Gaucher disease (GD) is a rare, inherited metabolic disorder categorized as a lysosomal storage disease. It results from a mutation in the GBA gene, leading to a deficiency in the enzyme glucocerebrosidase. This enzyme normally breaks down a fatty substance called glucocerebroside. Without sufficient activity, glucocerebroside accumulates within the lysosomes of cells, particularly in macrophages, causing damage to organs like the spleen, liver, and bones. Treatment focuses on either replacing the missing enzyme or reducing the amount of the fatty substance produced, managing the harmful buildup.
Enzyme Replacement Therapy
Enzyme Replacement Therapy (ERT) is the standard treatment for most patients with Type 1 Gaucher disease, administered through intravenous infusion. This therapy involves periodically providing a modified, laboratory-produced version of the deficient glucocerebrosidase enzyme. The recombinant enzymes are engineered to target the cells where the fatty material accumulates, primarily the macrophages. They bind to mannose receptors on the macrophage surface, allowing the drug to be taken up and delivered to the lysosomes.
Several FDA-approved drugs are available, including imiglucerase, velaglucerase alfa, and taliglucerase alfa. Patients typically receive an infusion every two weeks, though dosage and frequency are tailored to individual needs. ERT is effective at managing many symptoms of GD, leading to a measurable reduction in the size of the liver and spleen. Furthermore, ERT helps improve blood counts, such as increasing platelet and hemoglobin levels, and works to stabilize progressive bone disease.
Substrate Reduction Therapy
Substrate Reduction Therapy (SRT) offers an alternative approach to managing Gaucher disease, particularly for Type 1 patients who prefer or require an oral medication. Unlike ERT, SRT works by reducing the amount of glucocerebroside substrate the body manufactures. This is achieved by using a drug that inhibits the enzyme glucosylceramide synthase. By partially inhibiting this enzyme, the production of the fatty substance that accumulates in the cells is slowed down, lowering the toxic burden.
Specific medications used in SRT include miglustat and eliglustat. Eligibility is often reserved for patients with Type 1 GD who are not candidates for or do not wish to undergo biweekly intravenous infusions. Eliglustat is often favored over miglustat due to a more favorable side effect profile. Potential side effects include gastrointestinal issues and, in the case of miglustat, peripheral neuropathy.
Addressing Specific Symptoms and Disease Types
While ERT and SRT address the underlying metabolic defect, some symptoms require supportive care. Bone involvement is a common and painful feature, manifesting as bone pain, bone crises, or an increased risk of fractures. Management of skeletal issues includes using pain medications to alleviate discomfort, and sometimes bisphosphonates are administered to increase bone density. In cases of severe joint damage or repeated fractures, orthopedic surgery, such as joint replacement, may be necessary to restore function.
Managing the neurological forms of Gaucher disease (Types 2 and 3) presents a distinct challenge because therapeutic enzymes do not effectively cross the blood-brain barrier. ERT and SRT consequently have limited impact on the progression of central nervous system symptoms. Treatment for these types focuses on supportive and palliative care to improve the patient’s quality of life. This regimen includes using anticonvulsant medications to control seizures and implementing physical therapy to manage motor difficulties.