We propose to deliver a GALC pharmacological chaperone to restore enzyme activity for the treatment of Krabbe Disease caused by GALC deficiency. Krabbe disease is a rare, fatal degenerative disorder which destroys myelin sheath of the nervous system. Most of the cases (85-90%) occur in infants before 6 months of age and usually death occurs by age 2 years. The later onset patients usually die between 2 and 7 years of age. Hematopoietic stem cell transplant (HSCT), when done prior to onset of symptoms extend survival and attenuate neurodevelopmental symptoms in the majority of patients. However, there are several concerns with HSCT: it is an inherently risky procedure with 10-20% of patients dying from complications; patients are on lifelong immunosuppressive therapy; cognitive development while normal is slower; worse patients suffer a progressive often severe motor deterioration, and some progress and die. Gene therapy has had some success in mice and dog models of KD, extending life modestly, but is unlikely to cure the disease. There is substantial need for a safe, oral, CNS penetrant small molecule drug that can be used alone, or in conjunction with HSCT or any potential gene therapies, that not only prevent patients from dying but enables them to have a normal quality of life. Our objective is an orally active, safe, CNS penetrant small molecule pharmacological chaperone of mutated GALC that restores its activity in the lysosome to greater than 10% that of wild type enzyme. We have already identified a potent GALC inhibitor (IC50=17nM) that is close to a clinical candidate. The immediate next objective, over the first month of the project, is to demonstrate that the best inhibitors in hand can increase whole cell and lysosomal GALC activity in cells overexpressing GALC with three common disease causing mutations. In parallel, chemistry will use SBDD off the GALC and GALC- SapA dimer crystal structures, to design and synthesize new analogs with even higher affinity to GALC in the endoplasmic reticulum but low affinity to lysosomal GALC. Best new analogs will also be screened for improved pharmacological chaperone activity in cell lines overexpressing mutant GALC. By month 3, we will have also established cell lines from KD patients that can be used to confirm PC activity of the best analogs. The final objective for this proposal is to demonstrate that the best analog, with demonstrated PC activity in both cellular assays and with good CNS and peripheral exposure in mice, is able to increase GALC activity and reduce psychosine levels in liver, and potentially also in the CNS, of mice overexpressing a mutant disease causing GALC. To generate this mouse model we will transfect the mutant GALC into GALC KO mice using a AAV9 vector. At the end of this project, we plan to have identified a potent, patentable GALC pharmacological chaperone that increases GALC activity in patient cells, is orally bioavailable with good peripheral and CNS PK, and increases GALC activity and reduces psychosine levels in a mouse model overexpressing disease causing mutant GALC.

Public Health Relevance

for GALC pharmacological chaperones for the treatment of Krabbe Disease The GALC pharmacological chaperone project is seeking to discover a drug that restores GALC activity to treat Krabbe Disease, a very rare but fatal disease caused by defective GALC. Krabbe patients patients suffer progressive loss of neurological function and eventually die in a couple of years. If successful, this drug will restore the function of GALC sufficiently to prevent these patients from dying and, importantly, have a normal quality of life. There is no currently known reason why this drug should not continue to be effective as long patients remain on the drug.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Small Business Innovation Research Grants (SBIR) - Phase I (R43)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Lee, June
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Vascumab, LLC
United States
Zip Code