ESA-SRB-AOTA 2019

Deliverable transgenics can be used to rescue infertility in Sertoli cell androgen receptor knock-out mice. (#164)

Annalucia Darbey 1 2 , Pamela Brown 3 , Rod T Mitchell 1 , Lee B Smith 1 2
  1. MRC Centre for Reproductive Health, The University of Edinburgh, Edinburgh, United Kingdom
  2. The University of Newcastle, CALLAGHAN, NSW, Australia
  3. Biomolecular Core - SURF, The University of Edinburgh, Edinburgh, United Kingdom

Hypogonadism and male infertility are clinically prevalent conditions and have been linked to an increased risk of cardiovascular-metabolic diseases and earlier mortality [1, 2]. For most cases, the causes of impaired male reproduction remain idiopathic, with a genetic component often suggested to be a cause [3]. Consequently, it is critical to increase understanding and to develop new therapeutics for these conditions. The advancements in gene editing and vector delivery technologies have potential to improve diagnosis and to aid the development of treatments for men with reproductive disorders.

To investigate the potential of viral vectors in the adult testis, we first optimised their delivery to the interstitial and seminiferous tubule compartments and characterised their specific targeting of testicular somatic cells (the Leydig and Sertoli cells). Results revealed that adenoviral vectors were most suitable for targeting Leydig cells, as lentiviral targeting resulted in Leydig cell apoptosis. Conversely, rete injected lentiviral vectors were deemed the best strategy for Sertoli cell targeting, with previous studies demonstrating disrupted tubules following adenoviral delivery.

We then exploited the infertile Sertoli cell androgen receptor knock out (SCARKO) mouse to demonstrate the potential of this technology as a treatment for male infertility [4]. To do so, we utilised the specific targeting of lentiviral vectors to deliver a mouse androgen receptor (AR) transgene to adult SCARKO testis. This resulted in the rescue of Sertoli cell AR expression and subsequently the infertility phenotype with presence of mature spermatids observed within rescued seminiferous tubules.

These studies examine the targeting capabilities of viral vectors in testicular somatic cells using optimised techniques. They also demonstrate the rescue of gene expression and infertility in the adult testis. This technology could be further utilised for both the generation of testis specific mouse models and for exploitation for therapeutic purposes for the treatment of male reproductive disorders.

  1. Punab, M., et al., Causes of male infertility: a 9-year prospective monocentre study on 1737 patients with reduced total sperm counts. Hum Reprod, 2017. 32(1): p. 18-31.
  2. Saad, F. and L.J. Gooren, The role of testosterone in the etiology and treatment of obesity, the metabolic syndrome, and diabetes mellitus type 2. J Obes, 2011. 2011.
  3. Song, S.H., et al., Recent advances in the genetics of testicular failure. Asian J Androl, 2016. 18(3): p. 350-5.
  4. De Gendt, K., et al., A Sertoli cell-selective knockout of the androgen receptor causes spermatogenic arrest in meiosis. Proc Natl Acad Sci U S A, 2004. 101(5): p. 1327-32.