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Direct delivery of leptin to the hypothalamus using recombinant adeno-associated virus vectors results in increased therapeutic efficacy

Nature Biotechnology volume 19, pages 169–172 (2001)Cite this article

Abstract

The hormone leptin has been shown to be an afferent signal in a negative-feedback loop regulating body weight, and consequently, the administration of the gene product for the treatment of obesity has recently attracted considerable attention. Leptin is produced by adipocytes in response to increased trigyceride storage, and appears to affect body weight primarily through target cells in the hypothalamus. Although plasma levels of leptin correlate positively with adipose tissue mass in normal humans and animals1,2,3,4, recent studies have shown that obese humans and animals appear to be relatively resistant to the increased plasma levels of leptin1,5. Analysis of the levels of leptin in the cerebrospinal fluid suggests that the uptake of leptin across the blood–brain barrier may be saturable1. Taken together, these results suggest that therapeutic approaches to deliver leptin through the circulation may prove to be problematic. Although recent clinical trials have suggested that peripherally administered leptin might lead to a reduction in body weight in humans6, it is likely that the more effective delivery of leptin to cellular targets within the central nervous system will be necessary in order to fully reveal the therapeutic potential of the gene product. In an effort to provide a means for the delivery of leptin that obviates the need for the gene product to traverse the blood–brain barrier, we have evaluated the use of recombinant adeno-associated vectors to deliver leptin intraventricularly or directly to the hypothalamus.

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Figure 1: Expression of GFP after AAV vector-mediated transduction of muscle and brain.
Figure 2: Evaluation of parameters of weight loss in animals injected with AAV-hOB by different routes of administration (A) Measurement of body weight.
Figure 3: Photographs of animals injected with different AAV vectors by different routes of administration.

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Acknowledgements

This work was supported by the Howard Hughes Medical Institute. C.L is a Wenner-Gren Foundation post-doctoral fellow. R.C.M. is currently an equity-holding consultant with AMGEN, Inc. and receives sponsored research support from the company.

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Author notes

  1. Cecilia Lundberg

    Present address: Wallenberg Neuroscience Center, Division of Neuroscience, Lund University, SE-221 00, Lund, Sweden

Authors and Affiliations

  1. Department of Genetics, and Division of Molecular Medicine, Harvard Medical School, Children's Hospital, Boston, 02115, MA

    Cecilia Lundberg, Steven J. Jungles & Richard C. Mulligan

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Correspondence to Richard C. Mulligan.

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Lundberg, C., Jungles, S. & Mulligan, R. Direct delivery of leptin to the hypothalamus using recombinant adeno-associated virus vectors results in increased therapeutic efficacy. Nat Biotechnol 19, 169–172 (2001). https://doi.org/10.1038/84448

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