Intramuscular Administration of AAV1-Lipoprotein LipaseS447X Lowers Triglycerides in Lipoprotein Lipase–Deficient Patients
Lipoprotein lipase (LPL) deficiency is a monogenetic disorder that underlies persistently elevated triglyceride (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-adeno-associated virus subtype 1(AAV1) vector1,2 was injected in the leg musculature of 8 LPL-deficient patients at a dose of 1×1011 (n=4) or 3×1011 (n=4) 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 higher-dose 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 n.s. 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 demonstrated. Dietary composition and intake remained unaltered during the trial. Muscle function tests and MRI-assessed fat content were not different at the beginning versus the end of the trial.
The present findings show that a single intramuscular administration of AAV1-LPLS447X induces local LPL-expression and a significant albeit transient reduction of fasting TG in LPL-deficient patients, in absence of serious adverse events. The data indicate the need of immunosuppressive compounds combined with a higher vector dose in future trials. Importantly, this study provides the first preliminary evidence that intramuscular AAV1-based gene therapy might be feasible in humans.
Sources of Funding
This work was supported by the Dutch Heart Foundation (2000T039 and D98.011) and ZonMW (43100001).
J.J.M., J.T. are employees of Amsterdam molecular therapeutics, the manufacture of AMT-010. K.A.H., M.R.H., and J.J.K. have received consultancy fees.
Original received June 25, 2008; final version accepted September 8, 2008.
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