Importance of Research

Gaucher Disease Type 2 and Type 3 are just two of more than 20 lysosomal diseases that affect the brain and lead to death. A cure for one disease may be a cure for all.

Although neuronopathic Gaucher Disease (another name for GD2/3) is itself rare, the combined impact of all the lysosmal diseases that affect the brain represents a significant burden on society. One in every 6000 children is born with a lysosomal disease. The challenge for medical researchers is to understand the mechanism of lysosomal disease and to develop methods for delivering therapeutic molecular agents to the brain. Although each lysosomal disease has a different etiology (cause), it is likely that common pathogenic processes exist. Therefore, advances in understanding one lysosomal disease will likely benefit research of other lysosomal diseases, with possible overlap to non-lysosomal diseases that affect the brain.

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 that cause brain dysfunction in children.

A cure for GD2/3 may lead to a cure for all lysosomal diseases.

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 highlight the five targeted areas for research emphasized by the Children’s Gaucher Research Fund. They indicate direct and overlapping beneficial impact resulting from GD2/3 research.

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 that accumulates 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, the 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 children with Gaucher Disease 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 GD2/3

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. Pharmacological Chaperones for Treatment of GD2/3

Supplementing the deficient enzyme to the brain is limited by the presence of the blood-brain barrier that prevents the intravenously infused lysosomal enzyme from entering the brain. A potential new approach is the use of small molecules that function as “chemical chaperones”. These small molecules typically attach to the active site of the enzyme and prevent it from breaking down its substrate, a glycolipid. However, in low concentrations, these chaperones have the opposite effect. They allow the normal folding of the mutated enzyme and the transfer to its normal location in the cell allowing it to work better at breaking down the accumulating glycolipid storage material. Because of their size and their general similarity to molecules of glucose, chemical chaperones can be taken by mouth and may cross the blood-brain barrier to be widely distributed throughout this organ. For this reason neuronopathic Gaucher Disease, which is always associated with some residual enzyme activity, is particularly well suited for this therapeutic approach.

5. Gene Therapy in The Treatment of GD2/3

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.