Project 452819

Our major objective is to develop therapies for Sanfilippo disease, a devastating inherited childhood disorder using a novel type of drugs called nootropic peptides. When used in the form of nose drops, these drugs can be effectively delivered to the brain. In the brain they protect neurons, brain cells involved in memory and learning, restore communication between neurons and treat neuropsychiatric problems and dementia. Sanfilippo disease affects the lysosome, a cellular compartment responsible for degradation and recycling of big biological molecules, glycosaminoglycans. This causes rapid death of neurons, loss of memory and speech. Most of children become demented and die before the adulthood. No effective therapies for Sanfilippo diseases are available yet. Previously we identified defects in the patient's genes, that cause the disease, and generated mice that have the same defects in their genes. We found that these mice have defects in synapses, specialized structures by which neurons communicate with each other. We have also discovered that many proteins in synapses, necessary for transmission of signals between neurons, are reduced or do not have a normal localization. To treat these defects, we propose to use nootropic peptide ACTH(4-7)PGP, clinically approved for therapy of brain stroke. We demonstrated that treatment of Sanfilippo mice with this peptide restores defective exchange of signals between neurons in the hippocampus, a brain region involved in the formation and storage of memory. It also improved memory of these mice, increasing their ability to remember novel objects and their orientation in the maze. We now propose to test if the drug can improve the long-term outcome of the disease and our preliminary results are encouraging. The drug will quickly advance for testing in humans since the nootropic peptides have been approved for clinical and specifically pediatric applications in many countries and no side effects have been reported so far.