Azoospermia (no sperm in the ejaculate) affects 645,000 males between the ages of 20 and 50 in the United States alone. In 80 to 85 percent of these cases, the cause is non-obstructive azoospermia (NOA), which responds to current treatments less than half the time. The causes of NOA are frequently unknown, but it is believed that genetic mutations are responsible for half of idiopathic infertility. Genetic defects can be in the germ cells that produce sperm or in the surrounding somatic cells. Gene therapy can potentially be used to restore sperm production, but there are significant societal concerns about doing gene therapy in and around the germline because genetic modifications could be passed to the offspring. Policymakers regularly revisit this concern and have advised that germline gene therapy may be possible in the future. We have developed testicular somatic gene therapy and germline gene therapy methods for treating NOA that avoid the issue of passing genetic modifications onto the next generation.
Description
To establish the proof-in-principle for testicular somatic cell defects, we designed an adenovirus (Ad) vector to introduce a therapeutic human androgen receptor (hAR) gene into an AR-deficient mouse model of human NOA. Ad-hAR injections restored spermatogenesis in 90 percent of seminiferous tubules in the testes. Histology in these mice showed that Ad-hAR transfects only Sertoli cells — somatic cells that facilitate spermatogenesis— and not the sperm or sperm producing cells. As a result, none of the treated males’ progeny carried the transgene. In parallel, we devised a strategy for ex vivo gene editing (using CRISPR/Cas9) followed by transplantation of germline stem cells. In the case of homozygous recessive disease, we outline how this approach can be deployed for germline gene therapy without germline transmission to progeny. For men faced with one of the most intractable types of infertility, our gene therapy method offers a potential cure without the ethical concerns of germline transmission. As societal concerns about germline gene editing evolve, the technologies described here can be used to purposefully eliminate the world’s most devastating diseases from families.
Applications
· Somatic cell and germ cell gene editing for infertility
· Eliminating genetic diseases from families, as a long-term potential application
Advantages
· Transgenes are not passed down to offspring
· New treatment option for men with intractable infertility
· Treatment of both somatic and germ cell defects
Invention Readiness
In vivo data
IP Status
https://patents.google.com/patent/WO2019023492A1
