Efficacy and long-term safety of alipogene tiparvovec (AAV1-LPLS447X) gene therapy for lipoprotein lipase deficiency: an open-label trial
Open accessAbstract
We describe the 2-year follow-up of an open-label trial (CT-AMT-011-01) of AAV1-LPL(S447X) gene therapy for lipoprotein lipase (LPL) deficiency (LPLD), an orphan disease associated with chylomicronemia, severe hypertriglyceridemia, metabolic complications and potentially life-threatening pancreatitis. The LPL(S447X) 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 × 10(11) gc kg(-1), and cohort 3 (n=8) received 1 × 10(12) 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 LPL(S447X) expression and long-term changes in TG-rich lipoprotein characteristics were noted independently of the effect on fasting plasma TG.
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A triple regimen of ciclosporin, mycophenolate and corticosteroids was used in patients receiving high vector doses, and initially transient T cell activation was still seen in 64% of patients.
“A triple regimen of ciclosporin, mycophenolate and corticosteroids was used in patients receiving high vector doses (Gaudet et al., 2012), an established immunosuppression regimen used to prevent solid organ transplant rejection (Nelson et al., 2022). Initially, transient T cell activation was still seen in 64 % of patients.”
From Gene Therapy-Associated Uveitis (GTAU): Understanding and mitigating the adverse immune response in retinal gene therapy (2025) · cites this paper as Gaudet et al., 2012
Study Design (page not provided) reports ciclosporin and mycophenolate for cohorts 2 and 3, including the high-dose cohort, but does not include corticosteroids in the regimen; it also says a lower-dose cohort received immunosuppression. Results—Host immune response (page not provided) reports a moderate, non-persistent T-cell response in 9 of 14 subjects (64%). (LLM, conf=0.91)
Experimental — accuracy not yet measuredGlybera, an AAV1-based gene therapy for lipoprotein lipase deficiency, was approved in Europe in 2012.
“The fi rst approved AAV gene therapy drug was Glybera for treating lipoprotein lipase de fi ciency using AAV1 vector (7), which was approved in Europe in 2012.”
From A versatile toolkit for overcoming AAV immunity (2022) · cites this paper as [7]
In all Glybera patients, anti-AAV antibodies were not affected by immunosuppressants, and T cell response was observed in most patients.
“In all patients, anti-AAV antibodies were not affected by immunosuppressants, and T cell response was observed in most patients (7).”
From A versatile toolkit for overcoming AAV immunity (2022) · cites this paper as [7]
After alipogene tiparvovec, TG drifted back to baseline levels within 6 months, although a few exceptional cases experienced sustained benefits.
“Unfortunately, TG drifted back to baseline levels within 6 months, although a few exceptional cases experienced sustained benefits.84–87”
From Clinical review on triglycerides (2020) · cites this paper as [84]
Spinal anaesthesia was needed for intramuscular injections of the adeno-associated virus subtype 1 vector carrying hyperfunctional LPL p.S447X; TG normalized within 12 weeks.
“Spinal anaesthesia was needed for intramuscular injections of the adeno-associated virus subtype 1 vector carrying hyperfunctional LPL p.S447X; TG normalized within 12 weeks.84–86”
From Clinical review on triglycerides (2020) · cites this paper as [84]
Familial combined hyperlipidaemia has no monogenic component and is not linked to a single genetic cause, but its phenotype is high LDL cholesterol and/or high triglycerides.
“FCH has no monogenic component and is not linked to a single genetic cause, but the phenotype is high LDL-C and/or high TGs [358,359].”
From 2019 ESC/EAS guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk (2019) · cites this paper as [359]
Gene therapy for LPL deficiency has been developed and tested in clinical trials, and alipogene tiparvovec was approved by the EMA in 2013.
“Recently, gene therapy for LPL deficiency has been developed and tested in clinical trials 305 and the alipogene tiparvovec was approved by the EMA in 2013.”
From 2016 ESC/EAS Guidelines for the Management of Dyslipidaemias (2016) · cites this paper as [305]
In the initial Glybera regimen, 9/14 subjects showed humoral and cellular response against rAAV1.
“In the initial regimen, 9/14 subjects showed humoral and cellular response against rAAV1 (77).”
From Immunomodulation in Administration of RAAV: Preclinical and Clinical Adjuvant Pharmacotherapies (2021) · cites this paper as [77]
Acute pancreatitis can lead to chronic pancreatitis, signs of exocrine or endocrine pancreatic insufficiency, including pancreatic (type 3c) diabetes, and can be fatal.
“Acute pancreatitis can lead to chronic pancreatitis, 10,11 signs of exocrine or endocrine pancreatic insufficiency, including pancreatic (type 3c) diabetes, 12 and can be fatal.”
From Familial chylomicronemia syndrome: Bringing to life dietary recommendations throughout the life span (2018) · cites this paper as [12]
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- [34]Gaudet D Methot J Gagné C Déry S Tremblay K De Wal J Modifications in Triglyceride-Rich Lipoprotein Metabolism Induced by Alipogene Tiparvovec (AAV1-LPLS447X Gene Therapy) Correlate With Clinical Benefit in Patients with Lipoprotein Lipase Deficiency (LPLD) Circulation suppl Proceedings of the American Heart Association November 2010 Abstract 21355
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- Authors
- Gaudet, D., Méthot, J., Déry, S., Brisson, D., Essiembre, C., Tremblay, G., Tremblay, K., de Wal, J., Twisk, J., van den Bulk, N., Sier-Ferreira, V, & van Deventer, S.
- Affiliations
- Hôpital de Chicoutimi (CA)
- Corresponding author
- Gaudet, D
- Venue
- Gene Therapy
- Published
- 2012-06-21
- Volume
- 20
- Issue
- 4
- Pages
- 361-369
- ISSN
- 0969-7128 (ISSN-L)
- 1476-5462
- PMC
- PMC4956470
- OpenAlex
- W2067074806
- Cited by
- 404
- References
- 40
- Citations by year
- 2026: 12 · 2025: 17 · 2024: 17 · 2023: 25 · 2022: 23 · 2021: 22 · 2020: 32 · 2019: 33 · 2018: 31 · 2017: 38 · 2016: 33 · 2015: 50 · 2014: 40 · 2013: 25 · 2012: 4
- FWCI
- 24.49
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Gene Therapy (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Heart and Stroke Foundation of Canada
- Canada Research Chairs
- Health Canada
- Canadian Institutes of Health Research (82941_1)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
- Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
- Keywords
- lipoprotein lipase deficiency, long-term safety, hypertriglyceridemia, triglyceride-rich lipoproteins, immunosuppression, pancreatitis, chylomicronemia
- MeSH terms
- Dependovirus, Adult, Drug Tolerance, Fasting, Female, Humans, Immunosuppressive Agents, Lipoprotein Lipase, Hyperlipoproteinemia Type I, Male, Middle Aged, Pancreatitis, Prospective Studies, Triglycerides, Genetic Therapy, Treatment Outcome
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