Long-term monitoring of LPL gene replacement therapy: A lexicon of lessons for gene editing or oligonucleotide-based lipid lowering treatments

• Published in: Journal of clinical lipidology Vol. 19; no. 3; p. e69
• Main Authors: Chebli, Jasmine, Larouche, Miriam, Gaudet, Isabelle, Forest, François, Brisson, Diane, Gaudet, Daniel
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 01.05.2025
• ISSN: 1933-2874
• DOI: 10.1016/j.jacl.2025.04.096

Glybera® (alipogene tiparvovec) was the first gene replacement therapy to be approved in the occidental world. Glybera targeted lipoprotein lipase deficiency (LPLD) which causes persistent chylomicronemia. A 15-year safety follow-up was a requirement of the European Medicines Agency (EMA). The long-term trajectory of treated patients has not been reported and might provide useful data for the follow-up of dyslipidemic patients treated with emerging oligonucleotide or gene-based treatments. To review the long-term trajectory of patients treated with Glybera in light of the emergence of ASO, siRNA, gene replacement or gene editing treatments for lipid disorders. A total of 19 patients were treated with Glybera and followed for 15 years. Markers of efficacy, safety, and response to emerging therapies introduced over the years were monitored. After 3 months of Glybera administration, TG levels returned to baseline suggesting limited efficacy, while patients reported improved alertness and quality of life. One year after treatment, the analysis of injected muscle biopsies demonstrated the presence and lipolytic effectiveness of LPL, whereas chylomicron kinetic analyses using stable isotopes showed normalization. After 5 years, 44.4% of the participants still showed signs of improvement in chylomicron kinetics. The slight decrease in the incidence of pancreatitis observed after 5 years was difficult to relate to Glybera. A mitochondrial integration of the LPL transgene was noted in 2 subjects without further off-target signals. Four treated subjects died from consequences of LPLD, not of Glybera administration. Pregnancies occurred during the follow-up period and went well. Over time, most patients participated in trials using oligonucleotide-based treatments. No difference in response to these treatments was noted between subjects who received Glybera compared the others. Lessons learned from the long-term follow-up of Glybera treated patients are of interest for next generation of oligonucleotide-based or gene editing therapies for lipid disorders.