title: A pilot study of ex vivo gene therapy for homozygous familial hypercholesterolaemia.
abstract: The outcome of the first pilot study of liver-directed gene therapy is reported here. Five patients with homozygous familial hypercholesterolaemia (FH) ranging in age from 7 to 41 years were enrolled; each patient tolerated the procedure well without significant complications. Transgene expression was detected in a limited number of hepatocytes of liver tissue harvested four months after gene transfer from all five patients. Significant and prolonged reductions in low density lipoprotein (LDL) cholesterol were demonstrated in three of five patients; in vivo LDL catabolism was increased 53% following gene therapy in a receptor negative patient, who realized a reduction in serum LDL equal to approximately 150 mg dl-1. This study demonstrates the feasibility of engrafting limited numbers of retrovirus-transduced hepatocytes without morbidity and achieving persistent gene expression lasting at least four months after gene therapy. The variable metabolic responses observed following low-level genetic reconstitution in the five patients studied precludes a broader application of liver-directed gene therapy without modifications that consistently effect substantially greater gene transfer.
authors.affiliation: Institute for Human Gene Therapy, University of Pennsylvania Medical Center, Philadelphia, USA.
authors.forename: M
authors.initials: M
authors.lastname: Grossman
authors.forename: D J
authors.initials: DJ
authors.lastname: Rader
authors.forename: D W
authors.initials: DW
authors.lastname: Muller
authors.forename: D M
authors.initials: DM
authors.lastname: Kolansky
authors.forename: K
authors.initials: K
authors.lastname: Kozarsky
authors.forename: B J
authors.initials: BJ
authors.lastname: Clark
authors.forename: E A
authors.initials: EA
authors.lastname: Stein
authors.forename: P J
authors.initials: PJ
authors.lastname: Lupien
authors.forename: H B
authors.initials: HB
authors.lastname: Brewer
authors.forename: S E
authors.initials: SE
authors.lastname: Raper
mesh_terms: D000328:Adult; D000917:Antibody Formation; D017690:Cell Transplantation; D002478:Cells, Cultured; D002648:Child; D002784:Cholesterol / Q000097:blood; D005260:Female; D005500:Follow-Up Studies; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006579:Heterozygote; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000628:therapy*; D017403:In Situ Hybridization; D008055:Lipids / Q000097:blood; D008077:Lipoproteins, LDL / Q000097:blood; D008099:Liver / Q000166:cytology; D008297:Male; D010865:Pilot Projects; D011973:Receptors, LDL / Q000235:genetics* / Q000276:immunology; D016896:Treatment Outcome
chemical_list: D008055:Lipids; D008077:Lipoproteins, LDL; D011973:Receptors, LDL; D002784:Cholesterol