脂蛋白脂酶缺陷的实验性基因治疗

Experimental gene therapy on lipoprotein lipase deficiency

Lipoprotein lipase (LPL) plays a pivotal role in metabolism of plasma lipoprote in and affects atherogenesis. Mutations in human LPL gene demonstrate significa nt disturbances in plasma lipoproteins, including raised triglyceride (TG) and r educed HDL. Gene therapy to deliver and express a corrective LPL gene may improv e the lipoprotein profile and reduce the morbidity and potential atherogenic ris k from hypertriglyceridemia and dyslipoproteinemia in patients with complete or partial LPL deficiency. In early experiments adenoviral vector with human LPL ge ne achieved high ectopic LPL gene expression in vitro and subsequently it wa s appli ed successfully to normal and gene-knockout mouse models in vivo . It was further demonstrated in a larger, naturally occurring cat model of complete LPL deficien cy, which was remarkably similar in phenotype to the human disorder, that liver -t argeted expression of LPL resulted in correction of lipoprotein abnormalities an d improvement of impaired fat tolerance, thus clearly providing a key advance su pporting further development of LPL gene therapy as a viable therapeutic option for clinical LPL deficiency. Further studies with adenovirus-associate viral (AAV) vector to deliver LPL gen e to the muscle showed that long-term, stable transgene expression of LPL and ph e notypic correction were achieved in a rescued homozygous LPL deficient mouse mod el. This model combined with gene delivery will be utilized in future studies on the relationship between LPL and atherogenesis, which has not been explained co nvincingly yet.