Gene Therapy for Male Infertility

男性不育症的基因治疗

• 批准号: 10379350
• 负责人: Kyle Edwin Orwig
• 金额: $ 34.38万
• 依托单位: MAGEE-WOMEN'S RES INST AND FOUNDATION
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10379350
• 关键词: AKAP9 gene; Address; Adenovirus Vector; Adenoviruses; Anatomy; Androgen Receptor; CDK2 gene; CRISPR/Cas technology; Clinic; Clone Cells; Counseling; Couples; DNA Sequence Alteration; Defect; Deficiency Diseases; Development; Diabetes Mellitus; Diagnosis; Disease; Endocrine; Environment; Family; Family history of; Female; Fertility; Future; Genes; Genetic; Genome; Genomics; Germ Cells; Health; Hormonal; Human; Immunologics; Infertility; Inherited; Knock-out; Knockout Mice; Knowledge; Lead; Lentivirus; Link; Male Infertility; Malignant Neoplasms; Medical; Meiosis; Mental Retardation; Modeling; Modification; Mus; Mutation; Natural regeneration; Outcome; Phenotype; Predisposition; Specificity; Spermatogenesis; Technology; Testing; Testis; Toxic effect; Transgenes; Transplantation; United States; comorbidity; cost; diagnostic screening; egg; exome; gene therapy; genetic variant; genome editing; human model; idiopathic infertility; improved; in vivo; individualized medicine; integration site; male; man; mouse model; offspring; personalized medicine; programs; safety and feasibility; sertoli cell; sperm cell; spermatogenic epithelium structure; stem cells; targeted treatment; therapeutic gene; translation to humans; transmission process

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.

摘要：项目三：男性不育症的基因疗法 美国 10-15% 的夫妇受到不孕不育的影响，其中男性因素单独或与男性因素有关 约50%的病例与女性因素相结合。不孕症可能是由荷尔蒙、解剖学、 免疫或染色体缺陷、疾病或药物治疗，但通常来源不明 （特发性）。特发性不孕症很难咨询，治疗方案也依赖于经验。提高知识 该计划项目中获得的有关不孕症遗传基础的信息将有助于不孕症患者的咨询 情侣；证明诊断筛查开发的合理性；并可能导致患者特异性的发展 治疗方案。项目 III 将测试以下假设：1）支持细胞和生殖细胞基因疗法 可用于治疗伴有成熟停滞的非梗阻性无精症（NOA-MA）； 2）基因治疗 并且围绕种系可以实现有或没有种系传递和3)种系基因 NOA-MA 治疗可以消除家族谱系中的不孕症和共存躯体疾病。 项目 I 将发现特发性 NOA-MA 的遗传基础并调查个人或家族史 整体健康问题。项目 II 将验证项目 I 中确定的遗传变异并表征生育能力 以及人类 NOA-MA 小鼠模型中的总体健康合并症。该项目将证明以下原理： 体内或离体基因疗法可用于治疗人类 NOA-MA 小鼠模型的不育症。对于塞尔托利 细胞缺陷，目标1将证明体内Sertoli细胞基因治疗可以恢复SCARKO生育能力的原理 以及其他具有或不具有种系传播的人类 NOA-MA 小鼠模型。对于生殖细胞缺陷，目标 2将证明离体基因治疗随后移植精原干细胞可以的原理 在无种系的 NOA-MA Sohlh1 和 Tex11 小鼠模型中恢复精子发生和生育力 传播。 Aim 3 将在人类 NOA-MA 的 Hormad1 和 Mcm8 小鼠模型中测试种系基因治疗 与整体健康合并症相关。我们假设种系基因治疗将恢复 提高不育男性的生育能力，减少或消除不育症和相关的整体健康合并症 他的家族血统。我们将通过与项目 II 合作检查整体健康状况来检验这一假设 基因治疗处理的雄性 F1 后代的表型。该项目将建立安全性和可行性 在小鼠模型中进行男性不育的基因疗法，以支持未来向人类临床的转化。