Review of the clinical development of alipogene tiparvovec gene therapy for lipoprotein lipase deficiency
Introduction
Lipoprotein lipase deficiency (LPLD) is characterized by the inability of affected individuals to produce functionally active lipoprotein lipase (LPL). LPL is mainly produced in skeletal muscle, fat tissue, and heart muscle [1] and has multiple key functions, among which is the catabolism of triglyceride (TG)-rich lipoproteins, chylomicrons (CM) and very low-density lipoproteins (VLDL). Off-loading TG from CM (and VLDL) normally protects against excessive post-prandial rise in chylomicron mass and TG. In LPLD, LPL is dysfunctional and more than 12 h after meals hyperTG and chylomicronaemia are still present and visible as lipemia.
LPLD is an autosomal recessive disorder caused by loss-of-function mutations in the LPL gene. The LPL gene is located on chromosome 8p22 and comprises 10 exons. To date, more than 70 LPL gene mutations have been described, most of them associated with loss of catalytic function [2]. Patients are either homozygous for such mutations or compound heterozygous. In a few areas in the world, such as in South Africa and Eastern Quebec, the disease is more common, because of a “founder” effect, with the majority of diagnosed patients having the same few mutations [3]. The prevalence outside of founder populations is estimated to be 1–2 in a million of the population, and hence it is an orphan disease.
LPLD is the most common Mendelean cause of (hyper)chylomicronaemia. Other causes include Apolipoprotein CII (APOC2) or Glycosylphosphatidylinositol Anchored High Density Lipoprotein Binding Protein 1 (GPIHBP1) deficiency [4]. Some cases due to circulating anti-LPL antibodies have been reported [5]. As phenotypic presentation of LPLD may overlap with that of other causes of chylomicronaemia genetic diagnosis in this day and age may be the preferred way to establish the diagnosis definitively.
In LPLD, extreme concentrations of circulating large chylomicrons (chylomicronaemia) are present, which are thought to be responsible for causing most of the clinical manifestations. LPLD may present during infancy or childhood with (repeated) severe abdominal pain episodes or failure to thrive [1], [6], [7]. On physical examination, eruptive xanthomas, lipaemia retinalis, and hepatosplenomegaly may be detected. The most severe manifestation is acute pancreatitis, which can be lethal. Diabetes is another complication seen frequently in LPLD, and may be due to recurrent pancreatitis, ultimately resulting in endocrine as well as exocrine pancreatic insufficiency [1], [8], [9] and/or by impaired ‘energy metabolism and distribution’ related to broad LPL dysfunction in various tissues. Premature atherosclerosis can occur [10].
Fasting lactescent plasma often is the trigger to further work up and ultimate diagnosis. The severity of the symptoms being roughly proportional to level of chylomicronaemia, usually measured as whole plasma TG; TG concentrations above 10 mmol/L have been suggested to be critical levels [1] below which the risk of pancreatitis would be substantially reduced.
Currently, no drug therapy for LPLD is available, and patients are managed by a severely fat-restricted diet, which however does not fully eliminate the risk of pancreatitis or disease progression. Alipogene tiparvovec is being developed to control the symptoms and prevent complications of LPLD.
Section snippets
Lipoprotein lipase deficiency (LPLD) and pancreatitis
Acute pancreatitis is a heterogeneous inflammatory condition, which leads to significant morbidity or mortality in 20–30% of patients [11]. There are several genes associated with susceptibility to acute pancreatitis, which include the cationic trypsinogen (PRSS1 and PRSS2), chymotrypsinogen C (CTRC), pancreatic secretory trypsin inhibitor (SPINK1), cystic fibrosis transmembrane conductance regulator (CFTR) and calcium-sensin receptor (CASR) [12], [13], [14], [15]. Although not being the only
Conventional clinical management of LPLD
Clinical management of LPLD patients currently consists of severe reduction in dietary fat to less than 20% of caloric intake and the use of medium-chain TG. It is almost impossible to always, life-long, comply with such a dietary regimen. As shown in Fig. 2, even when LPLD patients are compliant to the diet and are tightly followed in a lipid clinic by a dietician and a medical team, TG do not decrease below the threshold of increased pancreatitis risk. In the prospective observational studies
Alipogene tiparvovec
Alipogene tiparvovec [Glybera®; AMT-011; AAV1-LPLS447X] contains the human LPL gene variant LPLS447X (the active component). The LPLS447X ‘gain-of-function’ variant is found in 20% of Caucasians and is associated with enhanced removal of proatherogenic apoB100-containing particles, including LDL-cholesterol [20], lower plasma TG levels, higher HDL cholesterol concentrations, and lower rates of cardiovascular disease, when compared to the general population [20], [21]. In addition, it may have
Alipogene tiparvovec is provided as a solution for intramuscular injection
AAV1-LPLS447X, initially designated AMT-010, was previously produced in a mammalian cell system which was not appropriate for large-scale production. Hence, this method has been superseded by a more efficient production system to produce alipogene tiparvovec (AMT-011).
