Familial Hypercholesterolemia

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Synthetic vectors are being evaluated for the treatment of familial hypercholesterolemia (FH) and hyperlipidemias. FH is an autosomal dominant disorder caused by mutations in the low-density lipoprotein (LDL) receptor. Patients have persistently elevated levels of LDL in their serum, which leads to the development of atherosclerosis and coronary artery disease (43). Tomita et al. (44) injected a complex of hemagglutinat-ing virus of Japan (HVJ) liposomes and a plasmid expressing the human LDL receptor into the hepatic portal vein of LDL receptor knockout mice. RNA was detected in the livers that peaked at days 7 to 10 after injection, but became undetectable by day 21. At day 7 there was a modest but statistically significant decrease in total cholesterol levels. Another approach being taken to treat hypercholesterolemia is to express apoli-poprotein E, which is involved in removing excess lipopro-teins and cholesterol from tissues. Rinaldi et al. (45) injected a plasmid that expresses apolipoprotein E (apoE) into the muscles of apoE-deficient mice. Very low levels of apoE (0.6 ng/ mL) were produced in the serum, but this was sufficient to decrease serum cholesterol levels by 25% to 43%, and this reduction persisted for 16 weeks. Athanasopolulos et al. (46) also injected an apoE plasmid into apoE-deficient mice, but did not detect measurable levels of apoE in serum nor a decrease in serum cholesterol levels. Nevertheless, they did observe a retardation in the development of atherosclerotic and xanthomatous lesions.

The above results suggest that the threshold for successfully treating at least some aspects of hypercholesterolemia may be quite low, requiring expression of less than 1% of normal apoE levels to realize some benefit. This concept is supported by studies in transgenic mice expressing apoE from adrenal glands where 1% to 2% of normal serum apoE levels did not reduce hyperlipidemia but inhibited atherosclerosis (47). However, it has also been demonstrated in studies using adenoviral or AAV vectors that higher levels of expression will confer greater protection against atherosclerosis. For example, a helper-dependent adenoviral vector expressing a 1000-fold higher level of apoE in the serum than plasmid vectors inhibited the formation of atherosclerotic lesions for greater than 2 years after a single injection (48). These results suggest that higher and more sustained expression from synthetic vectors is desirable for treating FH and other hyperlipid-emias.

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