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research for Krabbe,
Leukodystrophies and
Nervous System Disorders.

Hunter James Kelly Research Institute - Basic Science

Mission
To develop a multi-disciplinary approach to understand how myelin is formed, how it is damaged in disease, and how it may be repaired.

The Basic Science Research at the HJKRI focuses on discovering new insight and a more comprehensive understanding of Krabbe and similar diseases. The researchers at HJKRI create cellular and animal models to analyze the complex intricacies of the disease, to progress research from the animal model to clinical trials, and ultimately better treatments and a cure.

Objectives
  • To study myelin formation as a source for strategies of myelin repair
  • To study consequences of myelin damage, common to all diseases of myelin, such as inflammation or neurodegeneration which correlates best with disability (symptoms and problems of daily living)
  • To provide better cellular and animal models (cell based assays, transgenic mice or fish) for identifying mechanisms of disease
  • To exploit models to perform preclinical studies of therapies
  • To translate the research of HJKRI into prognostic, diagnostic treatment applications in cooperation with the University at Buffalo Department of Neurology and Hunter’s Hope Foundation


HJKRI_Wrabetz in Lab_Close Up with Blue BorderWrabetz Lab
Lawrence Wrabetz, MD
Director, HJKRI & Professor of Neurology, University at Buffalo

The Wrabetz Laboratory is interested in the molecular genetics of myelination. Translating past experiences, this lab now focuses on the generation of new mouse models of Krabbe Disease that carry authentic galactosylceramidase (GalC) mutations found in patients with diverse clinical phenotypes. These animal models will provide insight into the effect of different mutations on the function of the GalC protein and on the pathogenesis of the disease.
 

M. Laura Feltri, MD
Professor of Biochemistry, University at Buffalo
The Feltri Laboratory investigates how cells and cell interactions contribute to development of the nervous system and myelination. Ultimately, the goal of this work is to translate basic science into a cure for demyelinating diseases, such as Krabbe and other Leukodystrophies.

Pablo M. Paez, PhD
Assistant Professor of Pharmacology & Toxicology, University at Buffalo

The Paez Laboratory focuses on brain development. Understanding the cellular and chemical properties of the brain opens doors to novel interventions for neurodegenerative diseases, such as Krabbe and other Leukodystrophies.

 



HJKRI_Park_Headshot_with Blue BorderPark Lab
Yungki Park, PhD
Assistant Professor of Biochemistry, University at Buffalo
The Park Laboratory is working at the forefront of translational research. Utilizing advanced computational analysis and experimental laboratory methods, this team of researchers is investigating central nervous system myelination, with an ultimate goal of translating this knowledge to the treatment of demyelinating diseases, such as Krabbe.

The HJKRI is in the process of recruiting two additional Primary Investigators to study the cause, effects and potential therapies of Krabbe Disease, Leukodystrophies and other myelin related disorders. With a total of six Basic Science Laboratories, the HJKRI will solidify its place amongst myelin-focused research institutes.

 

Basic Science Activities

Pathology of Krabbe Disease

Pathology is the cause and effects of a disease. The Basic Science team at the HJKRI is working hard to determine how Krabbe Disease is caused and its specific effect on the brain, nervous system and the affected individual’s body as a whole.
Using cellular and animal models affected by these same diseases, researchers at the Institute are working to:
  • Identify the effect that no GALC in each brain cell type has on myelin and the overall degeneration of the nervous system
  • Identify other toxic substances besides psychosine that contribute to the disease

Anticipated Outcome:
There are two important consequences of this work. First, knowing which cell without GALC is the most important contributor to Krabbe Disease, means knowing which cell needs to receive GALC replacement. For example, if neurons, the “thinking” cells of the brain, are the most important contributor to disease, gene therapy strategies would need to be best at replacing GALC in neurons. Practically, that means scientists at HJKRI would focus on finding the best “vector”—a kind of gene therapy carrier or porter—to get GALC into neurons in the brain.

Second, if HJKRI scientists identified other toxins that cause Krabbe Disease, they would begin work on new ways to ‘detoxify’ them in the brain. Either the pathways that produce the toxins could be blocked, or once made, the toxins could be specifically broken down through chemical treatments.
Predicting Onset
Predicting disease onset, or when symptoms will occur, is crucial to ensuring Krabbe patients identified through newborn screening receive treatment at the optimal time. To improve doctor’s ability to diagnose and predict the severity and onset of the disease, we are studying other parts of the GALC gene that may suggest how the disease will unfold.
Using cellular and animal models, HJKRI researchers are investigating:
  • The effect of changes on GALC and how it interacts with other parts of the cell
  • How different mutations of the GALC gene cause more benign or more severe variations of Krabbe
  • How the most common GALC mutation, the 30-kb deletion, causes a different pathology than other mutations of Krabbe

Anticipated Outcome:
This is very exciting area, as Drs. Daesung Shin and Laura Feltri at HJKRI have found that some mutant GALC proteins never arrive to the right part of the cell to do their work. Dr. Shin is now exploring whether the assay for GALC activity should be performed on only parts (so-called fractions) of the cell in order to measure loss of GALC function in the most important part of the cell. This could improve the reliability of predicting whether or not a mutation will actually cause disease.

Better Treatments and a Cure for Krabbe and other Leukodystrophies
Currently, the only treatment available for Krabbe Disease is cord blood transplant, which has proven successful in halting the progression of the disease. While this life-saving treatment has given numerous affected children a chance at life, it is only available to those diagnosed before the onset of symptoms.
The HJKRI researchers are committed to improving the existing treatment, and to discovering new treatment options and ultimately a cure for Krabbe and all Leukodystrophies. Using cellular and animal models, HJKRI researchers are investigating:
  • How to compensate for the known limitations of cord blood transplants and gene therapy by improving these methods and finding alternative treatments
  • Why psychosine levels are elevated in Krabbe Disease and if inhibition of psychosine improves severity of disease in the animal model

Anticipated Outcome:
The HJKRI researchers are working together with other important researchers in Krabbe Disease to find new combinations of treatments that will work faster and better together than they do alone. Combined approaches (think quadruple agent chemotherapy or triple anti-HIV agents, for example) have already succeeded in other challenging and grave diseases like cancer or HIV/AIDS. One idea is to add gene therapy to cord blood transplant by replacing the GALC gene in the cells before they are transplanted. Another is to add neural precursor cell transplant to cord blood transplant in order to support myelination and enzyme replacement directly in the brain until the cord blood transplant can take effect. The HJKRI scientists hope to participate in a multi-center research project to explore the latter idea.