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Hypothalamic Gene Therapy by an Autoregulatory BDNF Vector to Prevent Melanocortin-4-Receptor-Deficient Obesity

Siu, Jason J, Siu
http://orcid.org/0000-0002-3684-9490
http://rave.ohiolink.edu/etdc/view?acc_num=osu1523884097811049

Abstract Details

2018, Doctor of Philosophy, Ohio State University, Neuroscience Graduate Studies Program.
Gene therapy refers to the delivery of a genetic payload to a specific tissue in order to ideally mitigate disease. Popularized in the 1980s, there was heavy optimism that viruses would deliver functional genetic elements into patients to cure their disease. However, widely publicized deaths set the field back for the following decade. With the technical development of a safer, expanded, and more effective vector toolkit, the gene therapy field has returned to tackle not just enzyme deficiencies but also to eradicate tumors. The basic and clinical findings in virology, neurology, and obesity have reached a point where it is possible to investigate environmental effects on psychosocial well-being, mimic those effects through viral gene transfer, and harness the benefits of an enriching environment to prevent or reverse monogenetic forms of obesity. Adeno-associated viral (AAV) vectors are frequently the vector of choice for neurological disease because they are not only effective in gene transfer but also, more importantly, relatively safe for patients. Obstacles to AAV gene therapy are even now transducing the correct cell type, expressing transgene at appropriate levels, and escaping eradication or nullification by the immune system. One method by which to refine these properties is modulating the viral capsid through DNA shuffling of an assortment of vector capsids. Our previous study demonstrated that one newly engineered hybrid primate AAV capsid was able to transduce adipose tissue more effectively than natural serotypes through a variety of routes of administration. We then were interested in whether these novel serotypes were superior to the gold standard serotype AAV9, which is often used to transduce adult spinal cord. With a range of transduction lengths and higher gene expression than AAV9, the novel hybrid vectors could be valuable tools for basic or translational research applications in neural and adipose tissue. From studies in psychoneuroendocrinology, we used our model of environmental enrichment to elucidate one molecule in the brain responsible for mediating the antiobese phenotype: brain-derived neurotrophic factor (Bdnf). BDNF has been known to function in learning and memory in hippocampus as well as energy homeostasis in various hypothalamic nuclei. BDNF lies downstream of an evolutionarily conserved pathway, beginning with leptin hormone from adipose tissue, to leptin receptor in the hypothalamus, proopiomelanocortin (POMC), α-melanocyte stimulating hormone (α-MSH), and melanocortin-4-receptor (MC4R). A mutation in any of these genes can lead to obesity, but MC4R mutations comprise the most common monogenic form of severe early-onset obesity. Lifestyle modifications are ineffective for these patients, and extreme measures such as bariatric surgery have substantial morbidity along with conflicting outcomes. Immediately downstream of MC4R is BDNF. AAV-mediated gene transfer of BDNF to hypothalamus mimics the effects of being an enriched environment; that is, obesity and diabetes are alleviated in both diet-induced and genetic mouse models. We further developed a built-in autoregulatory vector to adjust therapeutic gene expression by imitating the brain's natural physiological feedback to weight loss. This autoregulatory approach leads to reductions in mass until a healthy body weight is achieved and maintained. In this study, we determined that autoregulatory BDNF gene therapy in heterozygous Mc4r mice, which best resemble MC4R obese patients, is both safe and effective at preventing obesity long-term. The preclinical data suggest BDNF gene therapy is an attractive treatment alternative for MC4R obese patients. Altogether, AAV vectors are a useful vehicle to address fundamental biological questions and deliver genes to treat disease. Our approach to treat obesity is viral gene transfer into the hypothalamic feeding circuitry. Described here is work demonstrating that BDNF gene transfer is an effective therapeutic option for MC4R-deficient obesity. Lastly, recombinant viral vectors can be further improved to increase transduction efficiency in neural tissue. Considering obesity as a neural disorder, these data implicate potential areas of future investigation while allowing for a gene therapy approach to explore the biological mechanisms at each juncture of the hypothalamic-sympathoneural-adipocyte axis.
Lei Cao, PhD (Advisor)
Joseph Travers, PhD (Committee Member)
Dana McTigue, PhD (Committee Member)
Stephen Kolb, MD, PhD (Committee Member)
173 p.
Neurobiology; Neurosciences
gene therapy; aav; adeno-associated virus; obesity; mc4r; melanocortin-4-receptor; bdnf; brain-derived neurotrophic factor; autoregulation; spinal cord; monogenic obesity; metabolism; environmental enrichment; brain; fat

Recommended Citations

Citations

  • Siu, Siu, J. J. (2018). Hypothalamic Gene Therapy by an Autoregulatory BDNF Vector to Prevent Melanocortin-4-Receptor-Deficient Obesity [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1523884097811049

    APA Style (7th edition)

  • Siu, Siu, Jason. Hypothalamic Gene Therapy by an Autoregulatory BDNF Vector to Prevent Melanocortin-4-Receptor-Deficient Obesity. 2018. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1523884097811049.

    MLA Style (8th edition)

  • Siu, Siu, Jason. "Hypothalamic Gene Therapy by an Autoregulatory BDNF Vector to Prevent Melanocortin-4-Receptor-Deficient Obesity." Doctoral dissertation, Ohio State University, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=osu1523884097811049

    Chicago Manual of Style (17th edition)

osu1523884097811049
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This open access ETD is published by The Ohio State University and OhioLINK.