Lafora Disease was originally described over 100 years ago by Dr. Gonzalo Rodriquez-Lafora as a?myoclonus epilepsy with dementia.? A hallmark of the disease identified by Lafora are inclusions in the brain,now known as Lafora bodies (LBs). LD is a rapidly progressing invariably fatal epilepsy. Onset is inadolescence, in apparently healthy teenagers of both sexes, with headaches and insidious decline in cognitivefunction. Myoclonic seizures, staring spells, and generalized convulsions follow and all escalate over time.Initial response to antiepileptic drugs is lost within three years and a constant myoclonus with atypical absencebegins. The young person then develops dementia, often disinhibited, and seizes with increased frequency.The patient becomes bedridden and death comes after a protracted decade of unceasing myoclonus in theform of a particularly massive seizure, status epilepticus, or aspiration pneumonitis. Identification of the genetic basis for LD by members of our group has ushered in a new era in ourunderstanding of the formation of LBs leading to LD. We have made rapid progress, and have nowdemonstrated that eliminating LBs wholly cures LD in mouse models, opening up the real possibility of a cure.To that end, we propose the establishment of the Lafora Epilepsy Cure Initiative (LECI) Center. We haveassembled an international group of pioneers and leaders in the field. We propose to attack the disease frommultiple angles, targeting the full spectrum of molecular and cellular causes of LD and believe that we areuniquely positioned to realize the dream of treating and curing LD patients. The overall focus of this Program Project Grant is to: Diagnose, Treat, and eventually Cure LD. Fourcomplimentary projects and three integrated core facilities form the basis of this proposal. Our projects are:Project #1: Personalized diagnosis - defining how glycogen metabolism and proteostasis impact LD.Project #2: Genome editing, mRNA suppression and glycogen chain termination to inhibit glycogen storage astherapy for LD.Project #3: Suppressing glycogen storage with small molecule inhibitors as a therapeutic approach to LD.Project #4: Defining the therapeutic window for the treatment of LD. LD offers a unique window into both normal neuronal glycogen metabolism and epileptic disease when theprocess is perturbed. While this project aims at defining the basic mechanisms of LD and translating this workinto therapeutics and cures, our work is likely to reveal pathogenic mechanisms common to other epilepsies.The collective effort of the LD experts will both define LD therapy options and generate abundant newcollateral data that will uncover pathways connecting the bioenergetics of the brain with the generation ofseizures and epilepsy. These insights may be particularly informative to the most daunting aspect of epilepsy,namely intractability that afflicts over 30% of patients.
|Effective start/end date||7/1/16 → 6/30/21|
- National Institutes of Health