Safety profile of plasmid/liposomes and virus vectors in clinical gene therapy
Thomas Wirth1, Marja Hedman, Kimmo Mäkinen
1A.I. Virtanen Institute, Kuopio University Hospital, Kuopio, Finland.
Abstract:
Despite of more than 500 gene therapy trials worldwide very little systematic safety information is available from gene therapy. Safety information was collected from 146 consecutive patients who participated in three randomized, controlled phase II gene therapy trials in cardiovascular diseases and malignant glioma using adenoviruses, plasmid/liposomes and retrovirus packaging cells. Total follow-up time of the patients was 78794 days which equals 1.5 years per patient. The main outcome measures were serious adverse events, other adverse events and changes in general laboratory parameters. Except fever and increases in CRP values plasmid/liposomes were safe and well tolerated. The incidence of serious adverse events in adenovirus-treated patients was 0.9 and 4.0/10000 patient days in cardiovascular and malignant glioma trials as compared to 0.5 and 2.1 in randomized control patients, respectively. Transient fever, leukopenia and increases in CRP and liver enzymes were detected in virus-treated patients. No deaths from side effects or no new cancers were associated with gene therapy. It is concluded that gene therapy, like any other therapy, is associated with side effects which depend on the administered vector, dose, and route of delivery and properties of the transgene. However, given the limitations of this study and length of the follow-up, the safety profile of gene therapy seems to be acceptable for the treatment of severe human diseases.
Insights
Gene therapy shows an acceptable safety profile for severe diseases, with side effects varying by vector and delivery method. Serious adverse events were infrequent and no new cancers were observed.
Area of Science:
- Biomedical research
- Clinical trials
- Gene therapy safety
Background:
- Limited systematic safety data available for gene therapy despite numerous global trials.
- Gene therapy holds promise for treating severe diseases, necessitating robust safety evaluations.
Purpose of the Study:
- To systematically assess the safety and tolerability of gene therapy in patients undergoing clinical trials.
- To evaluate adverse events and laboratory parameter changes associated with different gene therapy vectors.
Main Methods:
- Analysis of safety data from 146 patients in three Phase II randomized controlled gene therapy trials.
- Inclusion of cardiovascular disease and malignant glioma indications, utilizing adenoviruses, plasmid/liposomes, and retroviruses.
- Comprehensive monitoring of serious adverse events, other adverse events, and laboratory parameters over a total follow-up of 78,794 days.
Main Results:
- Plasmid/liposome vectors were safe and well-tolerated, with only mild side effects like fever and elevated CRP.
- Adenovirus-treated patients experienced a slightly higher incidence of serious adverse events compared to controls.
- Transient side effects in virus-treated patients included fever, leukopenia, and elevated liver enzymes; no treatment-related deaths or new cancers were reported.
Conclusions:
- Gene therapy exhibits a manageable safety profile, with adverse events dependent on vector type, dose, and delivery route.
- The observed safety profile appears acceptable for treating severe human diseases, warranting further investigation.
- This study provides valuable systematic safety information for gene therapy, contributing to its clinical advancement.
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