“I’m eating and eating all day long now and hopefully soon I’ll be too big to fail”


Obesity is an important health issue worldwide, particularly in the United States where the prevalence of obesity has increased substantially over the last 2 decades. In 2005, among the total U.S. adult population surveyed, 60.5% were overweight, 23.9% were obese, and 3.0% were extremely obese. Research has shown that obesity increases the risk of developing a number of conditions including type 2 diabetes, hypertension, coronary heart disease, ischemic stroke, colon cancer, post-menopausal breast cancer, endometrial cancer, gall bladder-disease, osteoarthritis, and obstructive sleep apnea. Recognizing these important facts, our lab utilizes gene therapy tools to address basic questions in metabolism and energy homeostasis. At the same time, we believe that notwithstanding its multitrait etiology, obesity is an appropriate application for clinical gene therapy (1, 2).

Gene Therapy for Obesity: Rationale

The general perception is that conventional gene therapy is not appropriate for multi-trait disorder such as obesity. The argument is that even if one can achieve technical excellence in delivering and regulating genetic information in particular cell types or tissues, there are too many de-regulated genes to balance, and that the subset of these genes are going to be different in each particular case of obesity anyway. Yet, the counter-argument could be made that precisely because of the complex cumulative nature of this disorder manifesting in variable expressivity and variegation of many genes, one need to modulate only limited number of shared pathways, or maybe even a single gene, as long as this particular gene occupies a key position in a crucial metabolic pathway. One might picture a recognizable energy scale balancing two cups with hundreds of genes combining for energy intake in one cup while as many genes acting together for energy expenditure in the opposite cup. To shift a balance in the desired direction one need to either ‘reduce the weight’ in one cup by inhibiting the action of any gene in this pool or, conversely, induce the expression of any other gene in the opposite pool. In other words, regardless of the underlying causes, the treatment (gene target) could be a general one. In fact, a short list of such genes has been recently described. The investigators reviewed seven independent computational disease gene prioritization methods, and then applied them in concert to the analysis of 9556 positional candidate genes for T2DM and the related trait obesity. As a result, a list of nine primary candidate genes for T2DM and five genes for obesity had been generated. Two genes, lipoprotein lipase precursor (LPL) and branched-chain a-keto acid dehydrogenase (BCKDHA), are common to these two sets.

What are the best gene targets among various genes associated with this complex disorder? In general, genes regulating anabolic (inducing conservation and uptake of energy) and catabolic (promoting energy expenditure and decreasing FI) pathways are legitimate targets. For example, to reduce BW one would aim to downregulate the activity of the former (e.g. by utilizing siRNAs) and/or upregulate the latter (either by exogenous gene delivery or by control of endogenous gene). Furthermore, the mechanism of action of the targeted gene may require central (brain) or peripheral administration of a vector. The hypothalamus, a satiety center within the brain, is an attractive target because of its involvement in the integration of peripheral metabolic signals. In a clinical setting, however, the choice will most likely involve targeting peripheral organs involved in energy metabolism (gut, liver, muscle, or fat).

In search of the clinically relevant target we have successfully tested several unrelated target genes for the purpose of reducing food intake and body weight in diet-induced obese rodent models. These example include neurocytokines LIF and CNTF (3), adipokine Acrp30 (aka adiponectin) (4), growth factor Wnt10b (5), enzyme Stearoyl-CoA Desaturase (SCD1) (unpublished), Peptide YY (PYY) (in preparation).

References:

1. Zolotukhin S Gene therapy for obesity. Expert Opin Biol Ther. 2005 Mar; 5(3):347-57.

2. Zolotukhin S. Is there a Future for Gene Therapy in Obesity? Handbook of Obesity: Clinical Applications, 3-rd edition. 2007, Eds. George A. Bray and Claude Bouchard.

3. Prima V, Tennant M, Gorbatyuk OS, Muzyczka N, Scarpace PJ, Zolotukhin S. Differential modulation of energy balance by leptin, ciliary neurotrophic factor, and leukemia inhibitory factor gene delivery: microarray deoxyribonucleic acid-chip analysis of gene expression. Endocrinology. 2004 Apr;145(4):2035-45.

4. Shklyaev S, Aslanidi G, Tennant M, Prima V, Kohlbrenner E, Kroutov V, Campbell-Thompson M, Crawford J, Shek EW, Scarpace PJ, Zolotukhin S. Sustained peripheral expression of transgene adiponectin offsets the development of diet-induced obesity in rats. Proc Natl Acad Sci U S A. 2003 Nov 25;100(24):14217-22.

5. Aslanidi G, Kroutov V, Philipsberg G, Lamb K, Campbell-Thompson M, Walter GA, Kurenov S, Aguirre JI, Keller P, Hankenson K, MacDougald OA, and Zolotukhin S Ectopic expression of Wnt10b decreases adiposity and improves glucose homeostasis in obese rats. Am. J. Physiol. Endocrin. & Metabolism, 2007 Sep;293(3):E726-36.