fraction of IDL that escapes receptor mediated uptake and degradation is'converted to LDL in 
capillary beds (2). LDL is the primary carrier of cholesterol in the plasma and has been 
implicated in the development of atherosclerosis. Hepatic LDL receptors contribute to >90% of 
the high affinity uptake and degradation of LDL in vivo (39). A complete deficiency of LDL 
receptor activity in FH leads to a precarious metabolic state in which the catabolism of LDL and 
its precursor lipoprotein IDL is decreased. Diminished high affinity uptake of IDL leads to a 
marked overproduction of LDL, which in the setting of decreased LDL catabolism, results in 
massive hypercholesterolemia (11). 
Hepatocytes along with absorptive epithelia of the intestine have the unique function of 
expressing apoproteins associated with the other major lipoprotein of the endogenous pathway, 
HDL. Liver and bowel directly secrete nascent HDL particles which are converted to mature 
HDL through the action of a variety of enzymes. HDL is a very dynamic lipoprotein whose 
specific functions in cholesterol homeostasis remain poorly defined, but is most often associated 
with a process termed reverse cholesterol transport or the return of cholesterol from 
peripheral cells to the liver for excretion into bile. 
Liver is the only organ capable of excreting cholesterol from the body, a function which 
is critical to the maintenance of cholesterol balance in vivo (39). This is accomplished through 
the conversion of free cholesterol to bile acids and the formation of bile (composed of 
cholesterol and bile acids) which is secreted from hepatocytes and eventually excreted from the 
body. Biliary cholesterol is derived from a pool of metabolically active free cholesterol that is 
formed by de novo synthesis and receptor-mediated degradation of lipoproteins (40). In 
humans, over one gram of cholesterol is excreted per day by this route (39). 
In summary, the liver is the primary organ responsible for regulation of cholesterol 
homeostasis, in vivo, and the receptor for LDL plays an important role in this regulation. 
Hepatocytes are the cells primarily responsible for catabolizing LDL and the only cell capable of 
excreting cholesterol. We therefore believe that the hepatocyte is the preferred target for gene 
transfer in gene replacement therapies of FH. The success of orthotopic liver transplantation in 
the treatment of FH provides compelling support for the hypothesis that expression of hepatic 
LDL receptor activity is sufficient for metabolic correction in vivo (see Section II.B.5). It is 
possible, but unlikely, that expression of LDL receptor in non-hepatic tissues could improve 
the hyperlipidemia in FH without peripheral adverse effects. 
3. Clinical 
A risk/benefit assessment of gene therapy for FH requires a thorough understanding of 
the natural history of the disease. In general, FH homozygotes have severe 
hypercholesterolemia from birth and develop peripheral stigmata of the disease by age 4 
including cutaneous xanthomas, tendinous xanthomas, and arcus cornae (2). The most morbid 
and life limiting aspect of the disease relates to the development of a characteristic pattern of 
atherosclerosis. The coronary arteries and proximal aorta are severely involved while the 
cerebral arteries and distal aorta are relatively spared. Accelerated coronary atherosclerosis 
leads to a high incidence of myocardial infarction in children and teenagers. Disease in the 
ascending aorta led to a variety of complications, including narrowing of the coronary ostium 
and aortic stenosis due to valvular or supravalvular aortic disease. Patients usually die of 
sequelae of CAD before the age of 30. 
More detailed characterizations of FH homozygotes have demonstrated clinical 
heterogeneity based on genotype specific variations in the natural history of the disease. The 
basic premise is that molecular heterogeneity leads to genotype specific variation in the level of 
residual LDL receptor function which may correlate with severity and progression of the 
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