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Efficacy and long-term safety of alipogene tiparvovec (AAV1-LPLS447X) gene therapy for lipoprotein lipase deficiency: an open-label trial

Gene Therapy volume 20, pages 361–369 (2013)Cite this article

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Abstract

We describe the 2-year follow-up of an open-label trial (CT-AMT-011–01) of AAV1-LPLS447X gene therapy for lipoprotein lipase (LPL) deficiency (LPLD), an orphan disease associated with chylomicronemia, severe hypertriglyceridemia, metabolic complications and potentially life-threatening pancreatitis. The LPLS447X gene variant, in an adeno-associated viral vector of serotype 1 (alipogene tiparvovec), was administered to 14 adult LPLD patients with a prior history of pancreatitis. Primary objectives were to assess the long-term safety of alipogene tiparvovec and achieve a ⩾40% reduction in fasting median plasma triglyceride (TG) at 3–12 weeks compared with baseline. Cohorts 1 (n=2) and 2 (n=4) received 3 × 1011 gc kg−1, and cohort 3 (n=8) received 1 × 1012 gc kg−1. Cohorts 2 and 3 also received immunosuppressants from the time of alipogene tiparvovec administration and continued for 12 weeks. Alipogene tiparvovec was well tolerated, without emerging safety concerns for 2 years. Half of the patients demonstrated a ⩾40% reduction in fasting TG between 3 and 12 weeks. TG subsequently returned to baseline, although sustained LPLS447X expression and long-term changes in TG-rich lipoprotein characteristics were noted independently of the effect on fasting plasma TG.

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Acknowledgements

We thank all participants in the clinical study; staff from the Academic Medical Center (AMC), Amsterdam, the Children's Hospital of Philadelphia; IATEC, TCTC, ECOGENE-21 Clinical Research Center, the Chicoutimi Hospital and Amsterdam Molecular Therapeutics B.V. Medical writing support was provided by Pam Pickering, Conscience Creative LLP, Leatherhead, Surrey, UK. This study was supported by Amsterdam Molecular Therapeutics, The Netherlands. KT is a Université de Montréal post-doctoral and CCRP fellow, and receives support from the Canadian Heart and Stroke Foundation. JM was a Université de Montréal post-doctoral fellow, and received support from the Canadian Institutes for Health Research (CIHR) during the study, and DG was the holder of the Canada Research Chair in preventive genetics and community genomics (www.chairs.gc.ca), which is also supported by a CIHR team grant (no. CTP-82941; http://clinicaltrials.gov/ number: NCT01109498).

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Authors and Affiliations

  1. ECOGENE-21 Clinical Research Center, Chicoutimi Hospital, Chicoutimi, QC, Canada

    D Gaudet, J Méthot, S Déry, D Brisson, C Essiembre, G Tremblay & K Tremblay

  2. Department of Medicine, Université de Montreal, Chicoutimi Hospital, Chicoutimi, QC, Canada

    D Gaudet, J Méthot, D Brisson & K Tremblay

  3. Amsterdam Molecular Therapeutics (AMT) BV, Amsterdam, The Netherlands

    J de Wal, J Twisk, N van den Bulk, V Sier-Ferreira & S van Deventer

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  1. D Gaudet
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Correspondence to D Gaudet.

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Competing interests

The funding body (AMT) was involved in all aspects of the study (study design, data collection and analysis, and data interpretation in collaboration with the CRO and principal investigator. Five authors (J.dW., J.T., S.vD., N.vdB. and V.S-F) are employees of AMT. The remaining authors declare no conflict of interest. The principal investigator of the study (DG) has no financial interest in AMT and made all final editorial decisions regarding the manuscript.

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Gaudet, D., Méthot, J., Déry, S. et al. Efficacy and long-term safety of alipogene tiparvovec (AAV1-LPLS447X) gene therapy for lipoprotein lipase deficiency: an open-label trial. Gene Ther 20, 361–369 (2013). https://doi.org/10.1038/gt.2012.43

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