Alipogene tiparvovec, an adeno-associated virus encoding the Ser(447)X variant of the human lipoprotein lipase gene for the treatment of patients with lipoprotein lipase deficiency.

Amsterdam Molecular Therapeutics BV is developing alipogene tiparvovec (Glybera, AMT-011, AAV1-LPLS447X), a Ser(447)X variant of the human lipoprotein lipase (LPL) gene (LPLSer(447)X) in an adeno-associated virus vector, as a potential intramuscular gene therapy for the treatment of LPL deficiency. Familial LPL deficiency is a rare, autosomal-recessive disorder of lipoprotein metabolism that is characterized by severe hypertriglyceridemia with episodes of abdominal pain, acute pancreatitis and eruptive cutaneous xanthomatosis. The lack of functional LPL in patients with LPL deficiency causes an accumulation of triglyceride (TG)-rich lipoproteins in the plasma. The LPLSer(447)X variant is associated with decreased levels of plasma TGs and increased HDL cholesterol concentrations compared with wild-type LPL. Preclinical studies evaluating alipogene tiparvovec in a mouse model of LPL deficiency demonstrated a long-term, dose-dependent correction of the lipid abnormalities. The first clinical trials in patients with LPL deficiency appear promising, with a significant decrease in the levels of plasma TGs observed in the first 3 months following the administration of alipogene tiparvovec, and an increase in local LPL activity and protein levels observed after 6 months. In addition, a decrease in pancreatitis frequency was observed during a 3-year follow-up period. At the time of publication, a phase II/III trial in patients with LPL deficiency, being conducted to further support the submission of an MAA to the EMEA for alipogene tiparvovec, was ongoing. The compound is also under investigation for the treatment of type V hyperlipoproteinemia, Syndrome X and non-alcoholic steatohepatitis.