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Restoring spermatogenesis: Lentiviral gene therapy for male infertility in mice

Beadling, Randall (2015) Restoring spermatogenesis: Lentiviral gene therapy for male infertility in mice. Master's Thesis, University of Pittsburgh. (Unpublished)

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Abstract

Background: Male infertility of genetic origin affects nearly 1 in 40 men. Yet 80% of men with low sperm production are considered idiopathic due to negative genetic testing. Based on mouse studies there are several hundred possible candidate genes for causing isolated idiopathic male infertility due to their involvement in spermatogenesis and male germline-specific expression. Although little is known about their pathophysiology and epidemiology in human males, these genes represent vast potential for diagnosing and treating infertility. Lentiviral vector gene therapy has recently been shown to be effective in restoring gene expression, and has the potential to serve as treatment in male infertility caused by gene defects.
Methods: This project proposed to use a lentiviral vector to restore spermatogenesis in infertile, but viable male mice with a single-gene defect in Sertoli cells as a proof of concept project. Candidate genes were identified utilizing the Mouse Genome Informatics (MGI) database and literature review. One of these candidate genes, Dnaja1, was selected for experimental lentiviral vector gene therapy in mice.
Results: Several candidate genes expressed primarily in Sertoli cells known to cause isolated azoospermia were identified. Viral vector preparation was successful, but Dana1-/- mice were not produced, possibly indicating embryonic lethality.
Conclusion: Because the development of the vector was successful, and with the list of candidate genes identified, future experimentation using lentiviral gene therapy to restore spermatogenesis caused by single-gene defects is now ready to be performed. Selecting genes expressed in somatic cells, rather than germ cells, maintains the possibility of translating this research into clinical treatment for infertility by avoiding ethical implications of genetically altering the germ line. In the future, we hope to perform similar therapy on genes identified through the study of men with unexplained infertility. Of significance to public health, if successful this work may represent a novel treatment option for men who are born with single gene defects preventing sperm production and natural conception.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Beadling, Randallrjb70@pitt.eduRJB70
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairYatsenko, Alexyatsenkoan@mwri.magee.eduANY23
Committee MemberKammerer, Candace M.cmk3@pitt.eduCMK3
Committee CoChairWeeks, Daniel E.weeks@pitt.eduWEEKS
Date: 29 June 2015
Date Type: Publication
Defense Date: 14 April 2015
Approval Date: 29 June 2015
Submission Date: 13 April 2015
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Number of Pages: 82
Institution: University of Pittsburgh
Schools and Programs: Graduate School of Public Health > Human Genetics
Degree: MS - Master of Science
Thesis Type: Master's Thesis
Refereed: Yes
Uncontrolled Keywords: Male infertility spermatogenesis gene therapy lentivirus lentiviral viral mouse human genetics genetic counseling
Date Deposited: 29 Jun 2015 13:48
Last Modified: 19 Dec 2016 14:42
URI: http://d-scholarship.pitt.edu/id/eprint/24811

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