February 28 marks Rare Disease Day. UConn Health’s campus is lighting up this week to raise awareness of the more than 7,000 rare diseases and the importance of advancing research for them to find promising therapies and potential cures for patients.
One of the many incurable rare diseases is debilitating and deadly Krabbe Disease.
UConn School of Medicine’s Stephen J. Crocker, Ph.D., associate professor of neuroscience and immunology, has been awarded an NIH grant to gain greater insights into the genesis of the rare disease globoid cell leukodystrophy (GLD), also known as Krabbe disease.
“Because Krabbe disease is rare, most people have never heard of it,” says Crocker. “The disease’s development in the brain seems to be entirely spontaneous.”
This incurable genetic disease of the central nervous system causes profound white matter loss in the brain (demyelination), neurodegeneration and inflammation. More than one hundred years ago Danish neurologist Knud Krabbe first identified the disease in several infants in 1916. The often-fatal Krabbe disease affects 1 in 100,000 people, most often presenting in infants but can also have late onset in adults too.
Sadly, most parents are not aware their child has Krabbe disease until their child experiences the disease’s striking symptoms.
Krabbe symptoms include:
- Irritability and distinct crying
- Behavioral issues
- Muscle rigidity
- Loss of mental skills
- Loss of physical skills becoming wheelchair bound
- Seizures
- Blindness
- Difficulty swallowing
Only a few U.S. states currently conduct newborn screening blood tests for this genetic condition. Plus, there are currently no cures or ideal treatments for the disease. If the disease is diagnosed early within a child’s first 30 days of life a rigorous and risky bone marrow transplant can help improve their survival odds. Unfortunately, survival from Krabbe disease is only usually within a child’s first year of life, and most children with the disease die before age 5.
A Surprising Research Discovery for this Rare Disease
While doing comparative single-cell RNA sequencing in a mouse model of GLD Crocker’s laboratory surprisingly uncovered that there are remarkably high levels of CD8 T immune cells present in brain and spinal cord tissues of the disease.
“We have discovered that the levels of CD8 T immune cells are nine or ten-fold higher in Krabbe disease tissue then healthy tissue,” says Crocker. “We have also determined that if you block these T immune cells using antibodies, you can profoundly delay the clinical disease and prevent much of the neuropathology associated with Krabbe disease!”
The strong preliminary laboratory data findings supported a recent NIH grant application that was awarded funding. Crocker and his team will now further interrogate the role CD8 T cells play in Krabbe disease using advanced genetic profiling tools and RNA sequencing approaches. For the NIH research project, Crocker is collaborating with other immunology researchers at UConn School of Medicine, as well as collaborators at Johns Hopkins.
The research team hopes to determine how these immune cells come about in the brain, their basic biology, and how and when they are spontaneously activated leading to the development of Krabbe disease. Crocker hypothesizes that glial cells in the brain, which can become infected, inflamed, and change behavior to function as immune cells, may be the bad actors behind Krabbe disease.
Testing Current Medications for a Rare Disease
Crocker has also recently been awarded three-year grant funding from The Legacy of Angels Foundation. This private family foundation supports basic research and clinical trials for Krabbe disease after having children in their family affected by the disease.
This additional grant funding will allow Crocker and his lab to examine the possible impact existing FDA-approved medication treatments could have upon Krabbe disease models and GLD pathology.
“This new research project offers a high degree of translational medicine potential for discovering new therapeutic avenues to treat Krabbe patients by targeting the neuropathology of this disease,” says Crocker. “Because we now believe that T immune cells are heavily involved in Krabbe disease, we can potentially use already approved drugs, such as those used for MS, to have an incredible impact on Krabbe disease too. Even if these drugs are ultimately not a cure, they may help us delay the rapid decline in this disease enough to make other therapeutic options available to these patients, which would be a tremendous benefit.”
Crocker stresses the importance of both federal and private research funding for rare diseases.
“Research funding like this are the seeds we need for the initial first steps to help patients with rare diseases and grow our research to find future therapy solutions and cures,” says Crocker who looks forward to someday in the future translating his research findings to rare disease patients in need at the UConn Health MS Center which is home to a rare disease clinic.
And what is it like being a researcher investigating an often fatal, rare disease such as Krabbe?
“It’s motivating!” exclaims Crocker. “Especially as a neuroscientist when you get a chance to see a small child’s face and their family who are living with Krabbe disease. With our rare disease research, we can hopefully make a difference – that’s our dream.”
Crocker adds: “UConn is rare. A lot of people here at UConn are doing research on rare diseases. The insights we glean from rare disease research can have a much broader impact beyond that rare disease to all sorts of other diseases and biological systems too.”
This research is supported by NIH grant number R01 NS131327.
