Improving the outcome for patients devastated by lysosomal storage diseases began at CCHMC. In 1967 Drs. William F. Schubert and George Hug first showed that enzymes could be given to patients with Pompe disease, a lysosomal storage disease, and potentially improve their lives. Over the subsequent four decades, this pioneering work paved the way for revolutionary treatments to alleviate patients’ suffering and demise. During this period, Dr. Grabowski has led a quest to effectively treat these diseases. His establishment of the CCHMC STAR Lysosomal Disease Center has begun to fulfill this quest to transform basic research, into clinical trials, and into effective/life-saving treatments for affected children and adults.
The lysosomal storage diseases affect 1/7000 newborns and result from the defective or deficient activity of specific enzymes that are present in the subcellular organelles, lysosomes – a major recycling station in all cells of the body. Dr. Grabowski’s team of scientists and clinicians have made major advancements in the understanding of the molecular genetics and the pathobiology, in preclinical studies by creating unique disease models in mice, by conducting clinical trials (currently 12 trials) needed for FDA approval, toward developing innovative clinical treatment studies (currently 21), and by the formation of multidisciplinary/integrated medical teams at CCHMC and UC to treat affected patients and families. As an international leader, CCHMC’s STAR Lysosomal Disease Center now provides life-changing therapy to >240 (at CCHMC) and >1,000 (international) children and adults affected by lysosomal storage diseases. These include transformative therapies for Gaucher, Fabry and Niemann-Pick diseases, the Mucopolysaccharidoses I (MPS I, Hurler syndrome), II (Hunter disease), VI (Maroteaux-Lamy disease), and, of course, Pompe disease -- a long road from Drs. Schubert’s and Hug’s visionary experiments.
But, the quest continues since enzyme treatment, albeit highly effective for visceral disease, does not alter brain involvement. Basic and clinical research by Dr. Grabowski’s team continues to explore innovative research to improve the disease outcomes: 1) With the transplantation team, hematopoietic stem cells, that produce therapeutic enzymes, are being used in MPS I clinical studies to evaluate the utility in combination with enzyme therapy. 2) The enzyme crystal structures elucidated at CCHMC are being harnessed to engineer selected lysosomal enzymes to enhance efficacy through increasing their stability, delivery to specific cells, and catalytic activities. 3) Innovative metabolic pathway manipulations of the lysosomal diseases are being systematically evaluated to treat the CNS lysosomal diseases by either slowing the natural synthesis of the toxic biochemicals or by using small molecules, termed pharmacologic chaperones, to refold the mutant enzymes in situ to improve function. Testing in mouse disease models provides the platform for evaluating superior effectiveness of novel therapies. Such studies have potential application for treatment of common degenerative brain diseases. Clinical trials are already underway with novel treatments for selected lysosomal diseases in the CCHMC STAR Center. This Center provides a unique, integrated environment that blends basic science, pathobiology, and clinical science directed to improving the lives of families afflicted by these devastating inherited diseases, the lysosomal storage diseases.
