PMID- 29296625 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20230812 IS - 2329-0501 (Print) IS - 2329-0501 (Electronic) IS - 2329-0501 (Linking) VI - 7 DP - 2017 Dec 15 TI - Molecular Therapy of Melanocortin-4-Receptor Obesity by an Autoregulatory BDNF Vector. PG - 83-95 LID - 10.1016/j.omtm.2017.09.005 [doi] AB - Mutations in the melanocortin-4-receptor (MC4R) comprise the most common monogenic form of severe early-onset obesity, and conventional treatments are either ineffective long-term or contraindicated. Immediately downstream of MC4R-in the pathway for regulating energy balance-is brain-derived neurotrophic factor (BDNF). Our previous studies show that adeno-associated virus (AAV)-mediated hypothalamic BDNF gene transfer alleviates obesity and diabetes in both diet-induced and genetic models. To facilitate clinical translation, we developed a built-in autoregulatory system to control therapeutic gene expression mimicking the body's natural feedback systems. This autoregulatory approach leads to a sustainable plateau of body weight after substantial weight loss is achieved. Here, we examined the efficacy and safety of autoregulatory BDNF gene therapy in Mc4r heterozygous mice, which best resemble MC4R obese patients. Mc4r heterozygous mice were treated with either autoregulatory BDNF vector or YFP control and monitored for 30 weeks. BDNF gene therapy prevented the development of obesity and metabolic syndromes characterized by decreasing body weight and adiposity, suppressing food intake, alleviating hyperleptinemia and hyperinsulinemia, improving glucose and insulin tolerance, and increasing energy expenditure, without adverse cardiovascular function or behavioral disturbances. These safety and efficacy data provide preclinical evidence that BDNF gene therapy is a compelling treatment option for MC4R-deficient obese patients. FAU - Siu, Jason J AU - Siu JJ AD - Department of Cancer Biology and Genetics, College of Medicine, The Ohio State University, Columbus, OH 43210, USA. AD - Neuroscience Graduate Program, The Ohio State University, Columbus, OH 43210, USA. AD - Medical Scientist Training Program, The Ohio State University, Columbus, OH 43210, USA. FAU - Queen, Nicholas J AU - Queen NJ AD - Department of Cancer Biology and Genetics, College of Medicine, The Ohio State University, Columbus, OH 43210, USA. AD - The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA. FAU - Liu, Xianglan AU - Liu X AD - Department of Cancer Biology and Genetics, College of Medicine, The Ohio State University, Columbus, OH 43210, USA. AD - The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA. FAU - Huang, Wei AU - Huang W AD - Department of Cancer Biology and Genetics, College of Medicine, The Ohio State University, Columbus, OH 43210, USA. AD - The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA. FAU - McMurphy, Travis AU - McMurphy T AD - Department of Cancer Biology and Genetics, College of Medicine, The Ohio State University, Columbus, OH 43210, USA. AD - The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA. FAU - Cao, Lei AU - Cao L AD - Department of Cancer Biology and Genetics, College of Medicine, The Ohio State University, Columbus, OH 43210, USA. AD - Neuroscience Graduate Program, The Ohio State University, Columbus, OH 43210, USA. AD - Medical Scientist Training Program, The Ohio State University, Columbus, OH 43210, USA. AD - The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA. LA - eng GR - R01 CA163640/CA/NCI NIH HHS/United States GR - R01 CA166590/CA/NCI NIH HHS/United States GR - R21 CA178227/CA/NCI NIH HHS/United States GR - R01 AG041250/AG/NIA NIH HHS/United States GR - R56 AG041250/AG/NIA NIH HHS/United States PT - Journal Article DEP - 20170929 PL - United States TA - Mol Ther Methods Clin Dev JT - Molecular therapy. Methods & clinical development JID - 101624857 PMC - PMC5744069 OTO - NOTNLM OT - AAV OT - BDNF OT - gene therapy OT - hypothalamus OT - melanocortin-4 receptor OT - metabolic syndrome OT - obesity EDAT- 2018/01/04 06:00 MHDA- 2018/01/04 06:01 PMCR- 2017/09/29 CRDT- 2018/01/04 06:00 PHST- 2017/09/16 00:00 [received] PHST- 2017/09/26 00:00 [accepted] PHST- 2018/01/04 06:00 [entrez] PHST- 2018/01/04 06:00 [pubmed] PHST- 2018/01/04 06:01 [medline] PHST- 2017/09/29 00:00 [pmc-release] AID - S2329-0501(17)30104-3 [pii] AID - 10.1016/j.omtm.2017.09.005 [doi] PST - epublish SO - Mol Ther Methods Clin Dev. 2017 Sep 29;7:83-95. doi: 10.1016/j.omtm.2017.09.005. eCollection 2017 Dec 15.