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A pilot study of ex vivo gene therapy for homozygous familial hypercholesterolaemia

Nature Medicine volume 1, pages 1148–1154 (1995)Cite this article

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 ∼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.

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Authors and Affiliations

  1. Institute for Human Gene Therapy and Departments of Molecular and Cellular Engineering, Medicine, and Surgery, the University of Pennsylvania Medical Center and the Wistar Institute, Room 204, 3601 Spruce Street, Philadelphia, Pennsylvania, 19104-4268, USA

    Mariann Grossman, Daniel J. Rader, Daniel M. Kolansky, Karen Kozarsky, Steven E. Raper & James M. Wilson

  2. Department of Internal Medicine, The University of Michigan Medical Center, Ann Arbor, Michigan, 48109, USA

    David W.M. Muller

  3. Division of Cardiology, Department of Pediatrics, the University of Pennsylvania Medical Center, and the Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, 19104, USA

    Bernard J. Clark III

  4. The Christ Hospital Cardiovascular Research Center, Division of Lipid Metabolism and Preventive Atherosclerosis, and Medical Research Laboratories, Cincinnati, Ohio, 45219, USA

    Evan A. Stein

  5. Lipid Research Center, Laval University Hospital Medical Research Center, Quebec, G1 V4G2, Canada

    Paul J. Lupien

  6. Molecular Disease Branch, the National Heart, Lung and Blood Institute, National Institutes of Health, Building 10, Room 7N117, Bethesda, Maryland, 20892, USA

    H. Bryan Brewer Jr

Authors
  1. Mariann Grossman
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  2. Daniel J. Rader
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  4. Daniel M. Kolansky
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  5. Karen Kozarsky
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  6. Bernard J. Clark III
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  7. Evan A. Stein
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  8. Paul J. Lupien
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  9. H. Bryan Brewer Jr
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  10. Steven E. Raper
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  11. James M. Wilson
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Grossman, M., Rader, D., Muller, D. et al. A pilot study of ex vivo gene therapy for homozygous familial hypercholesterolaemia. Nat Med 1, 1148–1154 (1995). https://doi.org/10.1038/nm1195-1148

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