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III：男性不育症的基因疗法 不育会影响美国10-15％的夫妇，而男性因素单独涉及或在 大约50％的病例中与女性因素结合。不育可能是由荷尔蒙，解剖学引起的 免疫学或染色体缺陷，疾病或药物治疗，但通常是未知的起源 （特发性）。特发性不育症很难咨询，治疗方案是经验的。改善知识 关于该计划项目中获得的不育的遗传基础，将有助于咨询不育 夫妻；证明诊断屏幕的发展合理；并可能导致特定于患者的发展 治疗选择。项目III将测试以下假设：1）Sertoli细胞和生殖细胞基因疗法 可以用来用成熟的逮捕（NOA-MA）来治疗非焦化的无植物植物； 2）基因疗法 并且在有或没有种系传输的情况下，可以实现种系周围，3）种系基因 NOA-MA的治疗可以消除家庭谱系的不育症和合并症。 项目我将发现特发性NOA-MA的遗传基础，并调查个人或家庭历史 总体健康问题。项目II将验证项目I确定的遗传变异体并表征生育能力 人类NOA-MA的小鼠模型中的整体健康合并症。该项目将证明这样的原则 体内或体内基因疗法可用于治疗人NOA-MA小鼠模型中的不育症。对于Sertoli 细胞缺陷，AIM 1将证明体内Sertoli细胞基因疗法可以恢复Scarko的生育能力的原则 以及其他具有或没有种系传输的人NOA-MA的小鼠模型。对于生殖细胞缺陷，目标 2将证明以下原理：离体基因治疗，然后移植精子干细胞可以 在没有种系的NOA-MA的SOHLH1和TEX11小鼠模型中恢复精子发生和生育能力 传播。 AIM 3将测试人NOA-MA的Hormad1和MCM8小鼠模型中的种系基因治疗 与整体健康合并症有关的。我们假设种系基因疗法将恢复 对不育男性的生育能力，减少或消除不育和相关的总体健康合并症 他的家人血统。我们将通过与项目II合作来检验整体健康来检验这一假设 基因治疗治疗雄性F1后代的表型。该项目将确定 小鼠模型中男性不育症的基因疗法支持将来转化为人类诊所。