(TG) levels and consequently predisposes patients to potentially life-threatening pancreatitis. In view of the absence of adequate therapy, we developed a gene replacement strategy to lower TG levels in these patients. 1 This report summarizes the data of a first clinical trial (CT-AMT-010-01) in LPL-deficient individuals after intramuscular administration of a viral vector. In a 3-month open-label study, LPLS447X-adenoassociated virus subtype 1 (AAV1) vector1, 2 was injected in the leg musculature of 8 LPL-deficient patients at a dose of 11011 (n4) or 31011 (n4) genome copies per kilogram body weight (40 and 60 injections of 500 microliters, respectively). Primary objectives were to establish efficacy and safety of intramuscular application of this vector. The primary outcome measure was to achieve a reduction in individual median fasting plasma TG to a level equal to or less than 10 mmol/L on top of diet, or to achieve a reduction in median fasting plasma TG equal to or more than 40% on top of diet.

The treatment was well tolerated and no serious adverse events were observed. At 12 weeks, all patients presented with a decrease of median TG levels compared to baseline TG (P 0.007 versus baseline; Figure, a and b), corresponding to a mean TG reduction of 27% and 41% in low-and higherdose group, respectively (Figure, c and d). One patient in the low-dose and 3 patients in the high-dose group reached the primary efficacy end point. Twenty-six to 36 weeks after higher vector dose administration, a significant increase in local LPL protein and activity was detected in muscle homogenates. Follow-up data after 18 to 31 months, however, showed a loss of efficacy (plasma TG ns compared to baseline; Figure, c and d) potentially related to an immune response against AAV1-capsid proteins. 3 Whereas antibody formation against AAV1-capsid proteins was observed, no antibody response against LPL protein could be demon-