Nature Medicine
1, 1148 - 1154 (1995)
doi:10.1038/nm1195-1148
A pilot study of ex vivo gene therapy for homozygous familial hypercholesterolaemiaMariann Grossman1, Daniel J. Rader1, David W.M. Muller2, Daniel M. Kolansky1, Karen Kozarsky1, Bernard J. Clark III3, Evan A. Stein4, Paul J. Lupien5, H. Bryan Brewer Jr6, Steven E. Raper1
& James M. Wilson1, 7
1Institute 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
2Department of Internal Medicine, The University of Michigan Medical Center, Ann Arbor, Michigan 48109, USA
3Division of Cardiology, Department of Pediatrics, the University of Pennsylvania Medical Center, and the Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA
4The Christ Hospital Cardiovascular Research Center, Division of Lipid Metabolism and Preventive Atherosclerosis, and Medical Research Laboratories, Cincinnati, Ohio 45219, USA
5Lipid Research Center, Laval University Hospital Medical Research Center, Quebec G1 V4G2 Canada
6Molecular Disease Branch, the National Heart, Lung and Blood Institute, National Institutes of Health, Building 10, Room 7N117, Bethesda, Maryland 20892, USA
7Correspondence should be addressed to J.M.W. 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.
REFERENCES
- Brown, M.S. & Goldstein, J.L. A receptor-mediated pathway for cholesterol homeostasis. Science 232, 34−37 (1986). | PubMed | ISI | ChemPort |
- Goldstein, J.L. & Brown, M.S. Familial hypercholesterolemia. Lipoprotein and lipid metabolism disorders. In Metabolic Basis of Inherited Disease, 6th edn (eds Scriver, C.R., Beaudet, A.L., Sly, W.S. & Valle, D.) 1215−1250 (McGraw-Hill, New York, 1989).
- Uauy, R., Vega, G.L., Grundy, S.M. & Bilheimer, D.M. Lovastatin therapy in receptor-negative familial hypercholesterolemia: Lack of effect on low-density lipoprotein concentrations or turnover. J. Pediatr. 113, 387−392 (1988). | PubMed | ISI | ChemPort |
- Malloy, M.J., Kane, J.P., Kunitake, S.T. & Tun, P. Complimentarity of colestipol, niacin and lovastatin in treatment of severe familial hypercholesterolemia. Ann. intern. Med. 107, 616−623 (1987). | PubMed | ISI | ChemPort |
- Starzl, T.E. et al. Portacaval shunt in patients with familial hypercholesterolemia. Ann. Surg. 198, 273−283 (1983). | PubMed | ISI | ChemPort |
- Deckelbaum, R.J., Lees, R.S., Small, D.M., Hedberg, S.E. & Grundy, S.M. Failure of complete bile diversion and oral bile acid therapy in the treatment of homozygous familial hypercholesterolemia. New Engl. J. Med. 296, 465−470 (1977). | PubMed | ISI | ChemPort |
- Bilheimer, D.W., Goldstein, J.L., Grundy, S.M. & Starzl, T.E. Liver transplantation to provide low density lipoprotein receptors and lower plasma cholesterol in a child with homozygous familial hypercholesterolemia. New Engl. J. Med. 311, 1658−1664 (1984). | PubMed | ISI | ChemPort |
- Hoeg, J.M., Starzl, T.E. & Brewer, H.B. Liver transplantation for treatment of cardiovascular disease: Comparison with medication and plasma exchange in homozygous familial hypercholesterolemia. Am. J. Cardiol. 59, 705−707 (1987). | Article | PubMed | ISI | ChemPort |
- Thompson, G.R., Barbir, M., Okabayshi, K., Trayner, I. & Larkin, S. Plasmapheresis in familial hypercholesterolemia. Arteriosclerosis (Suppl.) 9, 1152−1157 (1989).
