Gaucher disease is a rare inherited disease that is caused by the absence or dysfunction of the lysosomal enzyme glucocerebrosidase (GCase), which normally breaks down the fatty substance glucocerebroside. Due to functional deficits of the enzyme, glucocerebroside accumulates in different tissues and organs such as the lungs, bone marrow, spleen, and liver, and subsequently causes the symptoms of the disease.
While current therapies can help manage most clinical symptoms of Gaucher disease, there is no medication to prevent or cure the disease.
Enzyme replacement therapy
In enzyme replacement therapy, functional GCase is delivered into the bloodstream through a vein to replace the dysfunctional enzyme in the patient’s body. The therapy can improve the clinical signs and symptoms of the disease, such as anemia, visceromegaly (enlargement of certain organs), skeletal disease, and thrombocytopenia (low platelet count). However, the brain damage that’s associated with Gaucher disease type 2 and 3 persists or progresses, despite the therapy, as the replacement enzyme cannot cross the blood-brain barrier.
Substrate reduction therapy
Substrate reduction therapy reduces the production of glucocerebroside — the fatty substance that accumulates in Gaucher disease patients — and the substrate of the defective enzyme. The treatment is taken orally, so is less invasive than enzyme replacement therapy.
Medications for bone pain
Glucocerebroside can accumulate in the cells of bone marrow and restrict blood flow, causing pain and fever. An adequate dose of enzyme replacement therapy usually reduces pain but non-steroidal anti-inflammatory drugs (NSAIDs) can also be used for pain relief. For severe pain, opioids may be prescribed.
Skeletal disease and bone lesions can lead to joint damage and other complications. Orthopedic surgery such as joint replacement can help to improve skeletal function and mobility.
Splenomegaly or an enlargement of the spleen is a common symptom of Gaucher disease. While painless, an enlarged spleen carries the risk of rupture, and may cause anemia (low levels of red blood cells) and thrombocytopenia. Total or partial splenectomy (removal of the spleen) used to be a standard procedure for Gaucher disease patients, but it’s done less often since the introduction of enzyme replacement therapy.
In severe cases, a blood transfusion may be necessary to treat anemia in Gaucher disease patients.
Currently in preclinical trials, gene therapy delivers a healthy copy of the GBA gene, which is mutated in Gaucher disease, into the body. It uses adeno-associated viral vectors, which are non-infectious viruses that are commonly used in gene therapy. Viral vectors carrying the functional GBA gene are injected intravenously and distributed in the bloodstream to deliver the therapy to the cells.
In Gaucher disease, mutations in the GBA gene interfere with proper folding of the GCase enzyme that the gene encodes for. Chaperones are small molecules that can help an enzyme to fold correctly, thus restoring its function. Because chaperones are very small molecules, they can cross the blood-brain barrier and may also be effective in treating neuronopathic Gaucher disease. Chaperone therapy is at the clinical trial stage.
Stem cell transplantation
Early trials of stem cell therapy for Gaucher disease involved the transplantation of hematopoietic stem cells derived from the bone marrow of healthy donors. Transplantation of donor cells requires a severe weakening of the recipient’s immune system to prevent rejection. The procedure also carries the risk of graft-versus-host disease, where the donor’s immune cells from the bone marrow attack the recipient’s tissues. These two factors make hematopoietic stem cell transplantation from donors a very risky procedure, so current research is exploring ways to use patient-derived cells instead.
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