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Lipoprotein lipase deficiency: immune responses to intramuscular administration of Alipogene tiparvovec in a phase II gene therapy clinical trial

Cellular immune responses to adeno-associated viral ( AAV ) vectors used for gene therapy have been linked to attenuated transgene expression and loss of efficacy.
The impact of such cellular immune responses on the clinical efficacy of Alipogene tiparvovec ( Glybera, AAV1-LPLS447X ), a gene-therapy consisting of intramuscular administration of a recombinant (r)AAV1 mediating muscle-directed expression of lipoprotein lipase ( LPL ), was investigated.

Five subjects with LPL-deficiency ( LPLD ) were administered intramuscularly with a dose of 1 x 1012 gc/kg Alipogene tiparvovec.
All subjects were treated with immune suppression starting shortly before administration of Alipogene tiparvovec and maintained until 12 weeks after administration.

Systemic antibody and T cell responses against AAV1 and LPLS447X, as well as local cellular immune responses in the injected muscle were investigated in 5 LPLD subjects.

Long term transgene expression was demonstrated despite a transient systemic cellular response and a stable humoral immune response against AAV1 capsid protein.

Cellular infiltrates were found in 4 of the 5 subjects but were not associated with adverse clinical events or elevation of inflammation markers. Consistent herewith, CD8-positive T cells in the infiltrates lacked cytotoxic potential.
Furthermore, FoxP3-positive/CD4-positive T cells were found in the infiltrates suggesting that multiple mechanisms contribute to local tolerance.

Systemic and local immune responses induced by intramuscular injection of Alipogene tiparvovec have no impact on safety and did not compromise LPL transgene expression.

These findings support the use of Alipogene tiparvovec in individuals with lipoprotein lipase deficiency and indicate that muscle directed AAV-based gene therapy remains a promising approach for the treatment of human diseases. ( Xagena )

Ferreira V et al, Hum Gene Ther 2013; Epub ahead of print