Janus Kinase inhibitor, blocks the production of interferon (INF), a protein. Previous research had established that AGS results from excessive production of INF, which causes a buildup of small pieces of DNA in the brain. This then triggers the immune system to turn on itself and target white matter, or myelin, in the brain. 

The number of pediatric patients enrolled in the compassionate use study grew from 11 to 35 over the span of a few years. Nevertheless, the study highlighted a gap in knowledge:

“There were a lot of things about [AGS] that were really clinical trial-ready, like available drugs and a well-defined patient population,” Dr. Vanderver said. “But there was really just not adequate information on how to measure outcomes. So, this grant was particularly geared toward that type of situation in rare disease.” 

Through the grant, Dr. Vanderver and her colleagues will use baricitinib to test functional outcome measures, magnetic resonance imaging (MRI) volumes and diffusion properties, and IFN scoring as outcome assessments for upcoming AGS clinical trials. But Dr. Vanderver emphasizes that the current project is not about testing whether or not baricitinib works. Instead, it focuses on the creation of appropriate assessments and biomarkers for testing the effectiveness of all proposed treatments for AGS.

“The next time we have a good idea to treat AGS, we will have better tools to understand whether or not this drug or other future drugs are effective for this disorder,” Dr. Vanderver said. “We have additional drug pipelines for this disease, and so it’s really, truly about making sure that we have the appropriate infrastructure to measure our points.”

A Team Effort

With three sites across the country and in Italy, the project will be able to determine the ease of obtaining outcome measures for all types of centers, including those that have less expertise in AGS or rare disease. A multi-site and multi-sector effort is also necessary because no single group would be able to put together such a long-term resource for measuring outcomes, according to Dr. Vanderver. 

“This effort requires multi-site investment because it’s not an investment that a single group is going to be able to make either on the industry side or the academic side,” Dr. Vanderver said. “But overall it will serve this community hopefully for years to come.”

In fact, the project will have big implications for obtaining approvals from the U.S. Food and Drug Administration (FDA) as well as health insurance providers. 

“Although the parents very much feel like this therapeutic approach is helpful, without the right tools to be able to measure that effect, it will be much harder to convince the FDA and health insurers that this is something they should provide coverage for,” Dr. Vanderver said. “My hope is that it would allow us to make an appropriate argument around which therapies are beneficial and which might not appropriately treat and take care of these otherwise very sick children.”