A Novel Approach to Ex Vivo Gene Therapy for Familial Hypercholesterolemia Using Human Amniotic Epithelial Cells as a Transgene Carrier

A Novel Approach to Ex Vivo Gene Therapy for Familial Hypercholesterolemia Using Human Amniotic Epithelial Cells as a Transgene Carrier

SATORU TAKAHASHI, KEIKO OHSUGI, TOKUO YAMAMOTO,¹ MASASHI SHIOMI² and NORIO SAKURAGAWA

Department of Inherited Metabolic Disease, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo 187-8502,
¹Tohoku University Gene Research Center, Sendai 981-8555, and
²Institute for Experimental Animals, Kobe University School of Medicine, Kobe 650-0017

This study has demonstrated the potential of human amniotic epithelial cells (HAEC) as a transgene carrier to treat patients with familial hypercholesterolemia (FH). One approach to liver-directed gene therapy is represented by transplantation of autologous hepatocytes that have been genetically modified in vitro. However, the hepatocytes must be isolated from surgically resected tissue and it is difficult to expand the hepatocytes in culture. In contrast, the advantages for using HAEC are the higher availability and the nonimmunogenicity after allotransplantation. Our strategy involved isolating HAEC from an amnion, transducing a human low-density lipoprotein receptor (LDLR) gene into these cells with a recombinant adenovirus, and transplanting the genetically modified cells into the liver of an animal model of FH. Each animal, treated with the LDLR-transduced HAEC, exhibited a substantial decrease in serum cholesterol with an eventual return to pretreatment level. Moreover, the transplanted HAEC migrated out of the sinusoids into the hepatic parenchyma and expressed the LDLRs until at least 20 days after transplantation. However, the transplanted HAEC markedly decreased in number after 10 days post-transplant with an increase of inflammatory cells. The temporary nature of the metabolic improvement may be associated with xenograft rejection and transient function of the adenoviral vector.

Keywords —— amniotic epithelial cells; cell transplantation; familial hypercholesterolemia; Watanabe heritable hyperlipidemic rabbit; gene therapy

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Tohoku J. Exp. Med., 2001, 193, 279-292

Address for reprints: Norio Sakuragawa, Department of Inherited Metabolic Disease, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1 Ogawashigashi, Kodaira, Tokyo 187-8502, Japan.

e-mail: sakuraga@ncnp.go.jp

A part of this study was presented at the 42th Annual Meeting of the Japanese Society of Inherited Metabolic Diseases, Kagoshima, Japan, November 12, 1999.