- Gordon, B.R. et al. Treatment of refractory familial hypercholesterolemia by low-density lipoprotein apheresis using an automated dextran sulfate Cellulose adsorption system. Am. J. Cardiol. 70, 1010−1016 (1992). | Article | PubMed | ISI | ChemPort |
- Goldstein, J.L., Kita, T. & Brown, M.S. Defective lipoprotein receptors and atherosclerosis. New Engl. J. Med. 309, 288−296 (1983). | PubMed | ISI | ChemPort |
- Ishibashi, S. et al. Hypercholesterolemia in low density lipoprotein receptor knockout mice and its reversal by adenovirus-mediated gene delivery. J. clin. Invest. 92, 883−893 (1993). | PubMed | ISI | ChemPort |
- Chowdhury, J.R. et al. Long-term improvement of hypercholesterolemia after ex vivo gene therapy in LDLR-deficient rabbits. Science 254, 1802−1805 (1991). | PubMed | ISI | ChemPort |
- Grossman, M., Wilson, J.M. & Raper, S.E. A novel approach for Introducing hepatocytes into the portal circulation. J. Lab. clin. Med. 121, 472−478 (1993). | PubMed | ISI | ChemPort |
- Grossman, M., Raper, S.E. & Wilson, J.M. Transplantation of genetically-modified autologous hepatocytes into non-human primates: Feasibility and short-term toxicity. Hum. Gene Ther. 3, 501−510 (1992). | PubMed | ISI | ChemPort |
- Wilson, J.M. et al. Clinical protocol: Ex vivo gene therapy of familial hypercholesterolemia. Hum. Gene Ther. 3, 179−222 (1992). | PubMed | ISI | ChemPort |
- Grossman, M. et al. Successful ex vivo gene therapy directed to liver in a patient with familial hypercholesterolemia. Nature Genet. 6, 335−341 (1994). | PubMed | ISI | ChemPort |
- Raper, S.E. et al. Safety and feasibility of liver-directed ex vivo gene therapy for homozygous familial hypercholesterolemia. Ann. Surg. (in the press).
- Rader, D.J. et al. The LDL receptor is not required for normal catabolism of Lp (a) in humans. J. clin. Invest. 95, 1403−1408 (1995). | PubMed | ISI | ChemPort |
- Grossman, G., Raper, S.E. & Wilson, J.M. Towards liver-directed gene therapy: Retrovirus-mediated gene transfer into human hepatocytes. Somatic Cell molec. Genet. 17, 601−607 (1991). | ISI |
- Adams, R.M. et al. Transduction of primary human hepatocytes with amphotropic and xenotropic retroviral vectors. Proc. natn. Acad. Sci. U.S.A. 89, 8981−8985 (1992). | ChemPort |
- Brown, M.S., Goldstein, J.L., Havel, R.J. & Steinberg, D. Gene therapy for cholesterol. Nature Genet. 7, 349−350 (1994). | PubMed | ISI | ChemPort |
- Ishibashi, S. et al. Hypercholesterolemia in low density lipoprotein receptor knockout mice and its reversal by adenovirus-mediated gene delivery. J. clin. Invest. 92, 883−893 (1993). | PubMed | ISI | ChemPort |
- Kozarsky, K.F. et al. In vivo correction of low density lipoprotein receptor deficiency in the Watanabe heritable hyperlipidemic rabbit with recombinant adenoviruses. J. biol. Chem. 269, 13695−13702 (1994). | PubMed | ISI | ChemPort |
- Hobbs, H., Brown, M.S. & Goldstein, J.L. Molecular genetics of the LDL receptor gene in familial hypercholesterolemia. Hum. Mut. 1, 445−466 (1992). | PubMed | ChemPort |
- Leitersdorf, E., Tobin, E.J., Davignon, J. & Hobbs, H.H. Common low-density lipoprotein receptor mutations in the French Canadian population. J. clin. Invest. 85, 1014−1023 (1990). | PubMed | ISI | ChemPort |
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