notes+on+Gaucher+disease+treatment

notes on Gaucher disease treatment

enzyme replacement therapy q Additional therapies include substrate reduction therapy and supportive care measures to manage associated conditions.

q Skeletal manifestations are associated with the greatest morbidity and, once present, are among the least responsive to enzyme replacement therapy (ERT).

q recombinant glucocerebrosidases [imiglucerase (Cerezyme) or velaglucerase alfa (VPRIV)] is the preferred treatment for patients with clinically significant manifestations of nonneuronopathic GD (type 1 GD) and is also considered in neuronopathic GD (type 3, but not type 2)

q The advance that was critical to the success of this technique was molecular targeting of the enzyme to tissue macrophages via mannose receptors expressed by these cells. ^ quite impressive actually

q The high cost of ERT (>$400,000 per year for a 70 kg patient who receives 60 U/kg every two weeks [1])

how the drugs are made Preparation — Imiglucerase (Cerezyme) is produced by recombinant DNA technology in a Chinese hamster ovary cell system and velaglucerase alfa (VPRIV) is produced by gene activation technology in a human cell line

q Major problems in the production and supply of imiglucerase (Cerezyme) in 2009 and 2010 led to a six month shortage resulting in interruption of treatment and dose reduction.

q Approximately one-quarter of patients still have thrombocytopenia ... after four to five years of therapy

q In some studies, ERT was found to reverse almost all of the systemic manifestations and appeared to stabilize the neurologic disease (except progressive myoclonic epilepsy) in some patients

side effects of treatment q The side effects are usually related to the IV infusion and include fever, chills, and flu-like symptoms [68]. The mechanism is thought to be immune-related, but acute IgE-mediated reactions are very rare

patients develop antibody against the enzyme q Approximately 13 to 15 percent of treated patients develop IgG antibody to the enzyme [18,68,70,71]. Many of these patients stop producing antibody after two to three years of therapy [70].

substrate reduction therapy q Substrate reduction therapy (SRT) is an option in patients with type 1 GD who are unwilling or unable to receive ERT

side effects q — Side effects of treatment include diarrhea (79 percent of patients in one study), weight loss, tremor, and peripheral neuropathy

q Before ERT was available, splenectomy was performed to improve thrombocytopenia and anemia. ^looks like there were a lot of problems with this approach

q Hematopoietic cell transplantation (HCT) can provide a definitive cure for GD [90-92]. However, this procedure is associated with substantial morbidity and mortality, and therefore has been effectively replaced by ERT in clinical practice [93,94].

Gene therapy option q Future treatment of GD may include gene therapy. In an animal model, gene therapy through retroviral transduction of bone marrow from mice with type 1 GD both prevented the development of GD and corrected an established GD phenotype

chemical chaperone with enzyme enhancement therapy (unsuccessful so far)

q Patients with GD have an increased risk of bleeding because of thrombocytopenia, defective platelet function, and/or coagulation factor abnormalities.

q Patients with severe liver disease and hepatopulmonary syndrome may require liver transplantation

q • The availability and efficacy of ERT has limited the indications for splenectomy and hematopoietic cell transplantation. Splenectomy is indicated if other measures fail to control life-threatening thrombocytopenia. Bone marrow transplantation may be an option in patients known to be at-risk for neuronopathic disease who present early in the disease course