Niemann-Pick

Our Research

All of our projects depend on the creation and advancement of direct infusion of drugs and therapies into the brain. We have developed a technique in which lipid-like nanoparticles and other therapeutic agents can be infused directly into brain tumors to give enhanced drug efficacy with reduced side effects. For many years, and continuing still, we have been working on development of direct drug delivery into the brain including cell transplantation, gene transfer and growth factor infusions for Parkinson's disease. Through gene therapy, we are working to eliminate this inherited lipid storage disorder by restoring the activity of the gene responsible for Niemann-Pick disease, acid sphingomyelinase. Prolonged treatment of Parkinson’s disease with L-DOPA may result in a characteristic movement disorder known as dyskinesia. By studying the effects of L-DOPA on the brain, we are developing gene therapy solutions to treat L-DOPA-induced dyskinesias. Using our image-guided delivery techniques AADC activity in the brain, important in the synthesis of several neurotransmitters, may be restored by gene therapy in patients lacking the gene for AADC.
ASM is synthesized in the endoplasmic reticulum (ER) as a 75 KDa N-glycosylated precursor. During transit through the Golgi membrane network, the enzyme precursor that contains high mannose oligosaccharides is directed to lysosomes by attachment of mannose-6-phosphate residues, but a subset undergoes processing into endoglycosidase-H-resistant molecules. These molecules are then diverted into the secretory pathway, ending up in the extracellular space or circulation. Both forms of the enzyme are optimally active at the normal lysosomal pH of 5.5 – 6.0 and are dependent on Zn ions for activity. However, some activity can be detected at neutral pH, suggesting that secreted ASM may be beneficial in the treatment of Niemann-Pick disease.
Rat Brain

Gene therapy for Niemann-Pick Disease

Niemann-Pick Type A disease (NPD-A) is a uniformly lethal lysosomal storage disorder in which infants are unable to process sphingomyelin to any significant extent due to a profound inactivity of the enzyme, acid sphingomyelinase (ASM). These children suffer both systemic manifestations, such as hepato- and spleno-megaly, and serious neuropathology that causes death in the first 3 years of life. A recombinant enzyme therapy is under development to treat the systemic disease in a milder form of Niemann-Pick disease (Type B). However, this enzyme therapy cannot treat the devastating neurological impact of the disease. As a consequence, all children with NPD-A die before their third year of life. We are developing a gene therapy to treat the neurological component of the disease and combine it with systemic enzyme therapy in a comprehensive approach to this terrible disease.

We have found that an adeno-associated viral vector (AAV9) carrying a normal copy of the ASM gene that is defective in NPD-A can be used to restore ASM broadly throughout the brain when it is injected into the spine. The cerebrospinal fluid (CSF) in the spine carries the injected vector into the brain and directs cells to start making ASM. We are working with foundations like WylderNation, the National Niemann-Pick Disease Foundation, the National Institutes of Health, and Genzyme-Sanofi to move this program forward.

For more detailed discussion of the science behind our Niemann-Pick program, please follow the links below to our most relevant published papers:

Salegio, E. A., A. P. Kells, R. M. Richardson, P. Hadaczek, J. Forsayeth, J. Bringas, S. P. Sardi, M. A. Passini, L. S. Shihabuddin, S. H. Cheng, M. S. Fiandaca and K. S. Bankiewicz (2010). "Magnetic resonance imaging-guided delivery of adeno-associated virus type 2 to the primate brain for the treatment of lysosomal storage disorders." Hum Gene Ther 21(9): 1093-1103 PMCID: 2936496

Salegio, E. A., L. Samaranch, R. W. Jenkins, C. J. Clarke, C. Lamarre, J. Beyer, A. P. Kells, J. Bringas, W. S. Sebastian, R. M. Richardson, K. H. Rosenbluth, Y. A. Hannun, K. S. Bankiewicz and J. Forsayeth (2012). "Safety study of adeno-associated virus serotype 2-mediated human Acid sphingomyelinase expression in the nonhuman primate brain." Hum Gene Ther 23(8): 891-902 PMCID: 3413900

Samaranch, L., E. A. Salegio, W. San Sebastian, A. P. Kells, J. R. Bringas, J. Forsayeth and K. S. Bankiewicz (2013). "Strong cortical and spinal cord transduction after AAV7 and AAV9 delivery into the cerebrospinal fluid of nonhuman primates." Hum Gene Ther 24(5): 526-532 PMCID: 3655626