A PILOT-STUDY OF EX-VIVO GENE-THERAPY FOR HOMOZYGOUS FAMILIAL HYPERCHOLESTEROLEMIA

The outcome of the first pilot study of liver-directed gene therapy is reported here. Five patients with homozygous familial hypercholestero laemia (FH) ranging in age from 7 to 41 years were enrolled; each pati ent tolerated the procedure well without significant complications. Tr ansgene expression was detected in a limited number of hepatocytes of liver tissue harvested four months after gene transfer from all five p atients. Significant and prolonged reductions in low density lipoprote in (LDL) cholesterol were demonstrated in three of five patients; in v ivo LDL catabolism was increased 53% following gene therapy in a recep tor negative patient, who realized a reduction in serum LDL equal to s imilar to 150 mg dl(-1). This study demonstrates the feasibility of en grafting limited numbers of retrovirus-transduced hepatocytes without morbidity and achieving persistent gene expression lasting at least fo ur months after gene therapy. The variable metabolic responses observe d following low-level genetic reconstitution in the five patients stud ied precludes a broader application of liver-directed gene therapy wit hout modifications that consistently effect substantially greater gene transfer.