Scientific Program

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This year’s scientific program brought together speakers and attendees from around the globe to present research on the genetics, pathogenesis and treatment of glycoproteinoses. These talks highlighted a continued shift in the field towards pathogenesis and therapy, and provided a more complete understanding of how different patient mutations affect enzyme function and how these enzyme defects cause pathology in affected tissues. The meeting commenced with an outstanding keynote lecture from Dr. William Sly, who provided a wonderful historical perspective on lysosomes and mannose 6-phosphate dependent targeting of lysosomal enzymes. Dr. Sly also shared his experience with GUSB deficiency and how the study of this disorder has moved from the bench to bedside. Translating basic science into tangible therapies for the glycoproteinoses represents the ultimate goal of researchers in this field. The meeting continued with a series of talks on the regulation of lysosomes and how defects in lysosomal function impact different tissues. Dr. Rosa Puertollano discussed the identification of new genes that promote lysosomal formation and function and how increasing the expression of these important transcription factors can induce cellular clearance of storage material. Dr. Babak Razani then spoke about the factors controlling lysosome formation and how these factors can be protective against atherosclerosis (hardening of arteries) through their ability to boost the turnover capacity of macrophages. Dr. Ana Maria Cuervo gave an excellent overview of another process involving lysosomes called chaperone-mediated autophagy and how this process contributes to the cellular response to different types of stress. Together, these lectures highlight the growing relationship between lysosomes and many vital functions within cells. In the next set of talks, we heard from Dr. Karin Ollinger who talked about lysosomal-mediated cell death and how changes in the permeability or “leakiness” of the lysosomal membrane affect this process. Dr. Steve Walkley shared a stimulating perspective on the neurological dysfunction associated with lysosomal storage disorders and discussed the importance of distinguishing these symptoms as developmental or degenerative. His talk highlighted the complexity of how lysosomal storage affects the function and survival of neurons and the importance of early therapeutic intervention.

This opening session was followed by two talks from speakers whose work has focused on alpha-mannosidosis. Dr. Dag Malm gave an informative overview and summarized the findings of his natural history of this disease. He also gave a promising update on the use of enzyme replacement therapy for this disease. Dr. Pirkko Heikinheimo spoke next about the characterization of several mutations found in alpha-mannosidosis patients and how these different mutations alter the function or properties of the enzyme. Categorizing the different mutations from a biochemical standpoint is important since it helps predict the significance of novel mutations and may also be informative for mutation-specific therapies. Dr. Alessandro D’Azzo spoke next about sialidosis, providing an overview of the disease and discussing the ways in which NEU1 deficiency alters processes in the cell including lysosomal exocytosis. Dr. D’Azzo also shared exciting new findings that relate NEU1 function to other diseases such as Alzheimer’s disease and cancer. The next two talks by Dr. Steven Gray and Dr. Rosanne Taylor provided updates on valuable animal models for AGU and fucosidosis. Dr. Gray shared an overview of the phenotypic characterization of the AGA knockout mouse and discussed the possibility of using gene therapy that directly target the brain to treat this disease. Dr. Taylor spoke about a variety of therapy options for fucosidosis as well as various concepts such as early stage neuroinflammation as mediators of pathogenesis. Her talk also highlighted the importance of large animal models for glycoproteinoses for testing the different therapies.

The following day of talks highlighted progress on mucolipidosis II and III as we heard from speakers who covered topics ranging from the molecular study of specific ML mutations to the pathogenic cascades in affected tissues such as the bone and heart. The session began with a presentation from Dr. Sara Cathey on the natural history of MLII and MLIII. Dr. Cathey discussed features of the cardiac and skeletal disease in ML patients and shared some information regarding the unique clinical features of certain ML genotypes including the K4Q. In the next talk, Dr. Stuart Kornfeld discussed recent work from his lab that has provided new insight into how specific ML mutations affect the function of the phosphotransferase enzyme. This investigation has lead to an important understanding of how the different domains of this enzyme act in a concerted manner to facilitate the addition of mannose 6-phosphate tags on different lysosomal hydrolases. Dr. Kornfeld also shared new insights into the function of the gamma subunit of phosphotransferase and how it associates with the alpha/beta subunits. In the next talk, Dr. Thomas Braulke provided a stimulating talk on ML pathogenesis by discussing findings in the brain and skeletal system of an MLII mouse model. Dr. Braulke discussed how the loss of mannose 6-phosphate biosynthesis affects bone forming (osteoblasts) and bone degrading (osteoclasts) cells differently. He also presented findings on how the sorting of lysosomal enzymes differs in MLII B and T cells and how effects on B cells in particular can result in altered antigen processing and antibody production. Dr. Heather Flanagan-Steet continued this session by sharing new insights into the cartilage and cardiac pathogenesis of MLII gained from the study of a zebrafish model for this disease. She discussed how secreted cathepsin proteases in MLII alter the signals needed for normal cartilage development. Blocking the activity of these cathepsins can reduce the pathogenesis in both the cartilage as well as the heart. The session finished with a talk by Dr. Terra Barnes about the connection between mutations in the enzymes of the Man-6-P biosynthetic pathway and persistent stuttering. Dr. Barnes work highlighted the use of new technology to monitor vocalizations in mice and how this process is affected in the context of MLII. Collectively, these talks reinforce the remarkable advances in ML research that have been made in the last five years.

In the final scientific session of the meeting, we heard several talks about advances in therapy for lysosomal diseases. The first speaker Dr. Kathy Ponder discussed the use of central nervous system-directed gene therapy for MPSVII. AAV gene therapy vectors carrying the normal copy of the GUSB gene were delivered into the spinal fluid of MPSVII dogs and resulted in impressive correction of storage. Dr. Fatima Bosch continued this theme with a talk about the use of gene therapy to treat MPSIII. Her results also support the utility of injecting gene therapy vectors into the spinal fluid as a viable treatment option for LSDs. The next speaker was Dr. Dao Pan who discussed how modifying therapeutic enzymes with different protein domains may help them get across the blood-brain barrier (BBB). The BBB represents a major obstacle to enzyme replacement therapy since enzymes given in the bloodstream are not able to reach the brain. Dr. Ida Annunziata

Written by Richard Steet and Stuart Kornfield.