Understanding The Gaucher Disease Process - How It Affects The Brain
With the possible exception of Krabbe disease, the mechanism by which the deficiency of an enzyme causes brain dysfunction is not known. Cell damage does not depend solely on the accumulation of storage material inside the cell. For example, in type II and III Gaucher disease, there is no visible storage in neurons. Yet, many of these neurons do not function normally and even die with time. There is some evidence that neuronal damage and dysfunction is a result of the accumulation of psychosine. Other offending molecules may exist. Blocking these toxic effects may be useful even in the absence of correction of the metabolic defect with enzyme replacement therapy. Therefore, understanding the mechanism of Gaucher disease is important because it may enable the design of new interventions to block damage to the cells. We hope that such new treatments will consist of small molecules that can cross the blood-brain barrier and enter the brain. The approach that will be developed for elucidating the pathogenesis of neuronopathic Gaucher disease is likely to be useful in developing treatments for other lysosomal storage disorders.

Rapheal Schiffmann M.D.
National Institutes of Health
Bethesda, Maryland

Enzyme Replacement - Targeting The Central Nervous System
The great benefit provided to patients with type 1 (non-neuronopathic) Gaucher disease through enzyme replacement is well establshed.  Somewhat less consistent responses have occurred in patients with type 3 (chronic neuronopathic) Gaucher disease.  A lack of benefit is especially apparent in type 3 patients with myoclonic seizures.   Patients with type 2 (acute neuronopathic) Gaucher disease have had reductions of spleen and liver enlargment following intravenously injected glucocerebrosidase, but no definitive improvement has occurred with regard to the pathologic involvement of the brain.  The primary reason for this lack of benefit is the inability of the enzyme to reach the brain because of the blood-brain barrier. Procedures are now under consideration for the direct infusion of glucocerebrosidase into the brain.  Investigations in experimental animals indicate that this approach may be useful and that it should be explored in appropriate additional studies, and hopefully eventually in patients with type 2 and type 3 Gaucher disease

Roscoe Brady M.D.
National Institutes of Health
Bethesda, Maryland

Substrate Depletion/Restriction In Treatment of Type 2
and 3 Gaucher Disease
The approaches to therapy for Gaucher disease have focused on supplying enzyme to the major involved cells. This enzyme would correct the inherited deficiency in the affected patient. This replenishment strategy includes direct enzyme replacement or various gene therapy approaches to supply sufficient enzyme to digest the accumulated glucosylceramide and other potentially toxic substrates. The goal is to normalize the movement of these compounds through the lysosome.

Almost two decades ago Norman Radin proposed an alternative or supplementary strategy to enzyme replenishment by focusing attention on decreasing the amount of substrate that enters the major cells involved by the diseases. This concept is based on the presence of a small, but not zero, amount of glucocerebrosidase activity within cells of patients affected with Gaucher disease. This level of so-called residual activity may vary in different patients due to different types of mutations or other factors.  Rough calculations suggest that >90% of the body's glucosylceramide is metabolized even in patients with mutations that lead to little residual enzyme activity. The well founded assumption is that the amount of residual activity present in cells is greater in type 1 than in type 3 and type 2. This means that the rate of glucosylceramide accumulation in type 3 and 2 is greater than in type 1, and that in type 1 Gaucher disease, patients have sufficient residual activity to avoid primary involvement of the brain. Thus, the accumulation rate of glucosylceramide is dependent upon both its rate of synthesis and its rate degradation. By decreasing the synthetic rate, potentially, the residual degradative activity could eliminate a greater percent of the substrates, and slow or stop the accumulation and the consequent disease manifestations. The ability to decrease the brain synthesis rate of glucosylceramide might decrease the rate of accumulation since the residual enzyme could digest a greater percentage of the fat entering the lysosome.

If this accumulation rate was decreased below the level that causes disease manifestations, it could represent an effective therapy for the neuronopathic variants. Recent studies in mouse models of Sandhoff disease provide proof of principle for this approach when substrate synthesis is blocked completely by genetic methods.

