Lipoprotein lipase deficiency - alipogene tiparvovec
Familial lipoprotein lipase deficiency (LLD) is an inherited condition in which lipoproteins - the substances that transport fats from the intestines to the bloodstream - cannot be broken down properly. LLD causes a build-up of fatty substances in the bloodstream, and symptoms such as pancreatitis, abdominal pain, spleen and liver enlargement and skin lesions result. There is no known treatment, other than to avoid dietary fat.
Familial lipoprotein lipase deficiency (LLD) is an inherited condition in which lipoproteins - the substances that transport fats from the intestines to the bloodstream - cannot be broken down properly. LLD causes a build-up of fatty substances in the bloodstream, and symptoms such as pancreatitis, abdominal pain, spleen and liver enlargement and skin lesions result. There is no known treatment, other than to avoid dietary fat.
A potential treatment based on gene therapy is being developed by Amsterdam Molecular Therapeutics. Alipogene tiparvovec is an adeno-associated virus-based gene therapy that expresses the human LPL gene.1 It is transported into the cell nucleus, and causes viable LPL protein to be produced. The treatment has been given orphan drug status in both Europe and the US. Initial studies on tissue taken from skeletal muscle biopsies from patients with the condition showed that it could indeed induce LPL production.
In a Phase I/II clinical trial, a group of eight LPL deficient patients with recurrent pancreatitis and hypertriglyceridaemia were given 1 x 1011 or 3 x 1011 genome copies/kg.2 PCR analysis of urine, saliva, serum, semen and muscle biopsies showed that the agent had been efficiently distributed around the body. Only small amounts of the vector DNA were detected, no acute toxicity was observed, and there was no T cell response to the agent. Two patients given the lower dose had long term expression of the therapeutic gene, and a reduction in triglyceride levels associated with active LPL being expressed in the injected muscle 26 to 32 weeks after administration.
In a three month open label study, similar doses were given to a group of patients to see if median fasting plasma triglycerides could be reduced on top of diet. It was well tolerated, and no serious adverse events were observed.3 After 12 weeks, all patients had a decrease in median triglyceride levels compared with baseline. At 26 to 36 weeks after administration of the higher dose, a significant increase in local LPL protein and activity was detected in the muscle. Efficacy was lost in follow up after 18 to 31 months. However, there was also evidence of a potential immune response, so future trials will have to include an immunosuppressant in the dosing regime.