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Grant of Fertility Innovation

Stephen Andrew Krawetz

Stephen Andrew Krawetz, PhD

 

Dr. Stephen A. Krawetz is the Charlotte B. Failing Professor of Fetal Therapy and Diagnosis, Associate Director of the C.S. Mott Center for Human Growth and Development in the Department of Obstetrics and Gynecology and Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, Michigan and founding Editor-in-Chief of Systems Biology in Reproductive Medicine. He received his PhD. in Biochemistry from the University of Toronto and then trained as an AHFMR post-doctoral fellow with Gordon Dixon at The University of Calgary. Dr. Krawetz has published over 200 manuscripts detailing the regulation of gene expression by chromatin structure emphasizing human spermatogenesis and its application to personalized medicine. Over the last two decades, his group established that the fitness of the paternal contribution reflects the relative diversity of sperm RNAs. They showed that at fertilization the spermatozoon delivers a cadre of unique RNAs to the oocyte. These RNAs may provide an essential component to early paternal genome reprogramming acting as genetic and epigenetic impactors of the fetal onset of adult disease. They provide a unique timestamp of the physical and reproductive health of Dad that is personalized to each child.

 

Project: A retrospective, controlled cohort study of sperm RNAs guiding the treatment of the idiopathic infertile couple

 

Male factor assessment as part of the typical ART work-up primarily relies on subjective characteristics like sperm morphology, motility and count. Except in the most severe cases, these measures are arguably of mixed value with respect to pregnancy outcome and certainly not diagnostic for the idiopathic male. Incorporating molecular techniques targeted to the male factor as part of clinical practice has been slow. Without reliable systemization, translation to the clinic remains at a standstill. We have met this challenge and are moving the technology forward as an integral part of treating the couple by standardizing male reproductive care. 

Our clinical and translational research team has shown that transcripts residing within the mature spermatozoa provide a wealth of information that reveals the potential of the spermatozoon to contribute to the birth of a healthy child. Using Next Generation Sequencing (NGS) we have defi ned a series of Sperm RNA Elements (SREs) that among a population of idiopathic infertile couples can identify males that can father a child by timed intercourse (TIC)/(IUI). We have shown that within a population of idiopathic infertile couples the absence of at least one of the members of the SRE-set lowers the success rate of fathering a child by TIC or IUI to ~25%. However, when treated by IVF/ICSI, the success rate recovers to ~75%, suggesting that we can effectively assign a treatment regimen. During the next phase we will test the hypothesis that human spermatozoal RNAs provide non-invasive biomarkers of male fecundity indicative of the birth rate and take home rate of a healthy child. This will be achieved using NGS to build upon our foundation by confi rming these initial results and increasing the sample size to increase the power of the SRE assay that identifies males capable of fathering a healthy child by TIC/IUI. This comprehensive testing will critically assess the utility of this assay while refining the collection of informative SREs. 

In keeping with this era of emerging precision medicine, this will provide a diagnostic that effectively considers the significance of the male contribution. As we realize the promise of personalized clinical care, one can envisage integrating sperm RNA-seq as part of a clinical program directed towards effectively decreasing the time to pregnancy while helping to ensure the birth of a healthy child.