Successful ex vivo gene therapy directed to liver in a patient with familial hypercholesterolaemia.
An ex vivo approach to gene therapy for familial hypercholesterolaemia (FH) has been developed in which the recipient is transplanted with autologous hepatocytes that are genetically corrected with recombinant retroviruses carrying the LDL receptor. We describe the treatment of a 29 year old woman with homozygous FH by ex vivo gene therapy directed to liver. She tolerated the procedures well and in situ hybridization of liver tissue four months after therapy revealed evidence for engraftment of transgene expressing cells. The patient's LDL/HDL ratio declined from 10-13 before gene therapy to 5-8 following gene therapy, improvements which have remained stable for the duration of the treatment (18 months). This represents the first report of human gene therapy in which stable correction of a therapeutic endpoint has been achieved.
Grossman
M
M
Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor 48109-0366.
Raper
S E
SE
Kozarsky
K
K
Stein
E A
EA
Engelhardt
J F
JF
Muller
D
D
Lupien
P J
PJ
Wilson
J M
JM
D000328:Adult; D001706:Biopsy; D002478:Cells, Cultured / Q000637:transplantation*; D003131:Combined Modality Therapy; D001026:Coronary Artery Bypass; D003327:Coronary Disease / Q000209:etiology / Q000601:surgery; D005260:Female; D005500:Follow-Up Studies; D005786:Gene Expression Regulation / Q000187:drug effects; D005813:Genes, Synthetic; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000097:blood / Q000150:complications / Q000188:drug therapy / Q000473:pathology / Q000628:therapy*; D017404:In Situ Hybridization, Fluorescence; D008075:Lipoproteins, HDL / Q000097:blood; D008077:Lipoproteins, LDL / Q000097:blood; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008148:Lovastatin / Q000494:pharmacology / Q000627:therapeutic use; D011973:Receptors, LDL / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics*; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000096:biosynthesis / Q000627:therapeutic use*; D012449:Safety; D015854:Up-Regulation / Q000187:drug effects
D008075:Lipoproteins, HDL; D008077:Lipoproteins, LDL; D011973:Receptors, LDL; D011994:Recombinant Proteins; D008148:Lovastatin