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Using microRNA technology to inhibit expression of androgen receptor protein in the testes of male mice, interfering with testosterone’s ability to support sperm production.
- Defined the micro-RNA (miRNA) to be delivered to Sertoli cells that would effectively suppress androgen receptor (AR) production and defined and created a construct with a cell specific promoter so that the miRNA would only be produced in the targeted cell. Tested this and demonstrated effectiveness in cultured cells.
- Engineered lentiviral particles to carry miRNAs into the cells. Further, the viral envelope of the lentivirus was modified to express a small peptide that bound to FSH receptors, which ensures that the lentivirus will “home” to FSHR-expressing Sertoli cells and, in addition, engineered the modified virus to make it non-infective to humans.
- Tested their construct in male mice, via injection into the efferent ducts of the testes, and showed suppression of fertility for 5 months (length of the study). Investigators also showed that they did not get as much specific targeting when the construct was given IV, indicating they need more refinement of the peptide targeting mechanism.
- Demonstrated that targeting the androgen-AR pathway with miRNA and cell-specific targeting viruses is a viable therapeutic option for development of a single-dose nonsurgical sterilant.
- Darbey A, Smith LB. Deliverable transgenics & gene therapy possibilities for the testes. Mol Cell Endocrinol. 2017 Dec 1. pii: S0303-7207(17)30609-3. doi: 10.1016/j.mce.2017.11.023. [Epub ahead of print]
- Smith LB, O’Shaughnessy PJ, Rebourcet D. Cell-specific ablation in the testis: What have we learned? Andrology. 2015; 3(6): 1035-1049.
- Willems A, Roesl C, Mitchell RT, Milne L, Jeffery N, Smith S, Verhoeven G, Brown P, Smith LB. Sertoli cell androgen receptor signalling in adulthood is essential for post-meiotic germ cell development. Mol Reprod Dev. 2015 Sept; 82(9): 626-627.
- Darbey A, Roesl C, Jeffery N, Smith SE, O’Hara L, Cruickshanks L, Mitchell RT, Brown P, Smith LB. Tissue repair in the testis through viral gene therapy. Poster & Oral presentation. 19th European Testis Workshop, Saint-Malo, France. June 11-15, 2016.
- Roesl C. Sterilisation via disruption of androgen signalling – a novel gene therapy approach. Oral presentation. Institute of Fundamental Sciences at Massey University, Palmerston North, New Zealand. May 7, 2015.
- Roesl C, Jefferey N, Smith SE, Cruickshanks L, Mitchell RT, Brown P, Smith LB. Single-injection sterility via lentiviral-mediated suppression of Androgen Receptor in Sertoli cells. Oral presentation. 8th International Symposium on Canine and Feline Reproduction (ISCFR), Paris, France. June 24, 2016.
- Roesl C, Jefferey N, Smith SE, Milne L, Brown P, Smith LB. Development of a single-injection non-surgical sterilant via modification of Measles Virus pseudotyped particles. Poster presentation. Gordon Research Conference: Cells and Viruses, Girona, Spain. June 21-26, 2015.
- Roesl C, Jefferey N, Smith SE, Milne L, Brown P, Smith LB. Development of a single-injection non-surgical sterilant via modification of Measles Virus pseudotyped particles. Poster presentation. British Society for Andrology BES Conference, Edinburgh, UK. November 2-4, 2015.
- Smith LB. Sterilisation via disruption of androgen signalling – a novel gene therapy approach. Oral presentation. Laval University, Quebec City, QC, Canada. September 11, 2015.
Translation of an androgen-miRNA sterilant: pre-clinical validation & a clinical trial in cats and dogs , Lee Smith, PhD - Project in progress
In their first, completed project, investigators used microRNA technology to inhibit expression of androgen receptor protein in the testes of male mice, thereby interfering with testosterone’s ability to support sperm production. Investigators showed efficacy in targeting the androgen-AR pathway and demonstrated induction of sterility in male mice for 5 months. In this new project, investigators will further refine their single-dose sterilant construct before initiating a clinical trial in cats and dogs.
Project in progress
- Kilcoyne K, Roesl C, Darbey A, Stewart H, Milne L, Mitchell R, Mellanby R, Brown P, Smith LB. Development of a single-injection non-surgical sterilant via androgen receptor targeting in Sertoli cells. Poster presentation. Gordon Research Conference: Mammalian Reproduction, Tuscany, Italy. July 28, 2018.