Gene Therapy for Male Infertility

摘要：项目III：男性不育症的基因治疗 在美国，10%-15%的夫妇受到不孕不育的影响，男性因素单独或与女性不孕不育有关 约50%的病例合并有女性因素。不孕症可能是由荷尔蒙，解剖学， 免疫或染色体缺陷、疾病或治疗，但往往来源不明 (特发性)。特发性不孕症很难咨询，治疗方案是经验性的。提高知识水平 本项目所获得的不孕症的遗传学基础将有助于不孕症的咨询。 夫妻；证明诊断筛查的开发是合理的；并可能导致针对患者的开发 治疗方案。项目III将检验以下假设：1)支持细胞和生殖细胞基因疗法 可用于治疗非梗阻性无精子症伴成熟停滞(NOA-MA)；2)基因治疗 在生殖系周围可以实现有或没有生殖系传递和3)生殖系基因 NOA-MA的治疗可以从家族谱系中消除不孕不育和共病的躯体疾病。 项目I将发现特发性NOA-MA的遗传基础，并调查其个人或家族病史 整体健康问题。项目二将验证项目一中确定的遗传变异并确定生育力特征 以及人类NOA-MA小鼠模型的总体健康合并症。这个项目将证明这一原则 体内或体外基因治疗可用于治疗人类NOA-MA小鼠模型的不孕症。对于支持服务 细胞缺陷，目标1将证明体内支持细胞基因治疗可以恢复SCARKO生育能力的原理 以及其他有或没有生殖系传播的人类NOA-MA小鼠模型。对于生殖细胞缺陷，目标是 2将证明体外基因治疗之后的精原干细胞移植可以 无生殖系NOA-MA小鼠模型Sohlh1和Tex11恢复精子发生和生育能力 变速箱。AIM 3将在人NOA-MA的Hormad1和Mcm8小鼠模型中测试生殖系基因治疗 与整体健康并存有关的疾病。我们假设生殖系基因疗法将恢复 增加不育男性的生育力，减少或消除不育症和相关的总体健康合并症 他的家族血统。我们将通过与Project II合作检查整体健康状况来检验这一假设 基因治疗雄性F1后代的表型。该项目将建立安全和可行的 小鼠模型中男性不育症的基因治疗，以支持未来移植到人类临床。

Abstract: Project III: Gene Therapies for Male Infertility Infertility impacts 10-15% of couples in the United States and a male factor is implicated alone or in combination with female factors in about 50% of cases. Infertility can be caused by hormonal, anatomical, immunological or chromosomal deficiencies, disease or medical treatments, but is frequently of unknown origin (idiopathic). Idiopathic infertility is difficult to counsel and treatment options are empirical. Improved knowledge about the genetic basis of infertility obtained in this program project will aid in the counseling of infertile couples; justify the development of diagnostic screens; and may lead to the development of patient-specific treatment options. Project III will test the hypotheses that: 1) Sertoli cell and germ cell gene therapies can be used to treat nonobstructive azoospermia with maturation arrest (NOA-MA); 2) gene therapy in and around the germline can be achieved with or without germline transmission and 3) germline gene therapy for NOA-MA can eliminate infertility and comorbid somatic diseases from the family lineage. Project I will discover the genetic basis of idiopathic NOA-MA and investigate personal or family histories of overall health problems. Project II will validate genetic variants identified in project I and characterize fertility and overall health comorbidities in mouse models of human NOA-MA. This project will prove the principle that in vivo or ex vivo gene therapies can be used to treat infertility in mouse models of human NOA-MA. For Sertoli cell defects, Aim 1 will prove the principle that in vivo Sertoli cell gene therapy can restore fertility in SCARKO and other mouse models of human NOA-MA with or without germline transmission. For germ cell defects, Aim 2 will prove the principle that ex vivo gene therapy followed by transplantation of spermatogonial stem cells can restore spermatogenesis and fertility in Sohlh1 and Tex11 mouse models of NOA-MA without germline transmission. Aim 3 will test germline gene therapy in Hormad1 and Mcm8 mouse models of human NOA-MA that are associated with overall health comorbidities. We hypothesize that germline gene therapy will restore fertility to the infertile male and reduce or eliminate infertility and associated overall health comorbidities from his family lineage. We will test this hypothesis by collaborating with Project II to examine overall health phenotypes in F1 progeny of gene therapy-treated males. This project will establish the safety and feasibility of gene therapies for male infertility in mouse models to support future translation to the human clinic.