Gene Therapy for Male Infertility

男性不育症的基因治疗

• 批准号: 10613346
• 负责人: Kyle Edwin Orwig
• 金额: $ 33.79万
• 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 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10613346
• 关键词: AKAP9 gene; Address; Adenovirus Vector; Adenoviruses; Anatomy; Androgen Receptor; CDK2 gene; CRISPR/Cas technology; Clinic; Clone Cells; Collaborations; Counseling; Couples; DNA Sequence Alteration; Defect; 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; 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; genome sequencing; human model; idiopathic infertility; improved; in vivo; individualized medicine; integration site; lentiviral integration; 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.

翻译后摘要：项目三：基因治疗男性不育症 在美国，不孕症影响10-15%的夫妇，男性因素单独或共同参与。 与女性因素相结合，约占50%。不孕症可能是由荷尔蒙，解剖， 免疫或染色体缺陷、疾病或药物治疗，但通常原因不明 （特发性）。特发性不孕症很难咨询，治疗方案是经验性的。改进知识 关于不孕症的遗传基础，在这个项目中获得的项目将有助于不孕症的咨询。 夫妇;证明诊断屏幕的发展;并可能导致发展的患者特异性 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阻滞（NOA-MA）; 2）基因治疗 和生殖系周围可以实现有或没有生殖系传输和3）生殖系基因 NOA-MA的治疗可以从家族谱系中消除不孕症和共病的躯体疾病。 项目I将发现特发性NOA-MA的遗传基础，并调查NOA-MA的个人或家族史。 整体健康问题。项目II将验证项目I中确定的遗传变异， 和人NOA-MA小鼠模型中的总体健康共病。这个项目将证明一个原则， 体内或离体基因疗法可用于治疗人NOA-MA小鼠模型的不育症。对于塞尔托利 细胞缺陷，目的1将证明体内支持细胞基因治疗可以恢复SCARKO的生育能力的原理 以及具有或不具有生殖系传递的人NOA-MA的其它小鼠模型。对于生殖细胞缺陷，Aim 2将证明体外基因治疗后进行精原干细胞移植的原理， 在Sohlh 1和Tex 11小鼠NOA-MA模型中恢复精子发生和生育力，无生殖系 传输目的3将在人NOA-MA的Hormad 1和Mcm 8小鼠模型中测试生殖系基因治疗 与整体健康共病相关的疾病。我们假设生殖系基因疗法可以恢复 降低或消除不孕症和相关的整体健康共病， 他的家族血统我们将通过与项目II合作来检验这一假设， 基因治疗处理的雄性的F1后代中的表型。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治疗，以支持未来向人类临床的转化。