ESA-SRB-AOTA 2019

Rescue of the HSD17B3 knock-out model using lentiviral delivery system. (#519)

Diane Rebourcet 1 , Rosa Mackay 2 , Annalucia Darbey 1 , Peter O’Shaughnessy 3 , Ana Monteiro 3 , Mike Curley 2 , Nathan Jeffery 2 , Laura Milne 2 , Sarah Smith 2 , Lee B Smith 1 2
  1. Priority Research Centre for Reproductive Science, The University of Newcastle, Callaghan, NSW, Australia
  2. MRC-Centre for Reproductive Health, University of Edinburgh, Edinburgh, UK
  3. Institute of Biodiversity, Animal Health and Comparative Medicine, University of Glasgow , Glasgow, UK

Male health and wellbeing is androgen dependent. Low circulating testosterone concentration is associated with many increasingly prevalent chronic and age-related clinical conditions (metabolic disorders such as obesity, cardiovascular disease) (1-2). The cause/consequence relationship to perturbed androgen action is unclear and androgen therapy is able to alleviate symptoms in many cases. However, the use of androgen therapy remains controversial due to a lack of solid scientific evidence regarding the cost/benefits and the potential adverse risks (3). An approach to improve endogenous androgen production, could be via modulating gene expression in testis somatic cells using a lentiviral delivery system.

 Androgens are synthesized by Leydig cells within the interstitial compartment. The final step in testosterone production, controlled by hydroxysteroid-dehydrogenase-17-beta-3 (HSD17B3), has been shown to occur in different compartments depending on the stage of development of the testis (3). In fetal life, the expression of HSD17B3 is restricted to the seminiferous tubules, in Sertoli cells and in adulthood, to the Leydig cells. With a view to support a healthy androgen profile throughout life and alleviate the secondary effects of testosterone replacement therapy, we exploited the HSD17B3 knock-out model, which displays similar ageing related disorders such as altered hormonal profile (testosterone and gonadotrophins) and obesity as the males aged. To determine whether we could rescue the phenotype observed in mutant males, we used an in vivo lentiviral delivery of HSD17B3 cDNA or control constructs, specifically targeting adult Sertoli cells in knock-out and wild type males.

Our preliminary data shows that the lentiviral delivery of HSD17B3 cDNA system is able to rescue the phenotype observed in the knock-out, as their bodyweight curve decreases significantly following the treatment. This opens doors to new approaches as a refinement over current androgen therapy strategies to compensate for male reproductive disorders and to support a healthy androgen profile throughout life.

  1. 1. Spitzer M, et al. Nat Rev Endocrinol 9: 414-424.
  2. 2. Shores MM. Curr Sex Health Rep 6: 235-243.
  3. 3. Huhtaniemi, I., et al. Asian J Androl, 16(2): 192–202.
  4. 4. Shima Y, et al. Mol Endocrinol 27(1):63-73.