What are the current data from mouse models or humans with Gaucher disease and how might this be done in humans?  Currently, there are no results from animal model studies of Gaucher disease that indicate that this approach will be useful for treatment, but this is being investigated. Using a drug, N-butyl-deoxynojirimycin (NBdNM), which inhibits glucosylceramide synthetase (GCStase), the rate of synthesis of this lipid can be decreased in brains of mice.  It should be mentioned that NBdNM is a poor inhibitor of GCStase and much more potent and specific inhibitors have been developed.  NBdNM has been used in humans as a potential adjunctive therapy for HIV/AIDS to inhibit the synthesis of specific compounds needed for propagation of the HIV virus. A major side effect that limited the usefulness of NBdNM in HIV/AIDS was diarrhea.  Currently, a European clinical trial is ongoing to test the potential use of NBdNM in the treatment of Gaucher disease.  But no data, side effect reports, or other information is available at this time.

For efficacy in Gaucher disease types 2 and 3, a significant decrease in the accumulation of the toxic lipids in the brain will be needed before the development of irreversible disease manifestations.

Gregory Grabowski M.D.
University of Cincinnati
Cincinnati, Ohio

Bone Marrow Transplant In Treatment of Type 2 and  3 Gaucher Disease
During the past two decades, bone marrow transplant has been either the only or the most effective treatment for selected metabolic diseases.  In the metabolic disorder, Gaucher disease, significant attention has been focused on enzyme replacement therapy.  While enzyme replacement therapy has revolutionized, in many ways, the treatment of patients with Gaucher disease, there are limits to its benefits.  For some children with Gaucher disease, bone marrow transplant becomes the therapy of choice after years of enzyme treatment. 

To improve therapies for children and adults with Gaucher disease, research is needed.  In the area of bone marrow transplant, research projects that address all levels of the problem are required.  For example, we need to understand more about the Gaucher disease process and the ways in which various organs such as the lungs, bones, and brain are harmed.  By improving our understanding of Gaucher disease, we will be able to develop new and more effective therapies for Gaucher disease.  In addition, we must continue to improve existing therapies such as bone marrow transplant.  It is well recognized that the effectiveness of bone marrow transplant must be balanced against its risks.

For many years, doctors have known about various transplant-related complications that can injure the heart, lungs, liver, and/or brain.  Some of these complications are both more severe and more frequent in children with metabolic disorders such as Gaucher disease.  One of the scientific goals of the Children's Gaucher Research Fund is to advance the field of transplantation by decreasing or avoiding these adverse effects while maximizing the benefits of the transplant.  These benefits will be extended to all children who must undergo transplant for fatal conditions such as metabolic disease, cancer, leukemia, aplastic anemia, sickle cell disease, or immune deficiency.

Olle Ringden. M.D., Ph.D	Charlie Peters M.D.
Karolinska Institute	University Of Minnesota
Stockholm, Sweden	Minneapolis, Minnesota

Gene Therapy In Treatment of Type 2 and 3 Gaucher Disease
Gene Therapy is a potential cure for Gaucher disease.  Gene Therapy involves:
- Injecting the patient with a substance called G-CSF to stimulate release of stem cells from the bone marrow into the blood.
- Collecting the stem cells from the patient's blood.
- Inserting a healthy copy of the GC gene into the autologous (patients own) stem cells.
- Returning the corrected stem cells to the patient, where they take up residence in the bone marrow and produce cells such as macrophages.

Successful gene therapy for Gaucher disease requires that the therapeutic GC gene be transferred effectively into stem cells that, when returned to the body, will produce "corrected" macrophages.  In other words, the transferred gene must work correctly and produce sufficient amounts of functional enzyme.  The most efficient way to transfer and express genes in human cells is through the use of viruses that act as gene carriers.  The viruses are modified so that they can still infect human cells but can no longer multiply and cause disease.  Modified viruses used for this purpose are called vectors.  Although promising, more research and clinical trials are necessary in determining the efficacy of gene therapy in the treatment of Type 2 and 3 Gaucher disease.