ABOUT THE GRANT

Krabbe disease (KD) is a rare, lethal inherited disorder of metabolism that most commonly affects infants and causes severe neurological
symptoms, with an average life expectancy of two years. Less commonly, KD can occur in late infancy, adolescence, and very rarely adulthood.
Treatment for KD isa stem cell transplant, which can most significantly improve survival and quality of life when given prior to the onset of symptoms.
The disease is caused by the loss of function of the enzyme galactosylceramidase (GALC). In the absence of GALC, another enzyme, acid ceramidase,
will take over some of the function of GALC and consequently produce a toxic small molecule, psychosine, that contributes to the symptoms of KD.
Abnormal function of acid ceramidase and the metabolites it regulates has also been reported in other neurological disorders, including Alzheimer’s
disease, but has not been as well studied in KD.

KD is diagnosed by first screening for loss of GALC activity and confirming the diagnosis with elevated psychosine and genetic testing. Psychosine
is effective at diagnosing infantile forms of KD but can be challenging to interpret in individuals with later-onset forms. Therefore, there is an urgent
need to identify new biomarkers that can accurately discern the different forms of KD.

The goals of this proposed research are multifold and include the detection of many metabolites at once in a sample using untargeted metabolomics
analyses. For this aim, we developed and validated an untargeted metabolomics method to test different sample types (plasma, dried blood spots,
and cerebrospinal fluid). In preliminary studies, we have shown that this approach can identify biomarkers that differentiate between clinical forms of
KD and are amendable to clinical laboratory implementation to aid current diagnostic testing. Additionally, we propose to complete metabolic flux analyses
to determine changes to metabolic pathways regulated by acid ceramidase in KD. This approach will help our understanding of disease-related changes to
cellular metabolism, uncover mechanisms surrounding GALC deficiency, and address the need to improve the diagnosis of KD; leading to outcomes that will
have a direct impact on improving patient care and uncovering new therapeutic targets.

An Interview with Rachel Wurth

Rachel Wurth, M.S., (MLS) ASCPCM is a PhD candidate in the Clinical and Translational Science Track at Mayo Clinic Graduate School of Biomedical Sciences. Rachel is conducting her thesis work in the clinical Biochemical Genetics Laboratory under the mentorship of Devin Oglesbee, PhD. She has designed and implemented an untargeted metabolomics platform that is broadly useful in characterizing the small molecule signature of inborn errors of metabolism for the purpose of biomarker discovery. The project has focused on characterizing the metabolic signature of Krabbe disease, a rare and devastating inherited neurological disease with a need for novel biomarker discovery to complement current clinical laboratory diagnostic testing. Through partnership with the clinical laboratory, Rachel aims to translate discovered biomarkers into novel diagnostic assays that can improve the detection, and prognostic monitoring of individuals with Krabbe disease.