title: Engineering a gene silencing viral construct that targets the cat hypothalamus to induce permanent sterility: An update.
abstract: The intent of this contribution is to provide an update of the progress we have made towards developing a method/treatment to permanently sterilize cats. Our approach employs two complementary methodologies: RNA interference (RNAi) to silence genes involved in the central control of reproduction and a virus-based gene therapy system intended to deliver RNAi selectively to the hypothalamus (where these genes are expressed) via the systemic administration of modified viruses. We selected the hypothalamus because it contains neurons expressing Kiss1 and Tac3, two genes essential for reproduction and fertility. We chose the non-pathogenic adeno-associated virus (AAV) as a vector whose tropism could be modified to target the hypothalamus. The issues that must be overcome to utilize this vector as a delivery vehicle to induce sterility include modification of the wild-type AAV to target the hypothalamic region of the brain with a simultaneous reduction in targeting of peripheral tissues and non-hypothalamic brain regions, identification of RNAi targets that will effectively reduce the expression of Kiss1 and Tac3 without off-target effects, and determination if neutralizing antibodies to the AAV serotype of choice are present in cats. Successful resolution of these issues will pave the way for the development of a powerful tool to induce the permanent sterility in cats.
authors.affiliation: Division of Neuroscience, Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, OR, USA.
authors.forename: G A
authors.initials: GA
authors.lastname: Dissen
authors.affiliation: Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, OR, USA.
authors.forename: K
authors.initials: K
authors.lastname: Adachi
authors.affiliation: Division of Neuroscience, Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, OR, USA.
authors.forename: A
authors.initials: A
authors.lastname: Lomniczi
authors.affiliation: Department of Comparative Medicine, Oregon Health and Science University, Portland, OR, USA.
authors.forename: T
authors.initials: T
authors.lastname: Chatkupt
authors.affiliation: Raymond G. Perelman Center for Cellular and Molecular Therapeutics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
authors.forename: B L
authors.initials: BL
authors.lastname: Davidson
authors.affiliation: Division of Neuroscience, Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, OR, USA.|Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, OR, USA.
authors.forename: H
authors.initials: H
authors.lastname: Nakai
authors.affiliation: Division of Neuroscience, Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, OR, USA.
authors.forename: S R
authors.initials: SR
authors.lastname: Ojeda
mesh_terms: D000818:Animals; D002415:Cats; D003267:Contraception / Q000379:methods / Q000662:veterinary*; D000229:Dependovirus; D015870:Gene Expression / Q000187:drug effects; D020868:Gene Silencing; D005818:Genetic Engineering / Q000379:methods / Q000662:veterinary; D005822:Genetic Vectors; D007031:Hypothalamus; D007246:Infertility / Q000209:etiology / Q000662:veterinary; D059648:Kisspeptins / Q000037:antagonists & inhibitors / Q000235:genetics; D015287:Neurokinin B / Q000037:antagonists & inhibitors / Q000235:genetics; D034622:RNA Interference
chemical_list: D059648:Kisspeptins; D015287:Neurokinin B
keywords: RNA interference; adeno-associated virus; microRNA