LBSL Research Update October 2018

Moser Center for Leukodystrophies
LBSL Research Update for Patients and Families
October 2018

Overview

Since its inception in March 2016, the LBSL research lab at the Moser Center for Leukodystrophies at Kennedy Krieger Institute has grown exponentially. In just under two years, we’ve hired six full- and part-time researchers; we plan to add two more in the coming year. We’ve launched a clinical research study and established fruitful, cost-saving collaborations with other research institutions in the U.S. and abroad. In April, we hosted what we think was the first-ever official summit for individuals with LBSL and their families. It was attended by dozens of people from across the world.

Most importantly, perhaps, we established testing models to better understand the underlying mechanisms of LBSL (short for leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation), and we are rapidly collecting information that will inform our search for treatments for this disease.

The three most important components of our LBSL work are clinical research, research using animal models, and research using stem cells:

Clinical Research

Clinical research is the foundation of any real medical research effort. Through clinical research, we measure and collect data from individuals with LBSL. Without data to show how individuals are impacted by a disease, we cannot prove if any future theories or drugs actually work. This is especially important with a rare disease like LBSL, where very little is known about the course of the disease, the rate of change of its symptoms, and what factors may predict future outcomes. Here are our clinical research highlights from the past year:

–  Our clinical research of individuals with LBSL kicked off in April 2018 with five U.S. subjects. It’s thought to be the first study of its type because of the special remote, wearable tracking devices we’re using. The devices, which look like Fitbit bands, feed information about an individual’s balance, gait, stamina and fine motor movements to our lab. The data is collected from the subject’s home in real time during a remote video call. Originally developed for tracking movements of astronauts in space, the goal here is to collect data without the physical and financial demands of travel. This research was recently featured in an article on WebMD.

–  With initial data from the five U.S. subjects, we’ve proven remote assessments are as accurate as in-person assessments.

– We are actively recruiting more individuals for the study. Information on how to join the study can be found on ClinicalTrials.gov.

– The study is entirely funded by donations, and each set of wearable devices and accompanying computer system costs roughly $20,000. We are applying for a government grant that would potentially offset about 50 percent of the costs for this program, but government grants are extremely competitive—funding is typically only distributed to about 10 percent of applicants[LLT1] .

– While the tracking measures developed by our team for individuals with LBSL are already being applied in clinical trials for other diseases, such as adrenoleukodystrophy and multiple sclerosis, this is the first time data is being obtained remotely. We hope this will help pave the way for the use of these tracking measures in an LBSL drug trial, when that day comes.

Animal Models

As many of you know, we’ve been working since 2016 in collaboration with a scientist in Germany to establish a viable mouse model with the DARS2 mutation. The goal is to create a “sick” mouse that we can use to analyze and test potential drug therapies. Here’s what we’ve learned so far:

–  Deactivating [LLT2] the DARS2 gene in a mouse embryo—or even brain stem cells—is not compatible with life (i.e., the mouse fetuses died before birth).

– Deactivating the gene in mature myelin-producing cells does not affect a mouse’s brain.

– Deactivating the gene in mature neurons creates extremely hyper and aggressive mice with abnormal brain pathology and severe behavioral abnormalities. (We named these mice CAMKII mice.)

We’re also working on deactivating the DARS2 gene in oligodendrocyte precursor cells (cells that eventually develop into mature myelin-producing cells). This new model may better resemble the classic human LBSL disease.

While all of this work is still in its early stages, and studies are ongoing, we’re already getting some interesting information from the very sick CAMKII mice. Even in failure, we are learning. For example:

–  For several months on a weekly basis, we gave the CAMKII mice a powerful antioxidant that could penetrate the blood-brain barrier[LLT3] . However, we did not see ANY behavioral improvement. We are currently examining the pathology of the mice. While these results were very disappointing, many more studies still need to be done to determine whether the drug actually got into the brain sufficiently, and whether it decreased oxidative stress. These additional studies will provide us with clues as to whether oxidative stress is an underlying culprit in LBSL, or whether it is just a bystander phenomenon.

– Through collaboration with private industry, we were able to run the CAMKII mouse cells through a special RNA sequencing study looking at gigabytes of data to determine which genes and molecular pathways are changed as a “downstream effect” of the DARS2 mutation. These studies will likely result in the discovery of new drug targets, which we will then pursue. We’re sifting through an extremely large amount of data but have already found several interesting abnormalities worthy of further investigation.

Stem Cells

Induced pluripotent stem cells (iPSCs) can now be derived from an individual’s own skin and blood cells, which is less controversial and less expensive than traditional methods for obtaining iPSCs. And unlike animal models, stem cells can show a perfect reflection of the disease in human form. To date, we have made the following progress:

– Working with a stem cell laboratory in Cleveland, we used iPSCs derived from patients[LLT4] with LBSL to create “minibrains.” Our collaborators created the minibrains free of charge. We’re now in the process of analyzing these minibrains to see if we can identify abnormalities. If we do, we’d like to expand our work to generate more minibrains from the skin and blood cells of other individuals with LBSL. This will help us understand the disease’s pathology in a way that would only be possible in the setting of an autopsy.[LLT5]

– The minibrains take more than six months to make, but we’ve learned from some of our Kennedy Krieger colleagues how to make nerve cells in our own lab in just two to three weeks from iPSCs derived from the cells of individuals with LBSL. Already, we’re seeing a series of changes in the shape of these nerve cells compared to “healthy” cells. We’re repeating the experiments, but remain concerned that we need more cell samples from individuals with LBSL—and more control samples—in order to draw conclusions.

– For our stem cell research to yield conclusive information ,we need to make more cell lines using cells from at least five more individuals with LBSL and five more control subjects. We collected blood cells from individuals with LBSL during the LBSL summit in April, but those cells remain frozen. We need money and time in order to continue our research.

Summary

We’ve made great progress in building the infrastructure of what is now a fully-functioning, fully-staffed, multidisciplinary LBSL research lab. One-third of the cost of building the lab was funded by donations, one-third by Kennedy Krieger’s existing budget; and one-third by in-kind collaborations with other research institutions. Going forward, we anticipate that keeping the lab firing on all cylinders[LLT6] will cost roughly $660,000 per year. We hope to work with families and organizations to keep this program on track, and we are actively working to secure grants from the National Institutes of Health.

In summary, I want to thank all of those supporting this work.

Our team was very motivated by everyone who came to our LBSL conference in April. We really enjoyed getting to know each and every person whom we’re working to help. We will continue to keep you updated.

Yours,

Ali Fatemi, MD
Director, Division of Neurogenetics and the Moser Center for Leukodystrophies