Before enzyme replacement therapy became available in the early 1990s, the treatment of type 1 Gaucher disease was merely palliative. Massive splenomegaly, causing severe anaemia and thrombocytopenia or leading to mechanical complaints, sometimes necessitated removal of the spleen. This almost invariably led to complete haematological recovery, especially of platelet counts. Whether splenectomy results in progressive storage of glycolipids at other sites, such as the liver, lung and bone marrow, has been subject to debate. Partial splenectomy has also been attempted to avoid the removal of the spleen as a major storage site, but splenic regrowth and surgical complications abandoned its use. In the majority of cases, splenectomy can be avoided with the institution of enzyme therapy. In rare instances, e.g. the presence of severe fibrosis, enzyme therapy may fail to reduce the size of the spleen, and splenectomy for persistent hypersplenism may still be necessary. For the palliative treatment of bone crises, analgesic drugs and bed rest are usually indicated. Bacterial osteomyelitis, which can be difficult to distinguish from bone crises, requires lengthy treatments with intravenous antibiotics. Orthopaedic procedures are sometimes indicated in cases of avascular necrosis or pathological fractures.
Enzyme replacement therapy
Early studies of enzyme replacement therapy involved either the intravenous infusion of small amounts of purified, unmodified glucocerebrosidase from placental tissue, or the administration of enzyme entrapped in liposomes or erythrocyte ghosts to facilitate macrophage uptake. The results of these studies were disappointing. However, improved targeting of the enzyme to macrophages was achieved (by modification of its glycosylation status and exposure of terminal mannose residues) and higher doses used. The first clinical trials with this new formulation showed a dramatic response in patients to regular intravenous infusion of this modified enzyme . The industrial scale production of placenta-derived glucocerebrosidase and the development of the recombinant enzyme (CeredaseTM and CerezymeTM) made possible a number of further clinical trials, which confirmed the beneficial effects of enzyme therapy. Extremely high costs have made this treatment available only for those living in developed countries, and lower dosing regimens have thus been considered. Initial studies were performed with bi-weekly infusions of 60 U/kg per month. Other investigators advocated that lower dosages at higher frequencies were more efficient and therefore more cost-effective. In addition, home treatment, which further lowers costs, was shown to be feasible and more convenient for the patients . In the Netherlands, a protocol was developed that allowed individualized treatment based upon each patient’s response, potentially providing an improved cost–benefit ratio . In most patients, improvement in cytopenia and decreases in splenic and hepatic size are apparent after 3–12 months of treatment. Improvements in the haemoglobin level and especially in the platelet count are usually faster in splenectomised than in non-splenectomised patients. Liver volumes usually normalize, while some degree of splenic enlargement commonly persists, even after long-term treatment. Retarded growth in children and quality of life improves with treatment. Bone disease tends to respond much less rapidly than organomegaly to enzyme replacement therapy, but this depends largely on the sensitivity of the methods employed to assess the response. Many tools have been applied to assess organ responses to enzyme replacement. Plain X-rays are very insensitive and have no place in the assessment of treatment response; they should only be used in cases of bone complications. Magnetic resonance imaging is probably the best way to obtain information on bone marrow invasion and structure. Several scoring systems have been developed based upon changes in T1- and T2-weighted patterns. Quantitative chemical-shift imaging (QCSI) is the most sensitive method to assess bone marrow infiltration. This technique was further developed at the AMC by Mario Maas and Erik Akkerman and measures the ratio of triglyceride to water in the bone marrow . In Gaucher disease patients, this ratio is greatly reduced, probably due to displacement of normal triglyceride-rich adipocytes in the bone marrow by Gaucher cells. AMC researchers have shown that the fat fraction of the bone marrow at the level of the lumbar spine relates to bone complications. Early reappearance of fatty marrow during enzyme replacement therapy can be detected with this technique. However, QCSI is not widely available and therefore limited in its use.
Despite the enormous success of enzyme therapy, several issues remain unresolved. For example, there is still no consensus about the criteria for initiation of treatment, the best way to monitor effects, and the most appropriate dosing regimen, particularly during the maintenance phase of treatment. The variability in clinical response to treatment and the extremely high costs (around $ 200 000 to 500 000 per patient per year) play an important role in these issues. As commitment to therapy is potentially life-long, the overall cost of care using enzyme therapy can be considerable, and very few reports are available about long-term therapeutic outcomes. Generally, therapeutic goals should be defined with the use of clinically relevant therapeutic endpoints, and protocols should be developed that aim to maintain an optimal effect while decreasing the burden of frequent infusions and the cost of care.
Substrate balance therapy
The accumulation of glucosylceramide is due to an imbalance between the rates of its synthesis and degradation. This concept forms the basis of a recently developed alternative oral therapy, termed substrate balance therapy (also known as substrate reduction therapy). Clearance of the accumulated glycolipid should be possible by attenuating the rate of synthesis of the substrate to a level that is matched to the residual activity of the endogenous, mutant glucosylceramidase. N-butyldeoxynojirimycin (OGT918 or miglustat) is an inhibitor of glucosylceramide synthesis, the first committed step in the biosynthesis of glycolipids. When tested in animal models of glycolipid storage disorders, the compound reduces the amount of storage material and delays the onset and progression of disease manifestations. Its mode of action suggests therapeutic potential in several of these diseases, including those with neurological involvement, since this small molecule is capable of crossing the blood–brain barrier. The first study in patients with a lysosomal storage disorder was initiated in 1998 in 28 type 1 Gaucher disease patients, who received 100 mg OGT918 orally three times daily . The results of this study were promising: improvements occurred for all key clinical features and biochemical abnormalities. Liver and spleen volumes showed a gradual decrease in the first 6 months of treatment, while haematological improvement was slower. The most common adverse event was diarrhoea, which occurred in almost 90% of patients, especially during the first 3 months of treatment. Compared to enzyme therapy, the effects of OGT918 are slower to manifest. This and the disadvantageous side effects have to be balanced against the advantages of oral administration. Enzyme therapy remains the first choice for patients with moderate to severe disease, but mildly affected patients or those with minimal residual disease after treatment with enzyme may prefer this oral alternative. New oral alternatives are currently being developed.