Speaker BIO:
Pierre Ray did his undergraduate studies in biology at the University of Grenoble. After obtaining an MSc at the University of East Anglia, UK he carried out his PhD at the Hammersmith Hospital in London on preimplantation genetic diagnosis (PGD) under Pr Alan Handyside supervision. Between 1999 and 2003 he developed the molecular diagnostics in the first French PGD centre in Paris. In 2003 he became professor in genetics and reproductive biology at Grenoble teaching hospital. He developed a research program focused on the identification and characterization of genes involved in male infertility. In 2007 he could demonstrate that mutations in the AURKC gene were responsible for the production large headed multiflagelled spermatozoa (macrozoospermia). In 2011 he demonstrated that a homozygous deletion of the DPY19L2 gene was found in most men with globozoospermia, a phenotype characterized by the presence of round spermatozoa devoid of acrosome. In 2014 he showed that mutations in the DNAH1 gene lead to the production of sperm with multiple morphological abnormalities of the flagella (MMAF syndrome). He now pursues his quest for the identification of infertility causing mutations by sequencing patients’ whole coding sequence (exome sequencing). This approach has allowed him to identify 12 new genes that are currently being investigated. The next objective of Pierre Ray’s team is now to develop personalised therapies allowing to replace missing or defective gene products and thus to cure some of the gene defects he identified. Different strategies are being tested in the mouse and clinical trials should be carried out in the near future.
Overview
The success rate following IVF-ICSI has now been stagnating for many years demonstrating the limitation of the whole IVF strategy that is proposed to most infertile patients. Alternative treatments will only be possible with an in-depth comprehension of all aspects of spermatogenesis and of the physiopathology of sperm defects. The basis of this comprehension stems from the identification of the genes involved and of their function. It is estimated that over 1000 genes are involved in spermatogenesis indicating that genetic abnormalities must be a frequent cause of male infertility, yet very few genes defects have so far been identified in man. Due to the increasing availability of exome and soon genome sequencing, the number of indentified genes is poised to explode. This will enable the clinician to have a better comprehension of his patient’s infertility and will help him to adopt the best course of treatment for his patient.
We also believe that male infertility might be among the pathologies that are best suited for targeted protein therapy and we are convinced that restoration of a functional spermatogenesis will be possible by reintroducing a deficient or missing protein as: 1) treatment success can be measured easily and objectively by a mere spermogram, 2) in man spermatogenesis lasts approximately 70 days. This corresponds to the necessary treatment duration to obtain functional gametes which can then be cryopreserved and used at a later date to initiate any number of pregnancies. This relatively short treatment is in sharp contrast with life-long supplementation needed for most other genetic diseases.
I will describe our work which has allowed us to identify over 12 candidate genes for various phenotype of male infertility. I will then describe our first attempts to develop some targeted therapies to compensate for missing of defective gene products.
