Following the trend of past conferences, the 5th Glycoproteinoses Conference, brought basic scientists and clinicians from around the world to Rome, Italy, to share with patients and their families the latest discoveries.This year’s Conference was special in many ways. It was the first to be held in Europe, with the intent of strengthening connections among affected families around the globe, so that everyone will be more informed and supported. This goal was achieved successfully, also because for the first time the scientific program included presentations from patients and family members. This initiative turned out to be particularly inspiring for the scientist, the clinicians, as well as for the patients and their families.
Each scientific session began with introductory lectures on other lysosomal storage diseases (LSDs) and then focused on a specific group of glycoproteinoses. Overall the Conference gave new insights into the current status of the research on glycoproteinoses and the translation of these studies to the clinic; it also emphasized the role of the lysosomal system in basic cellular processes that might parallel clinical conditions seen more frequently in adults .
Dr. Stuart Kornfeld opened the Conference with a beautiful keynote address that provided a historical perspective on glycoproteins and glycoprotein-storage diseases. Dr. Fran Platt then described the involvement of the cytoskeletal network in impaired phagocytosis of macrophages in Niemann-Pick type C disease, broadening our understanding of its pathogenesis. Day 1 continued with two sessions: one dedicated to α-mannosidosis and another focused on mucolipidosis II and III(MLII and MLIII, respectively). Dr. Dag Malm delivered a comprehensive, historical overview of α-mannosidosis. Dr. Sara Cathey then introduced a novel diagnostic method that labels and quantifies oligosaccharides in glycoproteinoses. Dr. Tommaso Beccari spoke about the lysosomal and plasmatic forms of α-mannosidase and summarized results of enzyme-replacement therapy (ERT) in a mouse model of the disease. Dr. Line Borgwardt reported the current status of a clinical trial for Valmanase alfa, the human recombinant α-mannosidase being tested as a potential ERT. Dr. Troy Lund gave an overview of hematopoietic cell transplantation in patients with glycoproteinoses, and the session closed with an interesting report by Dr. Balraj Doray, who described an engineered Glc-NAc-1 phosphotransferase that enhances the secretion of lysosomal enzymes.
Session II was opened by Dr. David Wenger, who presented encouraging results on treating Krabbe disease in the Twicher mouse with bone marrow transplantation and cerebral injection of an adeno-associated virus vector expressing the therapeutic enzyme. Dr. Thomas Braulke described impaired B-cell to plasma-cell differentiation and dysfunctional osteoblasts in an MLII-knockin mouse model. These findings were complemented by Dr. Heather Flanagan-Steet’s presentation on a zebrafish model of MLII, which presents with severe dysmorphic chondrocytes due to upregulation of TGFβ. Dr. Richard Steet then described a novel approach to labeling sialylated plasma membrane proteins in GNPTAB-null cells that uncovered changes in numerous glycoproteins, including multiple receptor tyrosine kinases, suggesting that impaired lysosomal targeting can impact the activity of key growth factor receptors. Dr. Enrico Moro showed results in zebrafish models of Gaucher disease and iduronate sulfatase deficiency, which have enabled the identification of the cellular pathways affected by the enzyme deficiencies. Dr. Allison Bradbury described the well-established center for large animal models of human genetic diseases [at the University of Pennsylvania (Philadelphia, PA)]. She emphasized the importance of using large animal models to test gene therapy and its effectiveness in ameliorating disease progression. Finally, Dr. Lin Liu closed Session II by presenting the BioID method and describing the association of the COPD subunit of the coatomer with the N-terminal portion of GNPTAB, which is required for proper localization to the Golgi.
On Day 2, Session III focused on sialidosis and galactosialidosis. The presentations provided a breadth of information, from studies of disease pathogenesis and links to adult diseases, to the development of new therapies and diagnostic methods. Prof. Generoso Andria opened the Session by highlighting landmark studies that led to the discovery of protective protein/cathepsin A (PPCA) as the primary defect in galactosialidosis. Dr. Alessandra d’Azzo provided an overview of the molecular pathophysiology of sialidosis and its connection to aging. Dr. Noelia Escobedo described defects in lymphatic pathways in the mouse model of sialidosis and their potential implications in neurodegeneration, and Dr. Ida Annunziata described mechanisms regulating lysosomal function. Dr. Vish Koppaka presented encouraging results from preclinical studies of recombinant PPCA therapy for galactosialidosis. Dr. Laura Canafoglia explained the different forms of myoclonus in sialidosis by using electroencephalographic approaches and differential therapy determined by diagnosis. Finally, Dr. Amelia Morrone presented the full array of diagnostic tests used to identify LSDs and their potential pitfalls.
The last day started with an introductory lecture by Prof. Renzo Guerrini who underlined the connection between lysosomal storage disorders and myoclonus epilepsy, a recurrent clinical complication in several glycoproteinoses. Session IV focused on Aspartylglucosaminuria, Fucodisosis and Schindler disease. Dr. Ritva Tikkanen conveyed a promising personalized therapy for AGA based on the use of betaine and an FDA-approved undisclosed substance. Dr. Xin Chen showed promising preclinical results using an adeno-associated virus approach that rescues behavioral phenotypes in a mouse model of AGA. Dr. Torben Lübke then detailed his development of the first mouse model of fucosidosis that faithfully recapitulates the human disease and an attempt to perform ERT with the missing enzyme. Dr. Matthew Ellinwood described the effect of ganglioside synthesis in the context of a Galnac transferase/AGA double-knockout model and its profound impairments in neuronal and glial interactions. Dr. Ida Schwartz presented a complex case report of a patient with MLIII in Brazil. Finally, Dr. Cinzia Bellettato, on behalf of Dr. Maurizio Scarpa, discussed the establishment of MetabERN, a unified registry for the European Reference Network.
Although reports about recent basic, translational, and clinical discoveries were fascinating and full of promise, the most invigorating and moving talks were given by patients and their families. Dr. Malm, Jenny Noble, Paul Wagner, Daniel and Faith Peach, and Jean and Paul Leonard talked about living with these diseases, their daily struggles, their faith in the scientists, and their hope for future treatments. The Conference closed with the motto, “Embrace and Endure,” and an arrivederci until we come together again in Atlanta, Georgia, for the 6th Glycoproteinosis Conference in 2019.