GALC Pharmacological Chaperone Drugs forKrabbe Disease

Project Summary We propose to deliver a GALC pharmacological chaperone to restore enzyme activity for the treatment of Krabbe Disease caused by GALC deficiencyKrabbe disease is a rarefatal degenerative disorder which destroys myelin sheath of the nervous systemMost of the casesoccur in infants beforemonths of age and usually death occurs by ageyearsThe later onset patients usually die betweenandyears of ageHematopoietic stem cell transplantHSCTwhen done prior to onset of symptoms extend survival and attenuate neurodevelopmental symptoms in the majority of patientsHoweverthere are several concerns with HSCTit is an inherently risky procedure withof patients dying from complicationspatients are on lifelong immunosuppressive therapycognitive development while normal is slowerworse patients suffer a progressive often severe motor deteriorationand some progress and dieGene therapy has had some success in mice and dog models of KDextending life modestlybut is unlikely to cure the diseaseThere is substantial need for a safeoralCNS penetrant small molecule drug that can be used aloneor in conjunction with HSCT or any potential gene therapiesthat not only prevent patients from dying but enables them to have a normal quality of lifeOur objective is an orally activesafeCNS penetrant small molecule pharmacological chaperone of mutated GALC that restores its activity in the lysosome to greater thanthat of wild type enzymeWe have already identified a potent GALC inhibitorICnMthat is close to a clinical candidateThe immediate next objectiveover the first month of the projectis 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 mutationsIn parallelchemistry will use SBDD off the GALC and GALCSapA dimer crystal structuresto design and synthesize new analogs with even higher affinity to GALC in the endoplasmic reticulum but low affinity to lysosomal GALCBest new analogs will also be screened for improved pharmacological chaperone activity in cell lines overexpressing mutant GALCBy monthwe will have also established cell lines from KD patients that can be used to confirm PC activity of the best analogsThe final objective for this proposal is to demonstrate that the best analogwith demonstrated PC activity in both cellular assays and with good CNS and peripheral exposure in miceis able to increase GALC activity and reduce psychosine levels in liverand potentially also in the CNSof mice overexpressing a mutant disease causing GALCTo generate this mouse model we will transfect the mutant GALC into GALC KO mice using a AAVvectorAt the end of this projectwe plan to have identified a potentpatentable GALC pharmacological chaperone that increases GALC activity in patient cellsis orally bioavailable with good peripheral and CNS PKand increases GALC activity and reduces psychosine levels in a mouse model overexpressing disease causing mutant GALC Project Narrative 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 Diseasea very rare but fatal disease caused by defective GALCKrabbe patients patients suffer progressive loss of neurological function and eventually die in a couple of yearsIf successfulthis drug will restore the function of GALC sufficiently to prevent these patients from dying andimportantlyhave a normal quality of lifeThere is no currently known reason why this drug should not continue to be effective as long patients remain on the drug