Sperm motility in mice with oligo-astheno-teratozoospermia restored by in vivo injection and electroporation of naked mRNA
Year: 2026
Type: preprint
Abstract: Oligo-astheno-teratozoospermia (OAT), a recurent cause of male infertility, is the most frequent disorder of spermatogenesis with a probable genetic cause. Patients and mice bearing mutations in the ARMC2 gene have a decreased sperm concentration, and individual sperm show multiple morphological defects and a lack of motility – a canonical OAT phenotype. Intracytoplasmic sperm injection (ICSI) is required to treat such a condition but it is associated with a small increase in birth defects in comparison to pregnancies not involving assisted conception. Consequently, new targeted treatments are needed to restore fertility. Here, a combination of in vivo injection and electroporation of capped and poly-A-tailed naked mRNA is tested as a strategy to treat ARMC2-related infertility in mouse. mRNAs coding for several reporter genes are tested and the efficiency and the kinetic of expression are assessed using in vivo and in vitro 2D and 3D imaging experiments. We show that mRNA-coded reporter proteins are detected for up to 3 weeks in germ cells, making the use of mRNA possible to treat infertility. We compare these results with those obtained with a non-integrative plasmid Enhanced Episomal Vector (EEV), which induces low and transient expression in spermatogenic cells. Consequently, injection and electroporation of naked mRNA-Armc2 into the testes of Armc2-deficient males were performed and we show the presence of normal and motile sperm in the epididymis. These motile sperm were able to produce embryos by IVF and ICSI. This study demonstrates, for the first time, that mRNA electroporation can restore sperm motility and partially fertilizing ability, providing a proof-of-concept for mRNA-based strategies to correct monogenic causes of male infertility and opening new avenues for male infertility treatment.
Source: eLife
Authors: Charline Vilpreux, Paul Fourquin, Guillaume Martinez, Magali Court, Florence Appaix, Jean-Luc Duteyrat, Maxime Henry, Julien Vollaire, Camille Ayad, Altan Yavuz, Geneviève Chevalier, Lisa De Macedo, Sofia Andrade Rebelo, Edgar Del Llano, Célia Tebbakh, Zine-Eddine Kherraf, Emeline Lambert, Sekou Ahmed Conte, Zeina Wehbe, Elsa Giordani, Véronique Josserand, Jacques Brocard, Coutton Charles, Bernard Verrier, Pierre F Ray, Corinne Loeuillet, Christophe Arnoult, Jessica Escoffier
Institutions: Centre National de la Recherche Scientifique, Inserm, Institut pour l'avancée des biosciences, Université Grenoble Alpes, Hôpital Couple Enfant, Lyon 1 Université, École Normale Supérieure de Lyon, Structure Fédérative de Recherche Biosciences, Institut de Biologie et de Chimie des Protéines, Laboratoire de Biologie Tissulaire et d'Ingénierie Thérapeutique, Centre Hospitalier Universitaire de Grenoble
Language: English
Subfield: Reproductive Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $2,500
OpenAlex ID: W7128733360