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A cutaneous gene therapy approach to human leptin deficiencies: correction of the murine ob/ob phenotype using leptin‐targeted keratinocyte grafts
Author(s) -
Larcher Fernando,
Del Rio Marcela,
Serrano Fernando,
Segovia José Carlos,
Ramírez Angel,
Meana Alvaro,
Page Angustias,
Abad José Luis,
GonzáLez Manuel A.,
Bueren Juan,
Bernad Antonio,
Jorcano José Luis
Publication year - 2001
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.01-0082com
Subject(s) - leptin , genetic enhancement , adipose tissue , endocrinology , medicine , transgene , lipodystrophy , genetically modified mouse , biology , gene , obesity , immunology , genetics , human immunodeficiency virus (hiv) , antiretroviral therapy , viral load
Leptin deficiency produces a phenotype of obesity, diabetes, and infertility in the ob/ob mouse. In humans, leptin deficiency occurs in some cases of congenital obesity and in lipodystrophic disorders characterized by reduced adipose tissue and insulin resistance. Cutaneous gene therapy is considered an attractive potential method to correct circulating protein deficiencies, since gene‐transferred human keratinocytes can produce and secrete gene products with systemic action. However, no studies showing correction of a systemic defect have been reported. We report the successful correction of leptin deficiency using cutaneous gene therapy in the ob/ob mouse model. As a feasibility approach, skin explants from transgenic mice overexpressing leptin were grafted on immunodeficient ob/ob mice. One month later, recipient mice reached body weight values of lean animals. Other biochemical and clinical parameters were also normalized. In a second human gene therapy approach, a retroviral vector encoding both leptin and EGFP cDNAs was used to transduce HK and, epithelial grafts enriched in high leptin‐producing HK were transplanted to immunosuppressed ob/ob mice. HK‐derived leptin induced body weight reduction after a drop in blood glucose and food intake. Leptin replacement through genetically engineered HK grafts provides a valuable therapeutic alternative for permanent treatment of human leptin deficiency conditions.—Larcher, F., Del Rio, M., Serrano, F., Segovia, J. C., Ramírez, A., Meana, A., Page, A., Abad, J. L., González, M. A., Bueren, J., Bernad, A., Jorcano, J. L. A cutaneous gene therapy approach to human leptin deficiencies: correction of the murine ob/ob phenotype using leptin‐tar‐geted keratinocyte grafts. FASEB J. 15, 1529–1538 (2001)