Personalized mRNA-LNP therapy for male sterility – SPERM-BACK

Infertility affects one couple in seven, with a male origin in 50% of cases. Around 10-15% of infertile men suffer from non-obstructive azoospermia (NOA), characterized by the absence of sperm in the ejaculate. Currently, a genetic cause is found in 30% of azoospermia cases. Couples affected by ANO are infertile and cannot benefit from intra-couple medically assisted reproduction, which requires both male and female gametes. This project aims to develop a new therapy for men who do not produce sperm and whose infertility is due to a single-gene genetic disorder. The solution envisaged is the injection of therapeutic messenger RNAs (mRNAs) encapsulated in lipid nanoparticles (LNPs). The mRNA-LNPs will be administered directly into the lumen of the seminiferous tubules, enabling transfection of germ cells and, potentially, restoration of sperm production. The project consists of four main tasks: 1. Development of an injection protocol to optimize reporter protein expression (injection routes, LNP concentration, expression kinetics) in mice; 2. Evaluation of the efficacy of mRNA-LNP therapy in the treatment of male azoospermia using an azoosperm mouse model; 3. Design and production of mRNA-LNP formulations optimized for human spermatogenic cells and 4. Demonstration of the feasibility of the mRNA-LNP strategy in a non-human primate model. This therapeutic solution is realistic because it is based on solid preliminary results showing that 1/ intra-testicular mRNA injection can treat infertility and 2/ mRNA-LNP efficiently transfects spermatogenic cells. This research could pave the way for clinical trials targeting male infertility linked to azoospermia.