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"Medical research funded by the Children's Gaucher Disease Research Fund will provide discoveries benefiting all lysosomal storage diseases, many inherited metabolic diseases, and especially diseases which cause brain dysfunction in children."
 Gaucher disease has served as a prototype disorder for understanding the molecular basis, pathophysiology and treatment of a class of inherited metabolic diseases, termed lysosomal storage diseases. The Children's Gaucher Research Fund hopes to continue this cutting-edge position for Gaucher disease research. Previous and future studies of Gaucher disease have had and will have continued impact on a broad range of fields including human genetics, complex lipid metabolism, novel therapeutic approaches and brain function. Gaucher disease is a multi-system disorder, that includes the brain, and research related to this disease will have overlapping benefits for a variety of childhood and adult disorders that involve these critical organs and metabolic processes. Such disorders include all of the lysosomal storage diseases, many of the inherited metabolic diseases, and human growth and development, particularly of the brain. These studies will also address much broader questions related to ongoing brain development and maturation throughout childhood and adulthood, and the role played by glycosphingolipids in these critical brain processes. Already studies of Gaucher disease and its neuronopathic variants have provided broad and important insights into the requirements of the developing brain for a large class of compounds termed glycosphingolipids. Major advances have been in elucidating the role of these complex fats in nerve conduction and cognitive abilities. Consequently, many of the advances made in the treatment of the central nervous system involvement in types 2 and 3 Gaucher disease will have clear and direct applications to fields ranging from brain development to dementing diseases.
The following paragraphs will highlight the five targeted areas for research emphasized by the Children's Gaucher Research Fund, and indicate direct and overlapping beneficial impact resulting from these targeted areas:
1. Understanding the Disease Process-How It Affects the Brain:
Currently, normal human brain development is poorly understood, but it is clear that complex glycosphingolipid metabolism is intimately involved with this process. The lipid in Gaucher disease, glucosylceramide is a major and key component to the development of more complex lipids that are central to normal brain development. By focusing research on the effects of Gaucher disease in the brain, their critical roles of glucosylceramide and its derivatives will be understood, and the roles in normal developmental processes will be elucidated. There is no question that understanding the role of glucosylceramide in Gaucher disease children will have far reaching ramifications in the understanding of such diverse diseases as cerebral palsy and the later onset of dementia.
2. Enzyme Replacement-Targeting the Central Nervous System:
Gaucher disease was the first lysosomal disease to be successfully treated with a protein replacement product, modified glucocerebrosidase. This success demonstrated the capability of directly targeting enzyme to specific tissues of involvement, particularly the macrophage. Already, this approach has had far- reaching impact in the development of other enzyme replacement strategies for other inherited disorders such as Fabry disease, Mucopolysaccharidosis type I and others. However, targeting enzyme to the brain substance in postnatal life has proved more challenging. Cracking the code for delivery of enzyme to the brain will have major implications for the development of protein therapies for a variety of childhood and adult diseases. Understanding such targeting signals for delivery of proteins across the blood brain barrier is central to modern developmental and therapeutic biology. Success in this objective would have major impact in diverse fields of medicine from brain function, to cancer, to development, and to the treatment of an array of childhood and adult onset brain degenerative diseases.
3. Substrate Depletion/Restriction for Treatment of Type 2 and 3 Gaucher Disease:
Much of the therapeutic focus for Gaucher disease has been on enzyme or gene replacement in an effort to eliminate the stored material in tissues of affected individuals. Another approach, that has received less attention, is the depletion or reduction of the amount of material, glucosylceramide that can be made. The development of small therapeutic chemical inhibitors of the glucosylceramide production could have impact on the development of the central nervous system disease in Gaucher disease. Such a new approach to therapy would again have broad reaching consequences for other lysosomal disease, but also in the areas of cancer and infectious disease, in particular. In cancer, glycosphingolipids change during progression to metastasis, a major issue in cancer biology. Inhibitors of glucosylceramide synthesis have been useful in treating AIDS, a very unexpected outcome.
4. Bone Marrow Transplant and Treatment of Type 2 and 3 Gaucher Disease:
The bone marrow is a multipotent source of cells that are used throughout the body. Successful application of bone marrow transplantation technology to Gaucher disease types 2 or 3 would have as a derivative benefit the ability to replace diseased cells in the brain with bone marrow-derived cells from normal donors. These replaced cells could then correct the defective or altered functions of these brain cells and reestablish more normal brain function. In Gaucher disease these cells would include a variety of cells in the brain that could then eliminate the stored toxic compounds. If successful, such approaches could have broad applicability to the treatment of more generalized dysfunctions of the brain that require specific bone marrow derived cellular types for correction. These may vary from autism, brain injury, and cellular re-growth in the brain, and dementing diseases of adults. Furthermore, physicians have known for many years about various treatment- related complications involving the heart, lungs, and/or liver. Some of these complications are both more frequent, and more severe in children with inborn errors of metabolism, such as Gaucher disease. Discovering safer ways to perform stem cell transplants in children with Gaucher disease will benefit transplant patients with leukemia, aplastic anemia, sickle cell anemia, and immunodeficiency conditions.
5. Gene Therapy in The Treatment of Type 2 and 3 Gaucher Disease:
In addition to being a prototype for enzyme therapy, Gaucher disease has been a major target for development of gene therapy. The central nervous system involvement again has been a particularly difficult target. Development of non-pathogenic viruses and/or alternative approaches for the specific delivery of genes to the brain has vast implications across all of medicine for the treatment of disorders that involve brain function and degenerative diseases. Thus, strategies developed for gene therapy of the brain involvement in Gaucher disease would be applicable across a wide variety of diseases and variants in the human condition.
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