Preclinical studies
Proof of principle of the efficacy of gene therapy with AAV1-LPLS447X was obtained in LPL deficient mice and cats. Intramuscular (IM) delivery of AMT-010 or AMT-011 to LPL deficient animals resulted in >95% reduction in plasma TG. In mice, the effect was long-term, lasting over a year, and was dose-dependent, with full correction of lipemia and reduction of plasma TG to near-normal levels at a dose of 1 × 1013 genome copies (gc)/kg. The safety studies of AMT-010 and AMT-011 showed both products
Clinical development program
LPLD is a very rare condition (prevalence worldwide 1–2 per million). As with most very rare conditions, the presentation and phenotypes, natural history and evolution, morbidity and mortality, and effects of therapies and interventions are incompletely understood. Therefore, prospective observational studies to document the natural history, presentation, evolution and burden of disease were included in the clinical development program. Not only were values for TG established, to assess the
Additional studies and pooled data on the incidence of pancreatitis in LPLD
The clinical development of alipogene tiparvovec started in 2005. All participants to the CT-AMT-010-01, 011-01 and 011-02 trials are intended to be followed for 15 years after dosing in a registry. This long-term follow-up will allow the ongoing assessment of safety and efficacy of gene therapy with AAV1-LPLS447X which includes continued collection of data on the incidence of pancreatitis. Modeling of pancreatitis data available from the entire program until October 2009, using a Cox
Risk assessment and ethical issues
In addition to long-term efficacy follow-up, specific features of risk associated with AAV1-LPLS447X gene transfer will be monitored over years. The objective is to strike the most appropriate balance between efficacy (reduced risk of pancreatitis and other LPLD co-morbidities) and safety (risk of severe adverse events) [31], [32]. For both efficacy and safety issues, risk is defined as the probability over time that an event is due to hazard or exposure [33]. The notion of risk is closely tied
Summary
LPLD is a serious chylomicronemic disorder. LPLD is associated with increased coronary artery disease and diabetes risk, but the most debilitating complication is pancreatitis. Acute pancreatitis is a complex, heterogeneous, highly morbid and potentially fatal disease. Efficacy results from the clinical studies on AAV1-LPLS447X appear promising, especially regarding reduced risk of acute pancreatitis events. In these studies, alipogene tiparvovec was in general well tolerated and safe. Further
Conflict of interest statement
All co-authors have been directly involved in the clinical development program of alipogene tiparvovec. JdW, AF and SvD are AMT employees. DG was the principal investigator for AMT-011-01 and AMT-011-02 studies and has received honoraria from AMT. SD was co-investigator in these studies and received honoraria for his involvement. JM was the AMT-011-01 and AMT-011-02 trials clinical pharmacist and has received honoraria for her participation. DB and KT are involved in the execution and the
Acknowledgements
Authors are thankful to all participants in the clinical studies and to the staff of the Academic Medical Center in Amsterdam, the ECOGENE-21 Clinical Research Center in Chicoutimi and Amsterdam Molecular Therapeutics (AMT) B.V. J. Méthot is a Université de Montréal post-doctoral fellow, received support from the Canadian Institutes of Health Research (CIHR). K. Tremblay is a Université de Montréal post-doctoral and CCRP fellow and receives support from ECOGENE-21. D. Gaudet holds the Canada
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